Review ArticleReview

Role of microRNAs in inflammation-associated liver cancer

Lin Huan, Lin-Hui Liang and Xiang-Huo He
Cancer Biology & Medicine December 2016, 13 (4) 407-425; DOI: https://doi.org/10.20892/j.issn.2095-3941.2016.0071

Abstract

Liver cancer, primarily hepatocellular carcinoma (HCC), is a major cause of cancer-related death worldwide. HCC is a suitable model of inflammation-induced cancer because more than 90% of HCC cases are caused by liver damage and chronic inflammation. Several inflammatory response pathways, such as NF-κB and JAK/STAT3 signaling pathways, play roles in the crosstalk between inflammation and HCC. MicroRNAs (miRNAs) are evolutionarily conserved, short endogenous, non-coding single-stranded RNAs that are involved in various biological and pathological processes by regulating gene expression and protein translation. Evidence showed that miRNAs play a pivotal role in hepatitis virus infection and serve as promoters or inhibitors of inflammatory response. Aberrant miRNA was observed during liver inflammation and HCC. Many dysregulated miRNAs modulate the initiation and progression of inflammation-induced HCC. This review summarizes the role and functions of miRNAs in inflammation-associated HCC, as well as the designed therapeutics targeting miRNAs to treat liver inflammation and HCC.

keywords

Inflammation and liver cancer

The implication of inflammation in the development of cancers is well recognized. In the 19th century, Virchow observed leukocytes in tissues that contained inflammatory infiltrates1, which later on was confirmed in several clinical cases2. However, these insights were not further examined until data collected from epidemiological studies and experimental models showed a link between chronic inflammation and various types of cancers3,4. Chronic inflammation occurs with continuous inflammatory signaling caused by viral, bacterial, and parasitic infections or chemical irritants; exposure to chemical irritants results in recruitment of inflammatory cells, increased production of reactive oxygen species (ROS), and reduced DNA repair5,6. Most cancer tissues show specific types of inflammatory response; this subset accounts for approximately 20% of human cancers worldwide and is considered an essential component of tumorigenesis, including tumor initiation, progression, growth, and metastasis5,7.

Liver cancer is one of the most difficult cancers to treat and is the second leading cause of cancer death worldwide, especially in China, where it accounts for half of total cancer incidence and death8. Liver cancer is strongly correlated with viral hepatitis infection; more than 90% of liver cancers are associated with chronic hepatitis or liver cirrhosis9. Inflammation plays an essential role in responding to harmful stimuli and insults. However, cell death-regeneration cycles are driven by persistent inflammation that occurs when inflammation-associated signaling cannot be inhibited and subsequently results in chronic injury.

Many factors provoke an inflammatory response in the liver and are well known risk factors for liver cancer. Liver cancer occurs during the progression of many chronic liver diseases associated with inflammation, such as hepatitis and steatohepatitis10. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are found in approximately 80%-90% of hepatocellular carcinoma (HCC) patients11. HBV is an enveloped DNA virus with double-stranded circular DNA. HBV integrates into the host genome, which results in genomic instability12. Chronic HBV infection is the dominant risk factor for liver cancers in Asia and Sub-Saharan Africa, particularly in China. HCV is a single-stranded RNA virus that interacts with numerous proteins in hepatocytes and promotes the progression of hepatocarcinogenesis13. Chronic HCV infection is the dominant risk factor for liver cancers in Japan, United States, and Europe. Cirrhosis contributes to hepatocarcinogenesis and is observed in most HCC patients with HBV or HCV infection14.

In addition to these viral infections, acetaldehyde and other metabolites generated by alcohol metabolism increase the amount of ROS and reduce DNA repair, which leads to HCC15. Epidemiological analysis revealed that alcohol consumption is positively associated with HCC incidence; diabetes is another risk factor for HCC because epidemiologic studies reported that patients with type 2 diabetes have nearly 2.5-fold increased risk for HCC16,17. Recently, obesity was defined as a risk factor with an important role in HCC development18. Inflammation induced by viral or non-viral infection promotes the initiation and progression of HCC; HCC develops in the background of chronic hepatitis19.

Several signaling pathways link inflammation and cancer. Constitutive activation of these inflammatory signaling pathways, such as NF-κB and JAK/STAT signaling pathways, occurs during the process of inflammation and is observed in various cancers. The first link between NF-κB and cancer was revealed in a study showing that cancer cells were more sensitive to apoptosis-inducing stimuli after the NF-κB signaling pathway was blocked20. Over the past decades, the diverse roles of NF-κB signaling have been discovered in various types of carcinomas, including head and neck squamous cell carcinoma, leukemia, and cancers of breast, liver, prostate, colon, and lung21. Constitutive NF-κB activation was observed in various cancers, where NF-κB induces the expression of many pro-survival and anti-apoptotic factors, such as c-IAP, XIAP, and members of the Bcl-2 family of proteins22,23. Analogously, the activation of NF-κB might downregulate the expression of tumor suppressors, such as phosphatase and tensin homolog (PTEN); the downregulated expression increases Akt signaling and suppresses the apoptosis of cancer cells24. In addition to its pro-survival function, NF-κB promotes cell cycle progression by inducing cyclin D1 and c-myc expression25,26. NF-κB signaling can also induce molecules such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases, and NF-κB can promote angiogenesis and invasion by driving the expression of these proteins in many cancers27. In 2004, a group from Israel confirmed that NF-κB is an effective therapeutic target to treat HCC28. HCC development in a mouse model was prevented through NF-κB inhibition by a modified form of IκB called super-repressor IκB.

Another well-known signaling pathway that links inflammation and cancer is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT). This signaling pathway is also constitutively activated in most cancers. STAT3, one of the most famous STAT family members, was identified as a transcription factor that binds to the IL-6-responsive element in hepatocytes29. This binding suggests that STAT3 is a key regulator of inflammation. However, inflammatory cytokines are not the only factors that activate STAT3 signaling. Numerous studies reported that STAT3 can also be activated by oncogenic proteins including Ras or Src30,31. Carcinogens, such as polychlorinated biphenyls, promotes liver cancer and regulates the activity of STAT3 in HCC and normal liver cells32. Therefore, STAT3 is a key role in inflammation regulation and cancer development. Likewise, the constitutive activation of STAT3 leads to the expression of Bcl-2 family proteins essential for survival, such as survivin and cIAP2; moreover, the apoptosis of cancer cells occurs when STAT3 is downregulated in tumors33–36. STAT3 promotes the proliferation of cancer cells by inducing cyclin D1 and c-myc expression37,38. In addition to molecules associated with proliferation and apoptotic inhibition, STAT3 regulates the expression of the metalloproteinase family and VEGF, consequently promoting angiogenesis and metastasis39. STAT3 is also activated in hepatocytes following interleukin stimulation. STAT3 is a key regulator of inflammation and cancer and thus might be an effective therapeutic target in inflammation-induced cancer. In 2006, Li et al.40 inhibited STAT3 expression with antisense oligonucleotides in HCC cells and found that STAT3 greatly reduced cell proliferation and migratory potential as well as induced apoptosis.

MiRNAs are a novel class of molecules linking inflammation and HCC

MiRNAs constitute a class of short endogenous non-coding RNAs that are highly conserved throughout evolution. The biogenesis of miRNAs requires multiple steps. The majority of miRNAs are transcribed in the nucleus by RNA polymerase II as a primary miRNA (pri-miRNA); the typical pri-miRNA contains stem-loop structures. Furthermore, these stem-loop structures are cleaved into precursor miRNAs (pre-miRNAs) by Drosha, an RNA-specific ribonuclease enzyme complex. Dicer functions in the biogenesis of miRNAs as pre-miRNAs are transported from the nucleus into the cytoplasm by Exportin 541. Dicer is an endonuclease that specifically recognizes double-stranded RNA complexes and transforms the pre-miRNA into a 20-22 nt miRNA duplex42. The mature miRNA is incorporated into an RNA-induced silencing complex (RISC) through its interaction with Ago proteins; this miRNA recognizes and binds to the 3’-UTR of target mRNAs43.

The first miRNA was discovered in Caenorhabditis elegans in 1993 and was identified as an essential regulator of postembryonic developmental events44. From that first discovery, additional miRNAs have been identified and investigated in multiple organisms. Currently, miRNAs are recognized as key mediators influencing nearly all biological processes, including development, immune response, differentiation, proliferation, apoptosis, invasion, and metastasis. In addition, the expression of numerous miRNAs is dysregulated during nearly all pathological processes. MiRNAs gained a widely accepted role in initiation and progression of various human cancers, including HCC; evidence indicated that these miRNAs act as oncogenes or tumor suppressors45,46. Multiple miRNAs are upregulated or downregulated during hepatocarcinogenesis. Some of these miRNAs might be significant to diagnosis or prognosis of HCC patients47. Numerous miRNAs are reported to be aberrantly expressed during hepatitis and hepatocellular carcinoma. Accumulating evidence revealed that miRNAs are a novel class of molecules linking inflammation and HCC.

MiRNAs associated with hepatitis virus infection and HCC

Chronic hepatitis virus infection leads to liver inflammation, damage, fibrosis, cell regeneration, and malignant transformation (HCC). Many miRNAs play a crucial role in the regulation of hepatitis virus-induced chronic infla-mmation and HCC (Table 1). For instance, miR-27 is upregulated by HCV infection and can promote cell migration and invasion by suppressing Spry2 in HCC cells106. MiR-146a expression is consistently increased in HCV-infected cells, primary hepatocytes, and liver tissue from HCV-infected patients. Increased miR-146a level promotes viral infection and is associated with the pathogenesis of liver disease107. In the following section, we will summarize the key roles of relevant miRNAs in hepatitis virus infection and HCC.

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Table 1

MiRNAs associated with hepatitis virus infection and HCC

Let-7

The first miRNA discovered in humans is let-7, which is highly conserved across animal species and promotes differentiation108,109. Recent studies revealed that let-7 is frequently downregulated in many cancers, such as breast, ovarian, prostate, lung, and liver cancers110. The HBV X protein (HBx) encoded by the HBV genome is a multifunctional transactivator that plays crucial roles in HBV-associated hepatocarcinogenesis. HBx lacks a DNA binding domain and acts as a trans-coactivator through interaction with other cellular transcription factors, by which HBx might regulate let-7 family members. In addition to HBx induction, HBV preS2 RNA can sequester let-7g, which in turn reduces intrinsic let-7g functions in HCC111. Wang et al.48 concluded that HBx-mediated down-regulation of let-7 might be responsible for reduced let-7 expression in HBV-associated HCC. MiRNAs from the let-7 family act as tumor suppressors in HCC by inhibiting proliferation and invasion, as well as inducing apoptosis by targeting many oncogenes including high mobility group proteins, Bcl-xL, STAT3, and c-myc51,112,113. Further clinical research suggested that let-7 expression level is associated with poor differentiation114.

MiR-122

MiR-122 is the most abundant miRNA expressed in the liver, which accounts for 70% of the total miRNAs in an adult liver115. The expression of miR-122 is increased in the liver during embryonic development, and the first identified target of this miRNA is cationic amino acid transporter 1116. In recent years, increasing evidence suggested that miR-122 plays an important role in initiation and progression of HCC. Li et al.117 found that miR-122 expression is low in patients with chronic hepatitis B and HCC tumors and has negative correlation with fibrotic stage, age, and liver transaminase levels. The downregulation of miR-122 in patients with chronic hepatitis B and HCC tissues is affected by HBV infection. HBx overexpression reduces the expression of miR-122118. PPARγ was identified as a transcription factor regulating miR-122 expression; the underlying cause of HBx-induced miR-122 downregulation might be the direct interaction between HBx and PPARγ, which blocks PPARγ nuclear translocation119. In 2013, Li et al.120 further reported that all four HBV mRNAs contain a binding site for miR-122 and act as a miRNA sponge sequestering miR-122 in HBV-infected cells. In addition, miR-122 knockout mice will possibly develop hepatitis, fibrosis, and HCC. The reduced miR-122 expression in HCC tissues is characterized by a poor prognosis and consistent with a suppressed hepatic phenotype and an increased metastatic potential121. Moreover, miR-122 expression can be suppressed by two inflammatory cytokines, IL-6 and TNF-α, which downregulate the miR-122 transcription factors C/EBPα and HNF3β and induce c-myc-mediated C/EBPα inhibition in chronic hepatic inflammation117. MiR-122 downregulation results in the upregulation of target genes that promote hepatocarcinogenesis, including pituitary tumor trans-forming gene binding factor (PBF), cyclin G1, PKM2, ADAM10, ADAM17, SRF, and PKR activator122–124.

MiR-101

MiR-101 is another miRNA that is downregulated by HBV infection125. HBV downregulates miR-101 expression by inhibiting its promoter activity. MiR-101 downregulation was reported in various cancers, including HCC, suggesting that miR-101 functions as a tumor suppressor52,126. Reduced miR-101 expression in HCC tissues is associated with advanced tumor progression and poor survival in HCC patients; the serum miR-101 level might be a potential HCC biomarker127,128. Overexpression of miR-101 sensitizes the HCC cells to apoptosis induced by serum deprivation and chemotherapeutic drugs. Mcl-1, a member of the Bcl-2 family, is a target of miR-101 and sensitizes cancer cells to apoptosis52. MiR-101 enhances cisplatin-induced apoptosis by targeting STMN1, RAB5A, and mTOR, as well as suppresses epithelial-mesenchymal transition (EMT) in hepatocytes via the regulation of ZEB1 expression, which results in E-cadherin down-regulation129,130.

MiR-155

In 2010, the first link between miR-155 and hepatitis viruses was based on the observation that miR-155 precursor (termed BIC) is responsible for HCV infection131. After patients with hepatitis C were treated with interferon alpha and ribavirin, the lowest BIC expression was detected in patients who lacked HCV RNA in both serum and peripheral blood mononuclear cells. Previously, miR-155 was identified as an onco-miR in various cancers, including lung, breast, stomach, and prostate cancers132,133. A mouse model revealed that miR-155 induced by inflammation could promote autoimmune inflammation by enhancing inflammatory T cell development134. MiR-155 up-regulation occurs before HCC carcinogenesis. A positive correlation was observed between miR-155 expression and IP-10 levels in the plasma, which is widely considered a marker of liver inflammation degree104. Upon NF-κB activation by HCV-RNA infection, miR-155 expression is induced. The upregulation of miR-155 in cases of hepatitis and HCC promotes hepatocyte proliferation and HCC tumor growth by activating the Wnt/β-catenin signaling pathway. In addition to HCC pathogenesis during chronic viral infections such as HCV, the upregulation of miR-155 was also observed in the pathogenesis of non-alcoholic steatohepatitis (NASH)-associated HCC. However, similar to HCV-induced miR-155, the activation of NF-κB signaling pathway plays a key role in miR-155 expression in HCC and other hepatocyte-derived cells. In a mouse model of NASH, miR-155 downregulated the tumor suppressor target C/EBPβ, thus promoting liver pathogenesis132.

MiR-21

MiR-21 is a well-established onco-miR that is upregulated in various cancers, including lung, breast, prostate, colon, stomach, pancreatic, and liver cancers135,136. The relationship between miR-21 and inflammation was observed in UV-exposed skin, where miR-21 was activated by PPAR via the TGF-β signaling pathway137. The upregulation of miR-21 was reported in other inflammation-associated tissues and cancers, such as allergy-induced airway inflammation, gastric cancer, pre-B-cell lymphoma, and colorectal cancer138–141. The relevance of miR-21 and inflammation in liver tissues was established by associating biomarkers with HCC diagnosis and prognosis. MiR-21 is expressed in tumor cells and tumor-associated fibroblasts. In 2010, miR-21 and miR-122 were analyzed in tissues obtained by needle biopsies from both HCV-infected and non-infected patients. The expression of miR-21 was positively correlated with fibrotic stage in patients with chronic hepatitis C; miR-21 promotes liver fibrosis by targeting the fibrosis inhibitor SMAD7135. In serum, miR-21 was significantly upregulated in patients with either chronic hepatitis B or HCC142. In addition, one study reported that HBx increases the expression of miR-21 and subsequently promotes the progression of HCC by targeting PTEN143. In another study, HBx-mediated miR-21 upregulation inhibits expression of the tumor suppressor PDCD4 in HCC cells144.

MiR-221

MiR-221 is another onco-miR that is upregulated in cancers such as breast, prostate, glioma, and liver cancers46,145–147. Moreover, the expression of miR-221 in later stages of HCC is higher than that in early stages148. Therefore, miR-221 is a poor prognosis risk factor because it was increased in mouse models of liver fibrosis and upregulated in the human liver in a fibrosis progression-dependent manner149,150. Overex-pression of miR-221 in isolated and purified primary hepatocytes increased cell proliferation151. HBx promotes the proliferation of HCC cells and upregulates the expression of miR-221 during both HBV infection and HCC98. HCV infection can also induce the upregulation of miR-22199. Several tumor-related genes were reported to be the targets of miR-221; among these genes, p27Kip1 is well-recognized147. The expression of miR-221/p27Kip1 axis was confirmed in glioblastomas, breast, lung, and liver cancers152–155. Other than p27Kip1, many miR-221 targets were reported, such as HDAC6, PTEN, and tissue inhibitor of metalloproteinase-3 (TIMP3)156,157. In mouse models of HCC, tumor-bearing mice that were treated with chol-anti-miR-221 have a survival advantage compared with mice in the control group. MiR-221 is a potential target for HCC treatment and functions by inhibiting the progression of HCC and promoting survival158. MiR-221 transgenic animal models exhibited a strong predisposition toward the development of HCC159.

MiRNAs as regulators of inflammatory signaling in HCC

Chronic inflammation can facilitate the development and progression of HCC by the constitutive activation of inflammation signaling pathways. Aberrant activation of these pathways promotes inflammation-associated hepatocarcinogenesis. Inhibition of these signaling pathways would be a novel therapeutic strategy to suppress this inflammation-associated process. Many miRNAs were reported to regulate the inflammatory signaling mediated by NF-κB and JAK/STAT3, among others, in HCC (Table 2). Our group screened several miRNAs that might suppress NF-κB activation. Among these miRNAs, miR-195, miR-194, and miR-127 suppressed NF-κB activation by directly or indirectly targeting NF-κB signaling; these miRNAs also function as tumor suppressors in HCC160,162,163. MiR-219 is reduced in HCC where it functions as a tumor suppressor; this miRNA might suppress JAK/STAT3 signaling via direct targeting of structural maintenance of chromosome 4 protein (SMC4)183. MiR-637 is a tumor suppressor that inhibits cell growth and induces apoptosis by suppressing STAT3 activation in HCC186. Some typical miRNAs that behave as regulators in inflammatory signaling are summarized below.

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Table 2

MiRNAs as regulators of inflammatory signaling in HCC

MiR-26a

MiR-26a was suggested to play an important role in cirrhosis and inflammation-induced HCC188. Reduced miR-26a expression was detected in HCC tissues; the decreased expression in HCC tissues might be an independent predictor of poor survival189. Clinical analysis revealed that the expression of miR-26a is negatively correlated with IL-6 mRNA and IL-6 protein level. As IL-6 is a direct target of miR-26a, the mRNA and protein levels of this cytokine are significantly reduced by miR-26a overexpression in HCC cells. MiR-26a functions as a tumor suppressor that inhibits tumor growth and metastasis, partly through the IL-STAT3 signaling pathway184. Furthermore, miR-26a regulates the recruitment of macrophages190. M-CSF expression was also reported as a predictor of frequent metastasis and poor survival; miR-26a affects macrophage polarization and inhibits macrophage recruitment by down-regulating M-CSF expression191. In addition, HCC cells transfected with miR-126b exhibit significantly reduced NF-κB reporter activity in response to TNFα. Two well-known upstream regulators of NF-κB signaling pathway, TAK1 and TAB 3, were identified as direct targets of miR-26b. MiR-26b prevents doxorubicin-induced NF-κB activation and promotes apoptosis in HCC cells164.

MiR-451

In one study, miR-451 was often downregulated in primary HCC tissues; reduced miR-451 expression was significantly associated with advanced TNM stage, lymph node metastasis, vascular invasion, and poor survival, indicating that miR-451 might act as a tumor suppressor in HCC192. MiR-451 might inhibit HCC tumorigenesis and metastasis by down-regulating cyclin D1 and c-myc at both mRNA and protein levels. Further study indicated that miR-451 overexpression affected the NF-κB nuclear translocation and significantly decreased NF-κB activity by directly targeting IKKβ. As expected, the inhibition of miR-451 significantly increased NF-κB activity in HCC cells176. Moreover, a recent study revealed that reduced expression of the IL-6 receptor was observed in cells that overexpressed miR-451, and that IL-6 receptor was a direct target of miR-451. MiR-451 reduced VEGF production in HCC cells by targeting the IL-6/STAT3 signaling pathway177.

MiR-124

MiR-124 is a well-known tumor suppressor that is frequently downregulated in various cancers. Numerous studies revealed that miR-124 inhibits inflammatory signaling by targeting STAT3 in different cancer types including glioblastoma, gastric cancer, endometrial cancer, colon cancer, and HCC179,193–196. Recently, NF-κB p65 was reported to be a direct miR-124 target in B-cell lymphomas. The downregulation of miR-124 in B-cell lymphomas enhances the NF-κB signaling pathway and upregulates genes, such as myc and Bcl-2, associated with proliferation, anti-apoptosis, metastasis, and pro-survival197. STAT3 was identified as a direct miR-124 target in HCC; one study found that miR-124 inhibited cell proliferation and induced apoptosis in HCC cells by targeting STAT3179. Moreover, an HNF4α-NF-κB feedback circuit that includes miR-124 was identified in HCC. Reduced HNF4α could be a biomarker for poor prognosis, as HNF4α suppresses HCC metastasis by inhibiting NF-κB activation. MiR-124 also plays an important role in RelA suppression by HNF4α. MiR-124 was identified as an HNF4α target that binds to the 3’UTR of RelA. MiR-124 significantly downregulates RelA expression, represses NF-κB activation, and inhibits HCC tumorigenesis198.

MiR-125b

MiR-125b is a well-recognized miRNA that participates in innate immune response199. Our group was the first to reveal the role of miR-125b in HCC. We discovered that miR-125b was significantly downregulated in HCC, could be used as a biomarker for prolonged HCC patient survival, and functions as a tumor suppressor47. MiR-125b inhibits the proliferation of HCC cells by inducing cell cycle arrest during G1/S transition via its target gene, Lin28B200. Zhao et al.201 found that miR-125b induced HCC apoptosis by suppressing Bcl-2. IL-6R was identified as a direct target of miR-125b. IL-6R was characterized as the subunit that binds to IL-6; the binding of IL-6 to IL-6R activates the JAK/STAT3 signaling pathway. MiR-125b can block the IL-6-induced phosphory-lation and nuclear translocation of STAT3 in HCC cells, which in turn promotes HCC apoptosis180,202. In addition, miR-125b serves as a tumor suppressor that inhibits migration and invasion of HCC cells by targeting the transcriptional co-activator with PDZ-binding motif (TAZ). MiR-125b can also suppress EMT by downregulating SMAD2 and SMAD4203,204. EZH2 was also associated with miR-125b downregulation205.

MiR-370

The role of miR-370 in carcinogenesis is controversial. Several studies revealed that miR-370 acts as tumor promoter in gastric cancer, prostate cancer, and AML; whereas other studies reported miR-370 as a tumor suppressor in leukemia and oral squamous carcinoma206–210. Xu et al.167 observed that the down-regulation of miR-370 was associated with HCC development in rats and correlated with poor survival in HCC patients, indicating that miR-370 serves as a tumor suppressor in HCC. The restoration of miR-370 inhibits proliferation, migration, and invasion of HCC cells and suppresses tumorigenesis of HCC by directly targeting Lin28A. Lin28A is a post-transcriptional modulator of mRNAs that can directly bind to p65 mRNA. MiR-370 represses NF-κB activation and inhibits the migration and invasion of HCC cells through downregulation of Lin28A. Sun et al.211 confirmed the tumor suppressor role of miR-370 in HCC cells, showing that miR-370 inhibited HCC cell proliferation and colony formation ability by activating the PI3K/Akt signaling pathway.

In addition to miRNAs that inhibit inflammatory signaling, some miRNAs, such as miR-155, miR-362, miR-301a, and miR-1180, promote the inflammatory response by repressing negative regulators of inflammatory signaling171–173,187. MiR-1180 is upregulated in HCC tissues and HCC-derived cell lines. The NF-κB signaling pathway is activated by miR-1180 overexpression, which occurs through the downregulation of miR-1180 direct targets, OTUD7B and TNIP2. Another study confirmed the expression of TNIP2, a direct target of miR-1180, in HCC cells212. The ectopic expression of miR-1180 promoted the proliferation of HCC cells and inhibited apoptosis because NF-κB induces the expression of genes that participate in pro-survival and anti-apoptotic processes. Ni et al.173 demonstrated that miR-362-5p, which is frequently upregulated in HCC, promoted NF-κB signaling by downregulating CYLD; CYLD is a protein that binds to NF-κB essential modulator and functions as a negative regulator of NF-κB signaling213.

MiRNAs as mediators of inflammatory signaling in HCC

Inflammatory signaling pathway activation was associated in hepatocarcinogenesis. These inflammatory pathways and related transcription factors can affect the development of HCC by regulating miRNA expression. Several studies confirmed that inflammatory signaling facilitates the development of HCC through the downregulation or upregulation of miRNAs in cells (Table 3).

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Table 3

MiRNAs as mediators of inflammatory signaling in HCC

MiR-21

Ning et al.198 observed feedback regulation of HNF4α and NF-κB in HCC. Their study revealed that HNF4α dramatically suppresses the NF-κB signaling pathway and that RelA overexpression or knockdown decreases or increases the expression of HNF4α, respectively. During chronic hepatic inflammation, NF-κB induced the expression of miR-21, which represses HNF4α expression and contributes to hepatocyte de-differentiation and hepatocarcinogenesis. In addition to direct induction of miR-21 expression by NF-κB, miR-21 transcriptional activity is enhanced by high-mobility group box-1 protein (HMGB1), an important participant in inflammation. HMGB1 is a conserved nuclear protein that functions as a chromatin binding factor and allows transcription factors to access specific DNA binding sites219. HMGB1 enhances p65/p50 or p50/p50 binding to specific DNA sites rather than the binding of p65/p65, c-Rel/c-Rel, p65/c-Rel, and p50/c-Rel220. Given its role in the inflammatory cascade, HMGB1 is upregulated in HCC and induces miR-21 expression in HCC cells. The HMGB1/miR-21 signaling axis inhibits the downstream targets RECK and TIMP3 as well as promotes cell proliferation, invasion, and migration221.

MiR-143

MiR-143 is upregulated in HCC tissues, indicating that miR-143 serves as a tumor promoter. MiR-143 expression was increased by HBx-mediated NF-κB activation, although metastasis will be suppressed by miR-143 inhibition214. NF-κB activates transcription by specifically binding to the putative miR-143 promoter, as the NF-κB binding site identifies 5.06 kb upstream of miR-143. MiR-143 promotes cell invasion and tumor metastasis by suppressing the direct target gene FNDC3B. Moreover, miR-143 inhibition results in apoptosis of HCC cells and suppression of HCC tumorigenesis222. In addition, miR-143 was upregulated in serum samples from patients with chronic hepatitis and HCC and therefore might be a useful biomarker for both diseases223.

MiR-221

In addition to the upregulation of miR-221 by HBV, miR-221 can also be induced by HCV infection in an NF-κB-dependent manner99. MiR-221 and NF-κB expression are upregulated after HCV infection. However, the increased expression of miR-221 was blocked after treatment with PDTC, an NF-κB inhibitor. This finding suggests that the HCV-induced upregulation of miR-221 requires NF-κB activation and that NF-κB signaling pathway plays an important role in inflammation-associated cancer.

MiR-224

The expression of miR-224 was upregulated in both cirrhotic livers and HCC samples, suggesting the use of miR-224 as a biomarker of liver inflammation and HCC. The upregulation of miR-224 begins in the pre-cancerous stage and continues during HCC development224. In one study, patients with lower miR-224 expression exhibited a favorable trend of survival. In addition, miR-224 levels were significantly higher in patients with advanced HCC stages than in patients with early stages. MiR-224 could be induced by a set of pro-inflammatory factors, such as TNFα, LPS, and LTα, suggesting that NF-κB signaling regulates miR-224. NF-κB binds to the regulatory region of miR-224 and upregulates miR-224 expression215. Inflammation-mediated activation of miR-224 promotes HCC cell migration and invasion by targeting Rho GTPase-activating proteins. As an onco-miR, the overexpression of miR-224 also facilitates the migration and invasion of HCC cells by targeting HOXD10 and promotes proliferation by targeting p21225,226.

MiR-197

MiR-197 is well-studied during the progression of various cancers in which it plays a role in apoptosis, proliferation, angiogenesis, metastasis, and drug resistance. A negative correlation between miR-197 expression and IL-6 and STAT3 protein levels was observed in HCC tissues, indicating that miR-197 is involved in the STAT3 signaling pathway182. IL-6 is a well-known pro-inflammatory factor that is upregulated during an inflammatory state227. The expression of mature miR-197 was reduced by IL-6 stimulation, whereas the expression of pri-miR-197 remained unchanged by IL-6 stimulation in HCC cells. Further investigation revealed that Drosha binding to pri-miR-197 decreased after IL-6 stimulation, indicating that IL-6 downregulated miR-197 in a post-transcriptional manner by inhibiting Drosha binding to pri-miR-197. Moreover, STAT3 was identified as a direct target of miR-197. As a tumor suppressor, miR-197 inhibits proliferation and invasiveness of HCC cells as well as suppresses the tumorigenesis of HCC xenografts182.

MiR-23a

The first evidence of the role of miR-23a in HCC development was revealed in 2008. MiR-23a induced by TGFβ is remarkably increased in HCC tissues and functions as an anti-apoptotic and pro-proliferative factor in HCC cells228. Later on, Wang et al.218 found that miR-23 can be induced by IL-6 and STAT3 signaling, as a potential STAT3 binding site was identified in the miR-23a promoter region. STAT3-activated miR-23a downregulates the target genes G6PC and PCG-aα and suppresses gluconeogenesis; this reduction in gluconeogenesis facilitates HCC tumorigenesis.

MiRNAs as therapeutic targets in inflammation-related HCC

MiRNAs have a well-recognized role in liver inflammation and hepatocarcinogenesis; many miRNAs are dysregulated during chronic liver inflammation and HCC progression. miRNAs were regarded as novel targets for HCC therapy; the first study using miRNA-based therapy was conducted in 2005. In that study, miR-122 expression was silenced by antagomirs, which act as efficient and specific silencers of endogenous miRNAs. One particular antagomir was injected into mice and dramatically reduced endogenous miR-122 levels229. MiR-122 is a liver-enriched miRNA that functions as a tumor suppressor. A clinical trial of treating HCV infection by miR-122 inhibition was performed because miR-122 targets HCV genomic RNA and promotes HCV viral translation. Jong-Kook Park and colleagues treated tumor-bearing mice with chol-anti-miR-221 or a cholesterol-labeled control oligo. Consistent with the in vitro results, improved survival was observed in the group of mice treated with chol-anti-miR-221158.

In addition, miR-21 is a tumor promoter and functions as a prognostic factor, as previously described. MiR-21 promotes the proliferation, metastasis, and tumorigenesis of HCC and was validated as an onco-miR involved in drug resistance. MiR-21 suppression by lenti-miR-21-i combined with 5-fluorouracil and pirarubicin treatment leads to significant suppression of HCC cell proliferation; 5-fluorouracil and pirarubicin downregulated the miR-21 expression through AP-1 signaling230.

Oncolytic viruses were proposed as a novel therapeutic strategy for cancer treatment. Ad5-based oncolytic viruses were proven effective and safe in clinical trials231. MiR-199 is significantly reduced in HCC tissues compared with normal tissues. MiR-199 was cloned into adenoviral vectors to produce miR-199 adenovirus. Tumor-bearing nude mice were intra-tumorally injected with either miR-199 adenovirus or PBS as a control. Tumor growth was dramatically suppressed in the group of mice treated with miR-199 adenovirus. These results were confirmed in a transgenic model in which mice were predisposed to HCC development. The group of mice treated with miR-199 adenovirus exhibited a reduced tumor burden and a decreased number of tumor nodules compared with the control group. It can be expected in the future that any miRNAs acting as tumor suppressors can be applied as therapeutic oncolytic viruses in a manner similar to miR-199232.

Another miRNA-based therapeutic strategy is the design of miRNA panels that targets a particular protein to modulate inflammatory response and HCC development. For example, repressor/activator protein (Rap) might protect telomeres. Rap1 is an integral component of the IκB kinase (IKK) complex. The association between the IKK complex and Rap1 is important for NF-κB activation because Rap1 serves as an adaptor to recruit IKKs and aids in phosphorylation of the NF-κB p65 subunit233. Rap1 knockdown sensitized cancer cells to chemotherapeutic drug-induced apoptosis. 5-fluorouracil is a widely used chemotherapy drug for advanced HCC patients, but many patients with HCC are highly resistant to this chemotherapy regimen. A set of 4 Rap1-miRNAs was designed to knock down Rap1, leading to a significant increase in the sensitivity of HepG2 cells to 5-fluorouracil-induced apoptosis234.

A number of miRNAs can be induced or inhibited during hepatitis because of viral or non-viral infections. Some miRNAs are also activated or repressed when inflammatory signaling pathways, such as NF-κB and JAK/STAT3 signaling, cannot be turned off. In turn, miRNAs that might function as oncogenes or tumor suppressors can promote or suppress both inflammatory cascades in hepatocarcinogenesis. This function indicates that miRNAs are novel regulators or mediators of liver inflammation and hepatocarcinogenesis (Figure 1). Tumor tissues can be highly complex and heterogeneous. The tumor microenvironment consists of many types of cells including tumor invading immune-cells, fibroblasts, vascular endothelial cells, lymphatic cells, and stromal components. Given that numerous components of tumor microenvironment are responsible for the initiation, development, and progression of human cancer235, the dysregulated miRNAs from tumor specimens might originate from different types of cells in the tumor microenvironment and function in human carcinogenesis by multiple ways. The next investigations should focus on the origin, location, action, and multi-function of the dysregulated miRNAs in initiation, development, and progression of HCC. Additionally, any study of cell lines might run the risk of false discovery. The results from cell lines cannot reflect the full aspects of the pathological process of HCC. The next investigations on the exact role of miRNAs in inflammation-associated HCC should be verified in patients and reliable HCC models.

Figure 1
Figure 1

A simplified sketch illustrates the development of liver inflammation and HCC and shows the key nodes in which aberrantly expressed miRNAs participate in inflammation-associated hepatocarcinogenesis. Many miRNAs are aberrantly expressed when liver inflammation occurs and play prominent roles in HCC development. MiRNAs might be regulated by constitutive inflammatory signaling pathways and participate in the development and progression of HCC. Additionally, miRNAs might modulate the inflammatory signaling pathways during the development and progression of HCC.

The 5-year overall survival of HCC is lower than 10% worldwide because many patients are diagnosed at advanced stages236. Therefore, discovering novel viable biomarkers for HCC early diagnosis is urgent. In the last decades, numerous pieces of evidence highlighted the regulatory roles of miRNAs in inflammation-associated HCC. Evidence also indicated that the dysregulated miRNAs might be useful as biomarkers for liver inflammation and HCC progression. In 2015, miRNAs were screened in a large-scale, multicenter, retrospective longitudinal study to explore effective and reliable strategies for monitoring at-risk populations that suffers from chronic inflammation as well as detect HCC at an early stage. Serum miR-29a, miR-29c, miR-133a, miR-143, miR-145, miR-192, and miR-505 might act as biomarkers in HCC because they are in significantly higher content in HCC compared with healthy controls or those with chronic inflammation. The classifier composed of these seven miRNAs could be more sensitive than α-fetoprotein in distinguishing patients with HCC from those who are cancer-free237. The distinction requires large-scale, multicenter, independent investigations to confirm its feasibility. Several studies illustrated the potential of miRNAs as therapeutic targets to prevent or treat HCC. However, additional profiles and detailed mechanisms of miRNA functions are required to provide a better understanding of their role in liver inflammation and hepatocarcinogenesis. The additional data will facilitate the application of more miRNAs into prevention and therapy for inflammation-associated HCC.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Acknowledgments

This work was supported by grants from the National Key Basic Research Program (Grant No. 2013CB910504), and the National Natural Science Foundation of China (Grant No. 81125016 and 81472565).

  • Received August 24, 2016.
  • Accepted September 18, 2016.
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This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

References

  1. 1.↵
    2. Mantovani A,
    3. Allavena P,
    4. Sica A,
    5. Balkwill F.
    Cancer-related inflammation. Nature. 2008; 454: 436–44.
    OpenUrlCrossRefPubMed
  2. 2.↵
    2. Bryant T.
    Remarks on some cases of inflammation of the breast simulating cancer. Br Med J. 1868; 2: 608–9.
    OpenUrlFREE Full Text
  3. 3.↵
    2. Balkwill F,
    3. Mantovani A.
    Inflammation and cancer: back to virchow? Lancet. 2001; 357: 539–45.
    OpenUrlCrossRefPubMed
  4. 4.↵
    2. Karin M.
    Nuclear factor-κb in cancer development and progression. Nature. 2006; 441: 431–6.
    OpenUrlCrossRefPubMed
  5. 5.↵
    2. Coussens LM,
    3. Werb Z.
    Inflammation and cancer. Nature. 2002; 420: 860–7.
    OpenUrlCrossRefPubMed
  6. 6.↵
    2. Shacter E,
    3. Weitzman SA.
    Chronic inflammation and cancer. Oncology. 2002; 16: 217–26, 229; discussion 230–2.
    OpenUrlCrossRefPubMed
  7. 7.↵
    2. Grivennikov SI,
    3. Greten FR,
    4. Karin M.
    Immunity, inflammation, and cancer. Cell. 2010; 140: 883–99.
    OpenUrlCrossRefPubMed
  8. 8.↵
    2. Torre LA,
    3. Bray F,
    4. Siegel RL,
    5. Ferlay J,
    6. Lortet-Tieulent J,
    7. Jemal A.
    Global cancer statistics, 2012. CA: Cancer J Clin. 2015; 65: 87–108.
    OpenUrlCrossRefPubMed
  9. 9.↵
    2. Edmondson HA,
    3. Peters RL.
    Tumors of the liver: pathologic features. Semin Roentgenol. 1983; 18: 75–83.
    OpenUrlCrossRefPubMed
  10. 10.↵
    2. Qiao L,
    3. Li X.
    Role of chronic inflammation in cancers of the gastrointestinal system and the liver: where we are now. Cancer Lett. 2014; 345: 150–152.
    OpenUrlCrossRefPubMed
  11. 11.↵
    2. El-Serag HB.
    Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012; 142: 1264–73.e1.
    OpenUrlCrossRefPubMed
  12. 12.↵
    2. Laurent-Puig P,
    3. Zucman-Rossi J.
    Genetics of hepatocellular tumors. Oncogene. 2006; 25: 3778–86.
    OpenUrlCrossRefPubMed
  13. 13.↵
    2. Levrero M.
    Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006; 25: 3834–47.
    OpenUrlCrossRefPubMed
  14. 14.↵
    2. Yang JD,
    3. Kim WR,
    4. Coelho R,
    5. Mettler TA,
    6. Benson JT,
    7. Sanderson SO, et al.
    Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011; 9: 64–70.
    OpenUrlCrossRefPubMed
  15. 15.↵
    2. Cederbaum AI,
    3. Lu YK,
    4. Wu DF.
    Role of oxidative stress in alcohol-induced liver injury. Arch. Toxicol. 2009; 83: 519–48.
    OpenUrlCrossRefPubMed
  16. 16.↵
    2. Persson EC,
    3. Schwartz LM,
    4. Park Y,
    5. Trabert B,
    6. Hollenbeck AR,
    7. Graubard BI, et al.
    Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality. Cancer Epidemiol Biomarkers Prev. 2013; 22: 415–21.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    2. El-Serag HB,
    3. Hampel H,
    4. Javadi F.
    The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin. Gastroenterol. Hepatol. 2006; 4: 369–80.
    OpenUrlCrossRefPubMed
  18. 18.↵
    2. Park EJ,
    3. Lee JH,
    4. Yu GY,
    5. He GB,
    6. Ali SR,
    7. Holzer RG, et al.
    Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and tnf expression. Cell. 2010; 140: 197–208.
    OpenUrlCrossRefPubMed
  19. 19.↵
    2. Block TM,
    3. Mehta AS,
    4. Fimmel CJ,
    5. Jordan R.
    Molecular viral oncology of hepatocellular carcinoma. Oncogene. 2003; 22: 5093–107.
    OpenUrlCrossRefPubMed
  20. 20.↵
    2. Ghosh S,
    3. May MJ,
    4. Kopp EB.
    NF-κb and rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16: 225–60.
    OpenUrlCrossRefPubMed
  21. 21.↵
    2. Escárcega RO,
    3. Fuentes-Alexandro S,
    4. García-Carrasco M,
    5. Gatica A,
    6. Zamora A.
    The transcription factor nuclear factor-kappa B and cancer. Clin Oncol. 2007; 19: 154–61.
    OpenUrlCrossRef
  22. 22.↵
    2. Deveraux QL,
    3. Roy N,
    4. Stennicke HR,
    5. Van Arsdale T,
    6. Zhou Q,
    7. Srinivasula SM, et al.
    IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 1998; 17: 2215–23.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    2. Lee JU,
    3. Hosotani R,
    4. Wada M,
    5. DoiR ,
    6. Kosiba T,
    7. Fujimoto K, et al.
    Role of Bcl-2 family proteins (Bax, Bcl-2 and Bcl-X) on cellular susceptibility to radiation in pancreatic cancer cells. Eur J Cancer. 1999; 35: 1374–80.
    OpenUrlCrossRefPubMed
  24. 24.↵
    2. Vasudevan KM,
    3. Gurumurthy S,
    4. Rangnekar VM.
    Suppression of PTEN expression by NF-κB prevents apoptosis. Mol Cell Biol. 2004; 24: 1007–21.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    2. Guttridge DC,
    3. Albanese C,
    4. Reuther JY,
    5. Pestell RG,
    6. Baldwin AS Jr..
    NF-κb controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol. 1999; 19: 5785–99.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    2. La Rosa FA,
    3. Pierce JW,
    4. Sonenshein GE.
    Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel family of transcription factors. Mol Cell Biol. 1994; 14: 1039–44.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    2. Dolcet X,
    3. Llobet D,
    4. Pallares J,
    5. Matias-Guiu X.
    NF-κb in development and progression of human cancer. Virchows Arch. 2005; 446: 475–82.
    OpenUrlCrossRefPubMed
  28. 28.↵
    2. Pikarsky E,
    3. Porat RM,
    4. Stein I,
    5. Abramovitch R,
    6. Amit S,
    7. Kasem S, et al.
    NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004; 431: 461–6.
    OpenUrlCrossRefPubMed
  29. 29.↵
    2. Akira S,
    3. Nishio Y,
    4. Inoue M,
    5. Wang XJ,
    6. We S,
    7. Matsusaka T, et al.
    Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994; 77: 63–71.
    OpenUrlCrossRefPubMed
  30. 30.↵
    2. Giordano V,
    3. De Falco G,
    4. Chiari R,
    5. Quinto I,
    6. Pelicci PG,
    7. Bartholomew L, et al.
    Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. J Immunol. 1997; 158: 4097–103.
    OpenUrlAbstract
  31. 31.↵
    2. Yu CL,
    3. Meyer DJ,
    4. Campbell GS,
    5. Larner AC,
    6. Carter-Su C,
    7. Schwartz J, et al.
    Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995; 269: 81–3.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    2. Tharappel JC,
    3. Lee EY,
    4. Robertson LW,
    5. Spear BT,
    6. Glauert HP.
    Regulation of cell proliferation, apoptosis, and transcription factor activities during the promotion of liver carcinogenesis by polychlorinated biphenyls. Toxicol Appl Pharmacol. 2002; 179: 172–84.
    OpenUrlCrossRefPubMed
  33. 33.↵
    2. Zushi S,
    3. Shinomura Y,
    4. Kiyohara T,
    5. Miyazaki Y,
    6. Kondo S,
    7. Sugimachi M, et al.
    STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer. 1998; 78: 326–30.
    OpenUrlCrossRefPubMed
  34. 34.
    2. Mahboubi K,
    3. Li F,
    4. Plescia J,
    5. Kirkiles-Smith NC,
    6. Mesri M,
    7. Du Y, et al.
    Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway. Lab Invest. 2001; 81: 327–34.
    OpenUrlCrossRefPubMed
  35. 35.
    2. Bhattacharya S,
    3. Schindler C.
    Regulation of Stat3 nuclear export. J Clin Invest. 2003; 111: 553–9.
    OpenUrlCrossRefPubMed
  36. 36.↵
    2. Ivanov VN,
    3. Bhoumik A,
    4. Krasilnikov MA,
    5. Raz R,
    6. Owen-Schaub LB,
    7. Levy DE, et al.
    Cooperation between STAT3 and c-Jun suppresses Fas transcription. Mol Cell. 2001; 7: 517–28.
    OpenUrlCrossRefPubMed
  37. 37.↵
    2. Masuda M,
    3. Suzui M,
    4. Yasumatu R,
    5. Nakashima T,
    6. Kuratomi Y,
    7. Azuma K, et al.
    Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 2002; 62: 3351–5.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    2. Kiuchi N,
    3. Nakajima K,
    4. Ichiba M,
    5. Fukada T,
    6. Narimatsu M,
    7. Mizuno K, et al.
    STAT3 is required for the gp130-mediated full activation of the c-myc gene. J Exp Med. 1999; 189: 63–73.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    2. Aggarwal BB,
    3. Kunnumakkara AB,
    4. Harikumar KB,
    5. Gupta SR,
    6. Tharakan ST,
    7. Koca C, et al.
    Signal transducer and activator of transcription-3, inflammation, and cancer. Ann N Y Acad Sci. 2009; 1171: 59–76.
    OpenUrlCrossRefPubMed
  40. 40.↵
    2. Li WC,
    3. Ye SL,
    4. Sun RX,
    5. Liu YK,
    6. Tang ZY,
    7. Kim Y, et al.
    Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin Cancer Res. 2006; 12: 7140–8.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    2. Davis BN,
    3. Hata A.
    Regulation of microRNA biogenesis: a miriad of mechanisms. Cell Commun Signal. 2009; 7: 18.
    OpenUrlCrossRefPubMed
  42. 42.↵
    2. Foulkes WD,
    3. Priest JR,
    4. Duchaine TF.
    DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer. 2014; 14: 662–72.
    OpenUrlCrossRefPubMed
  43. 43.↵
    2. Stappert L,
    3. Roese-Koerner B,
    4. Brüstle O.
    The role of microRNAs in human neural stem cells, neuronal differentiation and subtype specification. Cell Tissue Res. 2015; 359: 47–64.
    OpenUrl
  44. 44.↵
    2. Lee RC,
    3. Feinbaum RL,
    4. Ambros V.
    The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 75: 843–54.
    OpenUrlCrossRefPubMed
  45. 45.↵
    2. Negrini M,
    3. Ferracin M,
    4. Sabbioni S,
    5. Croce CM.
    MicroRNAs in human cancer: from research to therapy. J Cell Sci. 2007; 120: 1833–40.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    2. Murakami Y,
    3. Yasuda T,
    4. Saigo K,
    5. Urashima T,
    6. Toyoda H,
    7. Okanoue T, et al.
    Comprehensive analysis of microrna expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006; 25: 2537–45.
    OpenUrlCrossRefPubMed
  47. 47.↵
    2. Li W,
    3. Xie L,
    4. He X,
    5. Li J,
    6. Tu K,
    7. Wu J, et al.
    Diagnostic and prognostic implications of micrornas in human hepatocellular carcinoma. Int J Cancer. 2008; 123: 1616–22.
    OpenUrlCrossRefPubMed
  48. 48.↵
    2. Wang Y,
    3. Lu YW,
    4. Toh ST,
    5. Sung WK,
    6. Tan P,
    7. Chow P, et al.
    Lethal-7 is down-regulated by the hepatitis B virus X protein and targets signal transducer and activator of transcription 3. J Hepatol. 2010; 53: 57–66.
    OpenUrlCrossRefPubMed
  49. 49.
    2. Johnson SM,
    3. Grosshans H,
    4. Shingara J,
    5. Byrom M,
    6. Jarvis R,
    7. Cheng A, et al.
    Ras is regulated by the let-7 microRNA family. Cell. 2005; 120: 635–47.
    OpenUrlCrossRefPubMed
  50. 50.
    2. Mayr C,
    3. Hemann MT,
    4. Bartel DP.
    Disrupting the pairing between let-7 and hmga2 enhances oncogenic transformation. Science. 2007; 315: 1576–9.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    2. Lan F,
    3. Wang H,
    4. Chen Y,
    5. Chan C,
    6. Ng SS,
    7. Li K, et al.
    Hsa-let-7g inhibits proliferation of hepatocellular carcinoma cells by downregulation of c-Myc and upregulation of p16ink4a. Int J Cancer. 2011; 128: 319–31.
    OpenUrlCrossRefPubMed
  52. 52.↵
    2. Su H,
    3. Yang JR,
    4. Xu T,
    5. Huang J,
    6. Xu L,
    7. Yuan Y, et al.
    MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 2009; 69: 1135–42.
    OpenUrlAbstract/FREE Full Text
  53. 53.
    2. Xie Y,
    3. Yao Q,
    4. Butt AM,
    5. Guo J,
    6. Tian Z,
    7. Bao X, et al.
    Expression profiling of serum microRNA-101 in HBV-associated chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Cancer Biol Ther. 2014; 15: 1248–55.
    OpenUrl
  54. 54.
    2. Wei XF,
    3. Tan C,
    4. Tang CY,
    5. Ren GS,
    6. Xiang TX,
    7. Qiu Z, et al.
    Epigenetic repression of miR-132 expression by the hepatitis B virus X protein in hepatitis b virus-related hepatocellular carcinoma. Cell Signal. 2013; 25: 1037–43.
    OpenUrl
  55. 55.
    2. Liu K,
    3. Li X,
    4. Cao Y,
    5. Ge Y,
    6. Wang J,
    7. Shi B.
    Mir-132 inhibits cell proliferation, invasion and migration of hepatocellular carcinoma by targeting PIK3R3. Int J Oncol. 2015; 47: 1585–93.
    OpenUrl
  56. 56.
    2. Zhao J,
    3. Wang W,
    4. Huang Y,
    5. Wu J,
    6. Chen M,
    7. Cui P, et al.
    Hbx elevates oncoprotein aeg-1 expression to promote cell migration by downregulating miR-375 and miR-136 in malignant hepatocytes. DNA Cell Biol. 2014; 33: 715–22.
    OpenUrlCrossRefPubMed
  57. 57.
    2. Bandopadhyay M,
    3. Banerjee A,
    4. Sarkar N,
    5. Panigrahi R,
    6. Datta S,
    7. Pal A, et al.
    Tumor suppressor micro RNA miR-145 and onco micro RNAs miR-21 and miR-222 expressions are differentially modulated by hepatitis B virus X protein in malignant hepatocytes. BMC Cancer. 2014; 14: 721.
  58. 58.
    2. Ding W,
    3. Tan H,
    4. Zhao C,
    5. Li X,
    6. Li Z,
    7. Jiang C, et al.
    MiR-145 suppresses cell proliferation and motility by inhibiting ROCK1 in hepatocellular carcinoma. Tumor Biol. 2015; 37: 6255–60.
    OpenUrl
  59. 59.
    2. Yang XW,
    3. Zhang LJ,
    4. Huang XH,
    5. Chen LZ,
    6. Su Q,
    7. Zeng WT, et al.
    MiR-145 suppresses cell invasion in hepatocellular carcinoma cells: MiR-145 targets ADAM17. Hepatol Res. 2014; 44: 551–9.
    OpenUrlCrossRefPubMed
  60. 60.
    2. Noh JH,
    3. Chang YG,
    4. Kim MG,
    5. Jung KH,
    6. Kim JK,
    7. Bae HJ, et al.
    MiR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer. Cancer Lett. 2013; 335: 455–62.
    OpenUrlCrossRefPubMed
  61. 61.
    2. Gao F,
    3. Sun X,
    4. Wang L,
    5. Tang S,
    6. Yan C.
    Downregulation of microRNA-145 caused by hepatitis B virus X protein promotes expression of CUL5 and contributes to pathogenesis of hepatitis B virus-associated hepatocellular carcinoma. Cell Physiol Biochem. 2015; 37: 1547–59.
    OpenUrl
  62. 62.
    2. Xu X,
    3. Fan Z,
    4. Kang L,
    5. Han J,
    6. Jiang C,
    7. Zheng X, et al.
    Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest. 2013; 123: 630–45.
    OpenUrlCrossRefPubMed
  63. 63.
    2. Wu CS,
    3. Yen CJ,
    4. Chou RH,
    5. Chen JN,
    6. Huang WC,
    7. Wu CY, et al.
    Downregulation of microRNA-15b by hepatitis B virus X enhances hepatocellular carcinoma proliferation via fucosyltransferase 2-induced globo H expression. Int J Cancer. 2014; 134: 1638–47.
    OpenUrlCrossRefPubMed
  64. 64.
    2. Yang Y,
    3. Hou N,
    4. Wang XF,
    5. Wang LM,
    6. Chang SE,
    7. He K, et al.
    miR-15b-5p induces endoplasmic reticulum stress and apoptosis in human hepatocellular carcinoma, both in vitro and in vivo, by suppressing Rab1A. Oncotarget. 2015; 6: 16227–38.
    OpenUrlCrossRefPubMed
  65. 65.
    2. Zhang T,
    3. Zhang JP,
    4. Cui M,
    5. Liu FB,
    6. You XN,
    7. Du YM, et al.
    Hepatitis B virus X protein inhibits tumor suppressor miR-205 through inducing hypermethylation of miR-205 promoter to enhance carcinogenesis. Neoplasia. 2013; 15: 1282–91.
    OpenUrl
  66. 66.
    2. Cui M,
    3. Wang Y,
    4. Sun BD,
    5. Xiao ZL,
    6. Ye LH,
    7. Zhang XD.
    MiR-205 modulates abnormal lipid metabolism of hepatoma cells via targeting acyl-CoA synthetase long-chain family member 1 (ACSL1) mRNA. Biochem Biophys Res Commun. 2014; 444: 270–5.
    OpenUrlCrossRef
  67. 67.
    2. Liu FY,
    3. Zhou SJ,
    4. Deng YL,
    5. Zhang ZY,
    6. Zhang EL,
    7. Wu ZB, et al.
    MiR-216b is involved in pathogenesis and progression of hepatocellular carcinoma through HBx-miR-216b-IGF2BP2 signaling pathway. Cell Death Dis. 2015; 6: e1670.
  68. 68.
    2. Yu G,
    3. Chen X,
    4. Chen S,
    5. Ye W,
    6. Hou K,
    7. Liang M.
    MiR-19a, miR-122 and miR-223 are differentially regulated by hepatitis B virus X protein and involve in cell proliferation in hepatoma cells. J Transl Med. 2016; 14: 122.
    OpenUrlCrossRefPubMed
  69. 69.
    2. Wang CM,
    3. Wang Y,
    4. Fan CG,
    5. Xu FF,
    6. Sun WS,
    7. Liu YG, et al.
    miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma. Biochem Biophys Res Commun. 2011; 411: 586–92.
    OpenUrlCrossRefPubMed
  70. 70.
    2. Liu P,
    3. Zhang H,
    4. Liang X,
    5. Ma H,
    6. Luan F,
    7. Wang B, et al.
    HBV preS2 promotes the expression of TAZ via miRNA-338-3p to enhance the tumorigenesis of hepatocellular carcinoma. Oncotarget. 2015; 6: 29048–59.
    OpenUrl
  71. 71.
    2. Xu H,
    3. Zhao L,
    4. Fang Q,
    5. Sun J,
    6. Zhang S,
    7. Zhan C, et al.
    MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1α. PLoS One. 2014; 9: e115565.
  72. 72.
    2. Wang G,
    3. Sun Y,
    4. He Y,
    5. Ji C,
    6. Hu B.
    MicroRNA-338-3p inhibits cell proliferation in hepatocellular carcinoma by target forkhead box P4 (FOXP4). Int J Clin Exp Pathol. 2015; 8: 337–44.
    OpenUrl
  73. 73.
    2. Fu XY,
    3. Tan DM,
    4. Hou ZH,
    5. Hu ZL,
    6. Liu GZ.
    miR-338-3p is down-regulated by hepatitis B virus X and inhibits cell proliferation by targeting the 3′-UTR region of cyclinD1. Int J Mol Sci. 2012; 13: 8514–39.
    OpenUrlPubMed
  74. 74.
    2. Gao HJ,
    3. Liu C.
    miR-429 represses cell proliferation and induces apoptosis in HBV-related HCC. Biomed Pharmacother. 2014; 68: 943–9.
    OpenUrl
  75. 75.
    2. You X,
    3. Liu F,
    4. Zhang T,
    5. Li Y,
    6. Ye L,
    7. Zhang X.
    Hepatitis B virus X protein upregulates oncogene Rab18 to result in the dysregulation of lipogenesis and proliferation of hepatoma cells. Carcinogenesis. 2013; 34: 1644–52.
    OpenUrlCrossRefPubMed
  76. 76.
    2. Chen WS,
    3. Yen CJ,
    4. Chen YJ,
    5. Chen JY,
    6. Wang LY,
    7. Chiu SJ, et al.
    miRNA-7/21/107 contribute to HBx-induced hepatocellular carcinoma progression through suppression of maspin. Oncotarget. 2015; 6: 25962–74.
    OpenUrl
  77. 77.
    2. Xia W,
    3. Ni J,
    4. Zhuang J,
    5. Qian L,
    6. Wang P,
    7. Wang J.
    MiR-103 regulates hepatocellular carcinoma growth by targeting AKAP12. Int J Biochem Cell Biol. 2016; 71: 1–11.
    OpenUrl
  78. 78.
    2. Yen CS,
    3. Su ZR,
    4. Lee YP,
    5. Liu IT,
    6. Yen CJ.
    miR-106b promotes cancer progression in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol. 2016; 22: 5183–92.
    OpenUrlCrossRefPubMed
  79. 79.
    2. Shen G,
    3. Jia HY,
    4. Tai Q,
    5. Li YH,
    6. Chen DJ.
    miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis. 2013; 34: 211–9.
    OpenUrlCrossRefPubMed
  80. 80.
    2. Mosca N,
    3. Castiello F,
    4. Coppola N,
    5. Trotta MC,
    6. Sagnelli C,
    7. Pisaturo M, et al.
    Functional interplay between hepatitis B virus X protein and human miR-125a in HBV infection. Biochem Biophys Res Commun. 2014; 449: 141–5.
    OpenUrl
  81. 81.
    2. Bi Q,
    3. Tang S,
    4. Xia L,
    5. Du R,
    6. Fan R,
    7. Gao L, et al.
    Ectopic expression of miR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF. PLoS One. 2012; 449: 141–5.
    OpenUrl
  82. 82.
    2. Li JF,
    3. Dai XP,
    4. Zhang W,
    5. Sun SH,
    6. Zeng Y,
    7. Zhao GY, et al.
    Upregulation of microRNA-146a by hepatitis B virus X protein contributes to hepatitis development by downregulating complement factor H. mBio. 2015; 6: e02459–14.
    OpenUrl
  83. 83.
    2. Zhang Z,
    3. Zhang Y,
    4. Sun XX,
    5. Ma X,
    6. Chen ZN.
    microRNA-146a inhibits cancer metastasis by downregulating VEGF through dual pathways in hepatocellular carcinoma. Mol Cancer. 2015; 14: 5.
    OpenUrlCrossRefPubMed
  84. 84.
    2. Zou CC,
    3. Chen J,
    4. Chen K,
    5. Wang S,
    6. Cao YY,
    7. Zhang JN, et al.
    Functional analysis of miR-181a and fas involved in hepatitis B virus-related hepatocellular carcinoma pathogenesis. Exp Cell Res. 2015; 331: 352–61.
    OpenUrl
  85. 85.
    2. Korhan P,
    3. Erdal E,
    4. Atabey N.
    miR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met. Biochem Biophys Res Commun. 2014; 450: 1304–12.
    OpenUrlCrossRefPubMed
  86. 86.
    2. Zou CC,
    3. Li YG,
    4. Cao YY,
    5. Zhang JN,
    6. Jiang JR,
    7. Sheng YR, et al.
    Up-regulated microRNA-181a induces carcinogenesis in hepatitis B virus-related hepatocellular carcinoma by targeting E2F5. BMC Cancer. 2014; 14: 97.
    OpenUrl
  87. 87.
    2. Liu X,
    3. Zhang Y,
    4. Wang P,
    5. Wang H,
    6. Su H,
    7. Zhou X, et al.
    HBX protein-induced downregulation of microRNA-18a is responsible for upregulation of connective tissue growth factor in HBV infection-associated hepatocarcinoma. Med Sci Monit. 2016; 22: 2492–500.
    OpenUrl
  88. 88.
    2. Kong G,
    3. Zhang J,
    4. Zhang S,
    5. Shan C,
    6. Ye L,
    7. Zhang X.
    Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model. PloS One. 2011; 6: e19518.
  89. 89.
    2. Cao YY,
    3. Zhang JN,
    4. Xiong DM,
    5. Wang D,
    6. Wu T,
    7. Huang AL, et al.
    Hsa-miR-331-3p inhibits VHL expression by directly targeting its mRNA 3'-UTR in HCC cell lines. Acta Biochim Pol. 2015; 62: 77–82.
    OpenUrl
  90. 90.
    2. Cao Y,
    3. Chen J,
    4. Wang D,
    5. Peng H,
    6. Tan X,
    7. Xiong D, et al.
    Upregulated in hepatitis B virus-associated hepatocellular carcinoma cells, miR-331-3p promotes proliferation of hepatocellular carcinoma cells by targeting ING5. Oncotarget. 2015; 6: 38093–106.
    OpenUrl
  91. 91.
    2. Han SY,
    3. Han HB,
    4. Tian XY,
    5. Sun H,
    6. Xue D,
    7. Zhao C, et al.
    MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma. Oncotarget. 2016; 7: 42461–73.
    OpenUrl
  92. 92.
    2. Guo XF,
    3. Wang AY,
    4. Liu J.
    HIFs-miR-33a-Twsit1 axis can regulate invasiveness of hepatocellular cancer cells. Eur Rev Med Pharmacol Sci. 2016; 20: 3011–6.
    OpenUrl
  93. 93.
    2. Yang L,
    3. Ma Z,
    4. Wang D,
    5. Zhao W,
    6. Chen L,
    7. Wang G.
    MicroRNA-602 regulating tumor suppressive gene RASSF1A is over-expressed in hepatitis B virus-infected liver and hepatocellular carcinoma. Cancer Biol Ther. 2010; 9: 803–8.
    OpenUrlPubMed
  94. 94.
    2. Shyu YC,
    3. Lee TL,
    4. Lu MJ,
    5. Chen JR,
    6. Chien RN,
    7. Chen HY, et al.
    miR-122-mediated translational repression of PEG10 and its suppression in human hepatocellular carcinoma. J Transl Med. 2016; 14: 200.
    OpenUrl
  95. 95.
    2. Shimakami T,
    3. Yamane D,
    4. Jangra RK,
    5. Kempf BJ,
    6. Spaniel C,
    7. Barton DJ, et al.
    Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. Proc Natl Acad Sci U S A. 2012; 109: 941–6.
    OpenUrlAbstract/FREE Full Text
  96. 96.
    2. Huang JF,
    3. Wang Y,
    4. Guo YJ,
    5. Sun SH.
    Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology. 2010; 52: 60–70.
    OpenUrlCrossRefPubMed
  97. 97.
    2. Huang S,
    3. Xie Y,
    4. Yang P,
    5. Chen P,
    6. Zhang L.
    HCV core protein-induced down-regulation of microRNA-152 promoted aberrant proliferation by regulating wnt1 in HepG2 cells. PLoS One. 2014; 9: e81730.
  98. 98.↵
    2. Chen JJ,
    3. Tang YS,
    4. Huang SF,
    5. Ai JG,
    6. Wang HX,
    7. Zhang LP.
    HBx protein-induced upregulation of microRNA-221 promotes aberrant proliferation in HBV-related hepatocellular carcinoma by targeting estrogen receptor-α. Oncol Rep. 2015; 33: 792–8.
    OpenUrl
  99. 99.↵
    2. Ding CL,
    3. Xu G,
    4. Ren H,
    5. Zhao LJ,
    6. Zhao P,
    7. Qi ZT, et al.
    HCV infection induces the upregulation of miR-221 in NF-κB dependent manner. Virus Res. 2015; 196: 135–9.
    OpenUrl
  100. 100.
    2. Mukherjee A,
    3. Shrivastava S,
    4. Chowdhury JB,
    5. Ray R,
    6. Ray RB.
    Transcriptional suppression of miR-181c by hepatitis C virus enhances homeobox A1 expression. J Virol. 2014; 88: 7929–40.
    OpenUrlAbstract/FREE Full Text
  101. 101.
    2. Liu DJ,
    3. Wu JL,
    4. Liu MZ,
    5. Yin H,
    6. He JT,
    7. Zhang B.
    Downregulation of miRNA-30c and miR-203a is associated with hepatitis C virus core protein-induced epithelial-mesenchymal transition in normal hepatocytes and hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2015; 464: 1215–21.
    OpenUrlCrossRefPubMed
  102. 102.
    2. Wan D,
    3. Shen S,
    4. Fu S,
    5. Preston B,
    6. Brandon C,
    7. He S, et al.
    miR-203 suppresses the proliferation and metastasis of hepatocellular carcinoma by targeting oncogene ADAM9 and oncogenic long non-coding RNA HULC. Anticancer Agents Med Chem. 2015; 16: 414–23.
    OpenUrl
  103. 103.
    2. Kong LL,
    3. Ni QF,
    4. Lu YT,
    5. Ding WZ,
    6. Kong LB.
    miR-30c attenutes invasion and metastasis of hepatocellular carcinoma. Acta Univ Med Nanjing（Nat Sci）. 2014; 34: 937–43.
    OpenUrl
  104. 104.↵
    2. Zhang YL,
    3. Wei W,
    4. Cheng N,
    5. Wang KH,
    6. Li B,
    7. Jiang XQ, et al.
    Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology. 2012; 56: 1631–40.
    OpenUrlCrossRefPubMed
  105. 105.
    2. Xu H,
    3. Li G,
    4. Yue Z,
    5. Li C.
    HCV core protein-induced upregulation of microRNA-196a promotes aberrant proliferation in hepatocellular carcinoma by targeting FOXO1. Mol Med Rep. 2016; 13: 5223–9.
    OpenUrl
  106. 106.↵
    2. Singaravelu R,
    3. Chen R,
    4. Lyn RK,
    5. Jones DM,
    6. O'Hara S,
    7. Rouleau Y, et al.
    Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis. Hepatology. 2014; 59: 98–108.
    OpenUrlCrossRefPubMed
  107. 107.↵
    2. Sun X,
    3. Zhang J,
    4. Hou Z,
    5. Han Q,
    6. Zhang C,
    7. Tian Z.
    miR-146a is directly regulated by stat3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression. Cell Cycle. 2015; 14: 243–52.
    OpenUrlCrossRefPubMed
  108. 108.↵
    2. Pasquinelli AE,
    3. Reinhart BJ,
    4. Slack F,
    5. Martindale MQ,
    6. Kuroda MI,
    7. Maller B, et al.
    Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000; 408: 86–9.
    OpenUrlCrossRefPubMed
  109. 109.↵
    2. Kloosterman WP,
    3. Plasterk RHA.
    The diverse functions of microRNAs in animal development and disease. Dev cell. 2006; 11: 441–50.
    OpenUrlCrossRefPubMed
  110. 110.↵
    2. Wang Y,
    3. Lee CGL.
    MicroRNA and cancer--focus on apoptosis. J Cell Mol Med. 2009; 13: 12–23.
    OpenUrlCrossRefPubMed
  111. 111.↵
    2. Takata A,
    3. Otsuka M,
    4. Ohno M,
    5. Kishikawa T,
    6. Yoshikawa T,
    7. Koike K.
    Mutual antagonism between hepatitis b viral mRNA and host microRNA let-7. Sci Rep. 2016; 6: 23237.
    OpenUrl
  112. 112.↵
    2. Peng Y,
    3. Laser J,
    4. Shi G,
    5. Mittal K,
    6. Melamed J,
    7. Lee P, et al.
    Antiproliferative effects by let-7 repression of high-mobility group A2 in uterine leiomyoma. Mol Cancer Res. 2008; 6: 663–73.
    OpenUrlAbstract/FREE Full Text
  113. 113.↵
    2. Wu L,
    3. Wang Q,
    4. Yao J,
    5. Jiang H,
    6. Xiao C,
    7. Wu F.
    MicroRNA let-7g and let-7i inhibit hepatoma cell growth concurrently via downregulation of the anti-apoptotic protein B-cell lymphoma-extra large. Oncol Lett. 2015; 9: 213–8.
    OpenUrlPubMed
  114. 114.↵
    2. Zhu XM,
    3. Wu LJ,
    4. Xu J,
    5. Yang RW,
    6. Wu FS.
    Let-7c microRNA expression and clinical significance in hepatocellular carcinoma. J Int Med Res. 2011; 39: 2323–9.
    OpenUrlPubMed
  115. 115.↵
    2. Jopling C.
    Liver-specific microRNA-122: Biogenesis and function. RNA Biol. 2012; 9: 137–42.
    OpenUrlCrossRefPubMed
  116. 116.↵
    2. Chang J,
    3. Nicolas E,
    4. Marks D,
    5. Sander C,
    6. Lerro A,
    7. Buendia MA, et al.
    miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol. 2004; 1: 106–13.
    OpenUrlCrossRefPubMed
  117. 117.↵
    2. Li C,
    3. Deng M,
    4. Hu J,
    5. Li X,
    6. Chen L,
    7. Ju Y, et al.
    Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels. Oncotarget. 2016; 7: 17021–34.
    OpenUrl
  118. 118.↵
    2. Song K,
    3. Han C,
    4. Zhang JQ,
    5. Lu DD,
    6. Dash S,
    7. Feitelson M, et al.
    Epigenetic regulation of microRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis B virus X protein in hepatocellular carcinoma cells. Hepatology. 2013; 58: 1681–92.
    OpenUrlCrossRefPubMed
  119. 119.↵
    2. Choi Y-H,
    3. Kim H-I,
    4. Seong JK,
    5. Yu D-Y,
    6. Cho H,
    7. Lee M-O, et al.
    Hepatitis B virus X protein modulates peroxisome proliferator-activated receptor γ through protein-protein interaction. FEBS Lett. 2004; 557: 73–80.
    OpenUrlCrossRefPubMed
  120. 120.↵
    2. Li CF,
    3. Wang YZ,
    4. Wang SF,
    5. Wu B,
    6. Hao JL,
    7. Fan HX, et al.
    Hepatitis B virus mRNA-mediated miR-122 inhibition upregulates PTTG1-binding protein, which promotes hepatocellular carcinoma tumor growth and cell invasion. J Virol. 2013; 87: 2193–205.
    OpenUrlAbstract/FREE Full Text
  121. 121.↵
    2. Coulouarn C,
    3. Factor VM,
    4. Andersen JB,
    5. Durkin ME,
    6. Thorgeirsson SS.
    Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 2009; 28: 3526–36.
    OpenUrlCrossRefPubMed
  122. 122.↵
    2. Bai S,
    3. Nasser MW,
    4. Wang B,
    5. Hsu SH,
    6. Datta J,
    7. Kutay H, et al.
    MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem. 2009; 284: 32015–27.
    OpenUrlAbstract/FREE Full Text
  123. 123.
    2. FoRNAri F,
    3. Gramantieri L,
    4. Giovannini C,
    5. Veronese A,
    6. Ferracin M,
    7. Sabbioni S, et al.
    MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2009; 69: 5761–7.
    OpenUrlAbstract/FREE Full Text
  124. 124.↵
    2. Nakamura M,
    3. Kanda T,
    4. Sasaki R,
    5. Haga Y,
    6. Jiang X,
    7. Wu S, et al.
    MicroRNA-122 inhibits the production of inflammatory cytokines by targeting the PKR activator PACT in human hepatic stellate cells. PLoS One. 2015; 10: e0144295.
  125. 125.↵
    2. Zhang ZZ,
    3. Liu X,
    4. Wang DQ,
    5. Teng MK,
    6. Niu LW,
    7. Huang AL, et al.
    Hepatitis B virus and hepatocellular carcinoma at the miRNA level. World J Gastroenterol. 2011; 17: 3353–8.
    OpenUrlCrossRefPubMed
  126. 126.↵
    2. Sheng YR,
    3. Li JB,
    4. Zou CC,
    5. Wang S,
    6. Cao YY,
    7. Zhang JN, et al.
    Downregulation of miR-101-3p by hepatitis b virus promotes proliferation and migration of hepatocellular carcinoma cells by targeting Rab5a. Arch Virol. 2014; 159: 2397–410.
    OpenUrlCrossRef
  127. 127.↵
    2. Zhang YQ,
    3. Guo XD,
    4. Xiong L,
    5. Kong XY,
    6. Xu Y,
    7. Liu CF, et al.
    MicroRNA-101 suppresses SOX9-dependent tumorigenicity and promotes favorable prognosis of human hepatocellular carcinoma. FEBS Lett. 2012; 586: 4362–70.
    OpenUrlCrossRefPubMed
  128. 128.↵
    2. Zhuang C,
    3. Jiang W,
    4. Huang D,
    5. Xu L,
    6. Yang Q,
    7. Zheng L, et al.
    Serum miR-21, miR-26a and miR-101 as potential biomarkers of hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 2016; 40: 386–96.
    OpenUrl
  129. 129.↵
    2. Xu Y,
    3. An Y,
    4. Wang Y,
    5. Zhang C,
    6. Zhang H,
    7. Huang C, et al.
    miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncol Rep. 2013; 29: 2019–24.
    OpenUrlPubMed
  130. 130.↵
    2. Zhao S,
    3. Zhang Y,
    4. Zheng X,
    5. Tu X,
    6. Li H,
    7. Chen J, et al.
    Loss of microRNA-101 promotes epithelial to mesenchymal transition in hepatocytes. J Cell Physiol. 2015; 230: 2706–17.
    OpenUrl
  131. 131.↵
    2. Sidorkiewicz M,
    3. Grek M,
    4. Jozwiak B,
    5. Majda-Stanislawska E,
    6. Piekarska A,
    7. Bartkowiak J.
    Expression of microRNA-155 precursor in peripheral blood mononuclear cells from hepatitis C patients after antiviral treatment. Acta Virol. 2010; 54: 75–8.
    OpenUrlPubMed
  132. 132.↵
    2. Wang B,
    3. Majumder S,
    4. Nuovo G,
    5. Kutay H,
    6. Volinia S,
    7. Patel T, et al.
    Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology. 2009; 50: 1152–61.
    OpenUrlCrossRefPubMed
  133. 133.↵
    2. Chang S,
    3. Wang RH,
    4. Akagi K,
    5. Kim KA,
    6. Martin BK,
    7. Cavallone L, et al.
    Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155. Nat Med. 2011; 17: 1275–82.
    OpenUrlCrossRefPubMed
  134. 134.↵
    2. O'Connell RM,
    3. Kahn DA,
    4. Gibson WSJ,
    5. Round JL,
    6. Scholz RL,
    7. Chaudhuri AA, et al.
    MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010; 33: 607–19.
    OpenUrlCrossRefPubMed
  135. 135.↵
    2. Marquez RT,
    3. Bandyopadhyay S,
    4. Wendlandt EB,
    5. Keck K,
    6. Hoffer BA,
    7. Icardi MS, et al.
    Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans. Lab Invest. 2010; 90: 1727–36.
    OpenUrlCrossRefPubMed
  136. 136.↵
    2. Du T,
    3. Zamore PD.
    microPrimer: The biogenesis and function of microRNA. Development. 2005; 132: 4645–52.
    OpenUrlAbstract/FREE Full Text
  137. 137.↵
    2. Degueurce G,
    3. D'Errico I,
    4. Pich C,
    5. Ibberson M,
    6. Schütz F,
    7. Montagner A, et al.
    Identification of a novel PPARβ/δ/miR-21-3p axis in UV-induced skin inflammation. EMBO Mol Med. 2016; 8: 919–36.
    OpenUrlAbstract/FREE Full Text
  138. 138.↵
    2. Lu TX,
    3. Munitz A,
    4. Rothenberg ME.
    MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J Immunol. 2009; 182: 4994–5002.
    OpenUrlAbstract/FREE Full Text
  139. 139.
    2. Zhang ZY,
    3. Li ZJ,
    4. Gao CP,
    5. Chen P,
    6. Chen JJ,
    7. Liu WZ, et al.
    miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest. 2008; 88: 1358–66.
    OpenUrlCrossRefPubMed
  140. 140.
    2. Medina PP,
    3. Nolde M,
    4. Slack FJ.
    OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature. 2010; 467: 86–90.
    OpenUrlCrossRefPubMed
  141. 141.↵
    2. Peacock O,
    3. Lee AC,
    4. Cameron F,
    5. Tarbox R,
    6. Vafadar-Isfahani N,
    7. Tufarelli C, et al.
    Inflammation and miR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer. PLoS One. 2014; 9: e110267.
  142. 142.↵
    2. Xu J,
    3. Wu C,
    4. Che X,
    5. Wang L,
    6. Yu DK,
    7. Zhang TW, et al.
    Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog. 2011; 50: 136–42.
    OpenUrlCrossRefPubMed
  143. 143.↵
    2. Meng FY,
    3. Henson R,
    4. Wehbe-Janek H,
    5. Ghoshal K,
    6. Jacob ST,
    7. Patel T.
    MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007; 133: 647–58.
    OpenUrlCrossRefPubMed
  144. 144.↵
    2. Qiu X,
    3. Dong S,
    4. Qiao F,
    5. Lu S,
    6. Song Y,
    7. Lao Y, et al.
    HBx-mediated miR-21 upregulation represses tumor-suppressor function of PDCD4 in hepatocellular carcinoma. Oncogene. 2013; 32: 3296–305.
    OpenUrlCrossRefPubMed
  145. 145.↵
    2. Iorio MV,
    3. Ferracin M,
    4. Liu CG,
    5. Veronese A,
    6. Spizzo R,
    7. Sabbioni S, et al.
    MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005; 65: 7065–70.
    OpenUrlAbstract/FREE Full Text
  146. 146.
    2. Chan JA,
    3. Krichevsky AM,
    4. Kosik KS.
    MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005; 65: 6029–33.
    OpenUrlAbstract/FREE Full Text
  147. 147.↵
    2. Galardi S,
    3. Mercatelli N,
    4. Giorda E,
    5. Massalini S,
    6. Frajese GV,
    7. Ciafrè SA, et al.
    miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem. 2007; 282: 23716–24.
    OpenUrlAbstract/FREE Full Text
  148. 148.↵
    2. Rong MH,
    3. Chen G,
    4. Dang YW.
    Increased miR-221 expression in hepatocellular carcinoma tissues and its role in enhancing cell growth and inhibiting apoptosis in vitro. BMC Cancer. 2013; 13: 21.
    OpenUrlCrossRefPubMed
  149. 149.↵
    2. Karakatsanis A,
    3. Papaconstantinou I,
    4. Gazouli M,
    5. Lyberopoulou A,
    6. Polymeneas G,
    7. Voros D.
    Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog. 2013; 52: 297–303.
    OpenUrlCrossRefPubMed
  150. 150.↵
    2. Ogawa T,
    3. Enomoto M,
    4. Fujii H,
    5. Sekiya Y,
    6. Yoshizato K,
    7. Ikeda K, et al.
    MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut. 2012; 61: 1600–9.
    OpenUrlAbstract/FREE Full Text
  151. 151.↵
    2. Yuan QG,
    3. Loya K,
    4. Rani B,
    5. M?bus S,
    6. Balakrishnan A,
    7. Lamle J, et al.
    MicroRNA-221 overexpression accelerates hepatocyte proliferation during liver regeneration. Hepatology. 2013; 57: 299–310.
    OpenUrlCrossRefPubMed
  152. 152.↵
    2. le Sage C,
    3. Nagel R,
    4. Egan DA,
    5. Schrier M,
    6. Mesman E,
    7. Mangiola A, et al.
    Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 2007; 26: 3699–708.
    OpenUrlAbstract/FREE Full Text
  153. 153.
    2. Miller TE,
    3. Ghoshal K,
    4. Ramaswamy B,
    5. Roy S,
    6. Datta J,
    7. Shapiro CL, et al.
    MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 2008; 283: 29897–903.
    OpenUrlAbstract/FREE Full Text
  154. 154.
    2. Garofalo M,
    3. Quintavalle C,
    4. Di Leva G,
    5. Zanca C,
    6. Romano G,
    7. Taccioli C, et al.
    MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene. 2008; 27: 3845–55.
    OpenUrlCrossRefPubMed
  155. 155.↵
    2. Fu XH,
    3. Wang Q,
    4. Chen JS,
    5. Huang XH,
    6. Chen XL,
    7. Cao LQ, et al.
    Clinical significance of miR-221 and its inverse correlation with P27Kip1 in hepatocellular carcinoma. Mol Biol Rep. 2010; 38: 3029–35.
    OpenUrlPubMed
  156. 156.↵
    2. Garofalo M,
    3. Di Leva G,
    4. Romano G,
    5. Nuovo G,
    6. Suh SS,
    7. Ngankeu A, et al.
    miR-221& 222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009; 16: 498–509.
    OpenUrlCrossRefPubMed
  157. 157.↵
    2. Bae HJ,
    3. Jung KH,
    4. Eun JW,
    5. Shen QY,
    6. Kim HS,
    7. Park SJ, et al.
    MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. J Hepatol. 2015; 63: 408–19.
    OpenUrl
  158. 158.↵
    2. Park J,
    3. Kogure T,
    4. Nuovo GJ,
    5. Jiang J,
    6. He L,
    7. Kim JH, et al.
    miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 2011; 71: 7608–16.
    OpenUrlAbstract/FREE Full Text
  159. 159.↵
    2. Callegari E,
    3. Elamin BK,
    4. Giannone F,
    5. Milazzo M,
    6. Altavilla G,
    7. FoRNAri F, et al.
    Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology. 2012; 56: 1025–33.
    OpenUrlCrossRefPubMed
  160. 160.↵
    2. Huan L,
    3. Bao C,
    4. Chen D,
    5. Li Y,
    6. Lian J,
    7. Ding J, et al.
    MicroRNA-127-5p targets the biliverdin reductase B/nuclear factor-κB pathway to suppress cell growth in hepatocellular carcinoma cells. Cancer Sci. 2016; 107: 258–66.
    OpenUrlCrossRefPubMed
  161. 161.
    2. Liu Y,
    3. Hei Y,
    4. Shu Q,
    5. Dong J,
    6. Gao Y,
    7. Fu H, et al.
    VCP/p97, down-regulated by microRNA-129-5p, could regulate the progression of hepatocellular carcinoma. PLoS One. 2012; 7: e35800.
  162. 162.↵
    2. Bao C,
    3. Li Y,
    4. Huan L,
    5. Zhang Y,
    6. Zhao F,
    7. Wang Q, et al.
    NF-κB signaling relieves negative regulation by miR-194 in hepatocellular carcinoma by suppressing the transcription factor HNF-1α. Sci Signal. 2015; 8: ra75.
    OpenUrlAbstract/FREE Full Text
  163. 163.↵
    2. Ding J,
    3. Huang SL,
    4. Wang Y,
    5. Tian Q,
    6. Zha RP,
    7. Shi HB, et al.
    Genome-wide screening reveals that miR-195 targets the TNF-α/Nf-κB pathway by down-regulating IκB kinase alpha and TAB3 in hepatocellular carcinoma. Hepatology. 2013; 58: 654–66.
    OpenUrlCrossRefPubMed
  164. 164.↵
    2. Zhao N,
    3. Wang R,
    4. Zhou L,
    5. Zhu Y,
    6. Gong J,
    7. Zhuang SM.
    MicroRNA-26b suppresses the NF-κB signaling and enhances the chemosensitivity of hepatocellular carcinoma cells by targeting TAK1 and TAB3. Mol Cancer. 2014; 13: 35.
    OpenUrlCrossRefPubMed
  165. 165.
    2. Wang L,
    3. Yao J,
    4. Sun H,
    5. Sun R,
    6. Chang S,
    7. Yang Y, et al.
    miR-302b suppresses cell invasion and metastasis by directly targeting AKT2 in human hepatocellular carcinoma cells. Tumor Biol. 2015; 37: 847–55.
    OpenUrl
  166. 166.
    2. Zhao L,
    3. Zhang YB.
    miR-342-3p affects hepatocellular carcinoma cell proliferation via regulating NF-κB pathway. Biochem Biophys Res Commun. 2015; 457: 370–7.
    OpenUrlCrossRefPubMed
  167. 167.↵
    2. Xu WP,
    3. Yi M,
    4. Li QQ,
    5. Zhou WP,
    6. Cong WM,
    7. Yang Y, et al.
    Perturbation of microRNA-370/lin-28 homolog A/nuclear factor kappa B regulatory circuit contributes to the development of hepatocellular carcinoma. Hepatology. 2013; 58: 1977–91.
    OpenUrlCrossRefPubMed
  168. 168.
    2. Jiang F,
    3. Wang XX,
    4. Liu QQ,
    5. Shen J,
    6. Li Z,
    7. Li Y, et al.
    Inhibition of TGF-β/SMAD3/NF-κB signaling by microRNA-491 is involved in arsenic trioxide-induced anti-angiogenesis in hepatocellular carcinoma cells. Toxicol Lett. 2014; 231: 55–61.
    OpenUrlCrossRefPubMed
  169. 169.
    2. Zhang S,
    3. Shan C,
    4. Kong G,
    5. Du Y,
    6. Ye L,
    7. Zhang X.
    MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-κB-inducing kinase (NIK). Oncogene. 2012; 31: 3607–20.
    OpenUrlCrossRefPubMed
  170. 170.
    2. Song WH,
    3. Feng XJ,
    4. Gong SJ,
    5. Chen JM,
    6. Wang SM,
    7. Xing DJ, et al.
    microRNA-622 acts as a tumor suppressor in hepatocellular carcinoma. Cancer Biol Ther. 2015; 16: 1754–63.
    OpenUrl
  171. 171.↵
    2. Tan G,
    3. Wu L,
    4. Tan J,
    5. Zhang B,
    6. Tai WC,
    7. Xiong S, et al.
    miR-1180 promotes apoptotic resistance to human hepatocellular carcinoma via activation of NF-κB signaling pathway. Sci Rep. 2016; 6: 22328.
    OpenUrl
  172. 172.
    2. Zhou P,
    3. Jiang W,
    4. Wu LL,
    5. Chang RM,
    6. Wu KM,
    7. Wang ZM.
    miR-301a is a candidate oncogene that targets the homeobox gene gax in human hepatocellular carcinoma. Dig Dis Sci. 2012; 57: 1171–80.
    OpenUrlCrossRefPubMed
  173. 173.↵
    2. Ni F,
    3. Zhao H,
    4. Cui HQ,
    5. Wu ZS,
    6. Chen L,
    7. Hu ZQ, et al.
    MicroRNA-362-5p promotes tumor growth and metastasis by targeting CYLD in hepatocellular carcinoma. Cancer Lett. 2015; 356: 809–18.
    OpenUrl
  174. 174.
    2. Lu S,
    3. Wu JD,
    4. Gao YY,
    5. Han GY,
    6. Ding WZ,
    7. Huang XL.
    MicroRNA-4262 activates the NF-κB and enhances the proliferation of hepatocellular carcinoma cells. Int J Biol Macromol. 2016; 86: 43–9.
    OpenUrl
  175. 175.
    2. Zhang LS,
    3. Yang LX,
    4. Liu XY,
    5. Chen W,
    6. Chang LF,
    7. Chen LL, et al.
    MicroRNA-657 promotes tumorigenesis in hepatocellular carcinoma by targeting transducin-like enhancer protein 1 through nuclear factor kappa B pathways. Hepatology. 2013; 57: 1919–30.
    OpenUrlCrossRefPubMed
  176. 176.↵
    2. Li HP,
    3. Zeng XC,
    4. Zhang B,
    5. Long JT,
    6. Zhou B,
    7. Tan GS, et al.
    miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β. Carcinogenesis. 2013; 34: 2443–51.
    OpenUrlCrossRefPubMed
  177. 177.↵
    2. Liu X,
    3. Zhang A,
    4. Xiang J,
    5. Lv Y,
    6. Zhang X.
    miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway. Oncol Rep. 2016; 36: 1385–92.
    OpenUrl
  178. 178.
    2. Aboulnasr F,
    3. Hazari S,
    4. Nayak S,
    5. Chandra PK,
    6. Panigrahi R,
    7. Ferraris P, et al.
    IFN-λ inhibits miR-122 transcription through a stat3-HNF4α inflammatory feedback loop in an IFN-α resistant HCV cell culture system. PLoS One. 2015; 10: e0141655.
    OpenUrl
  179. 179.↵
    2. Lu YX,
    3. Yue XP,
    4. Cui YY,
    5. Zhang JF,
    6. Wang KW.
    MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3. Biochem Biophys Res Commun. 2013; 441: 873–9.
    OpenUrlCrossRefPubMed
  180. 180.↵
    2. Gong J,
    3. Zhang JP,
    4. Li B,
    5. Zeng C,
    6. You K,
    7. Chen MX, et al.
    MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene. 2012; 32: 3071–9.
    OpenUrl
  181. 181.
    2. Lin YH,
    3. Wu MH,
    4. Liao CJ,
    5. Huang YH,
    6. Chi HC,
    7. Wu SM, et al.
    Repression of microRNA-130b by thyroid hormone enhances cell motility. J Hepatol. 2015; 62: 1328–40.
    OpenUrl
  182. 182.↵
    2. Wang H,
    3. Su X,
    4. Yang M,
    5. Chen T,
    6. Hou J,
    7. Li N, et al.
    Reciprocal control of miR-197 and IL-6/STAT3 pathway reveals miR-197 as potential therapeutic target for hepatocellular carcinoma. Oncoimmunology. 2015; 4: e1031440.
    OpenUrl
  183. 183.↵
    2. Zhou B,
    3. Chen H,
    4. Wei D,
    5. Kuang Y,
    6. Zhao X,
    7. Li G, et al.
    A novel miR-219-SMC4-JAK2/Stat3 regulatory pathway in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2014; 33: 55.
    OpenUrl
  184. 184.↵
    2. Yang X,
    3. Liang L,
    4. Zhang XF,
    5. Jia HL,
    6. Qin Y,
    7. Zhu XC, et al.
    MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology. 2013; 58: 158–70.
    OpenUrlCrossRefPubMed
  185. 185.
    2. Zhou P,
    3. Huang G,
    4. Zhao YY,
    5. Zhong D,
    6. Xu ZZ,
    7. Zeng YJ, et al.
    MicroRNA-363-mediated downregulation of S1PR1 suppresses the proliferation of hepatocellular carcinoma cells. Cell Signal. 2014; 26: 1347–54.
    OpenUrlPubMed
  186. 186.↵
    2. Zhang JF,
    3. He ML,
    4. Fu WM,
    5. Wang H,
    6. Chen LZ,
    7. Zhu X, et al.
    Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. Hepatology. 2011; 54: 2137–48.
    OpenUrlCrossRefPubMed
  187. 187.↵
    2. Yan XL,
    3. Jia YL,
    4. Chen L,
    5. Zeng Q,
    6. Zhou JN,
    7. Fu CJ, et al.
    Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4-miR155-SOCS1-MMP9 axis. Hepatology. 2013; 57: 2274–86.
    OpenUrlCrossRefPubMed
  188. 188.↵
    2. Zhou J,
    3. Yu L,
    4. Gao X,
    5. Hu J,
    6. Wang JP,
    7. Dai Z, et al.
    Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol. 2011; 29: 4781–8.
    OpenUrlAbstract/FREE Full Text
  189. 189.↵
    2. Ji J,
    3. Shi J,
    4. Budhu A,
    5. Yu Z,
    6. Forgues M,
    7. Roessler S, et al.
    MicroRNA expression, survival, and response to interferon in liver cancer. N Eng J Med. 2009; 361: 1437–47.
    OpenUrlCrossRefPubMed
  190. 190.↵
    2. Chai ZT,
    3. Zhu XD,
    4. Ao JY,
    5. Wang WQ,
    6. Gao DM,
    7. Kong J, et al.
    MicroRNA-26a suppresses recruitment of macrophages by down-regulating macrophage colony-stimulating factor expression through the PI3K/Akt pathway in hepatocellular carcinoma. J Hematol Oncol. 2015; 8: 56.
    OpenUrl
  191. 191.↵
    2. Zhu XD,
    3. Zhang JB,
    4. Zhuang PY,
    5. Zhu HG,
    6. Zhang W,
    7. Xiong YQ, et al.
    High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008; 26: 2707–16.
    OpenUrlAbstract/FREE Full Text
  192. 192.↵
    2. Huang JY,
    3. Zhang K,
    4. Chen DQ,
    5. Chen J,
    6. Feng B,
    7. Song HZ, et al.
    MicroRNA-451: Epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma. Oncotarget. 2015; 6: 18613–30.
    OpenUrl
  193. 193.↵
    2. Zheng YB,
    3. Xiao GC,
    4. Tong SL,
    5. Ding Y,
    6. Wang QS,
    7. Li SB, et al.
    Paeoniflorin inhibits human gastric carcinoma cell proliferation through up-regulation of microRNA-124 and suppression of PI3K/Akt and STAT3 signaling. World J Gastroenterol. 2015; 21: 7197–207.
    OpenUrl
  194. 194.
    2. Li Y,
    3. Zhang Z,
    4. Liu X,
    5. Huang T,
    6. He W,
    7. Shen Y, et al.
    miR-124 functions as a tumor suppressor in the endometrial carcinoma cell line HEC-1B partly by suppressing STAT3. Mol Cell Biochem. 2013; 388: 219–31.
    OpenUrl
  195. 195.
    2. Li W,
    3. Huang H,
    4. Su J,
    5. Ji X,
    6. Zhang X,
    7. Zhang Z, et al.
    miR-124 acts as a tumor suppressor in glioblastoma via the inhibition of signal transducer and activator of transcription 3. Mol Neurobiol. 2016, doi: 10.1007/s12035-016-9852-z.
    OpenUrlCrossRef
  196. 196.↵
    2. Zhang J,
    3. Lu Y,
    4. Yue X,
    5. Li H,
    6. Luo X,
    7. Wang Y, et al.
    miR-124 suppresses growth of human colorectal cancer by inhibiting STAT3. PLoS One. 2013; 8: e70300.
  197. 197.↵
    2. Jeong D,
    3. Kim J,
    4. Nam J,
    5. Sun H,
    6. Lee YH,
    7. Lee TJ, et al.
    MicroRNA-124 links p53 to the NF-κB pathway in B-cell lymphomas. Leukemia. 2015; 29: 1868–74.
    OpenUrl
  198. 198.↵
    2. Ning BF,
    3. Ding J,
    4. Liu J,
    5. Yin C,
    6. Xu WP,
    7. Cong WM, et al.
    Hepatocyte nuclear factor 4α-nuclear factor-κB feedback circuit modulates liver cancer progression. Hepatology. 2014; 60: 1607–19.
    OpenUrlCrossRefPubMed
  199. 199.↵
    2. Tili E,
    3. Michaille JJ,
    4. Cimino A,
    5. Costinean S,
    6. Dumitru CD,
    7. Adair B, et al.
    Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol. 2007; 179: 5082–9.
    OpenUrlAbstract/FREE Full Text
  200. 200.↵
    2. Liang LH,
    3. Wong CM,
    4. Ying Q,
    5. Fan DNY,
    6. Huang SL,
    7. Yao J, et al.
    MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. Hepatology. 2010; 52: 1731–40.
    OpenUrlCrossRefPubMed
  201. 201.↵
    2. Zhao AH,
    3. Zeng Q,
    4. Xie XY,
    5. Zhou JN,
    6. Yue W,
    7. Li YL, et al.
    MicroRNA-125b induces cancer cell apoptosis through suppression of Bcl-2 expression. J Genet Genomics. 2012; 39: 29–35.
    OpenUrlPubMed
  202. 202.↵
    2. Jia HY,
    3. Wang YX,
    4. Yan WT,
    5. Li HY,
    6. Tian YZ,
    7. Wang SM, et al.
    MicroRNA-125b functions as a tumor suppressor in hepatocellular carcinoma cells. Int J Mol Sci. 2012; 13: 8762–74.
    OpenUrlCrossRefPubMed
  203. 203.↵
    2. Li J,
    3. Fang L,
    4. Yu W,
    5. Wang Y.
    MicroRNA-125b suppresses the migration and invasion of hepatocellular carcinoma cells by targeting transcriptional coactivator with PDZ-binding motif. Oncol Lett. 2015; 9: 1971–75.
    OpenUrl
  204. 204.↵
    2. Zhou JN,
    3. Zeng Q,
    4. Wang HY,
    5. Zhang B,
    6. Li ST,
    7. Nan X, et al.
    MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4. Hepatology. 2015; 62: 801–15.
    OpenUrl
  205. 205.↵
    2. Au SLK,
    3. Wong CLC,
    4. Lee JMF,
    5. Fan DNY,
    6. Tsang FH,
    7. Ng IOL, et al.
    Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology. 2012; 56: 622–31.
    OpenUrlCrossRefPubMed
  206. 206.↵
    2. Lo SS,
    3. Hung PS,
    4. Chen JH,
    5. Tu HF,
    6. Fang WL,
    7. Chen CY, et al.
    Overexpression of miR-370 and downregulation of its novel target TGFβ-RII contribute to the progression of gastric carcinoma. Oncogene. 2012; 31: 226–37.
    OpenUrlCrossRefPubMed
  207. 207.
    2. Wu Z,
    3. Sun H,
    4. Zeng W,
    5. He J,
    6. Mao X.
    Upregulation of mircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1. PLoS One. 2012; 7: e445825.
  208. 208.
    2. Dixonmciver A,
    3. East P,
    4. Mein CA,
    5. Cazier JB,
    6. Molloy G,
    7. Chaplin T, et al.
    Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS One. 2008; 3: e2141.
  209. 209.
    2. Zhang XL,
    3. Zeng JP,
    4. Zhou MR,
    5. Li BN,
    6. Zhang YY,
    7. Huang T, et al.
    The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia. Mol Cancer. 2012; 11: 56.
    OpenUrlCrossRefPubMed
  210. 210.↵
    2. Chang KW,
    3. Chu TH,
    4. Gong NR,
    5. Chiang WF,
    6. Yang CC,
    7. Liu CJ, et al.
    miR-370 modulates insulin receptor substrate-1 expression and inhibits the tumor phenotypes of oral carcinoma. Oral Dis. 2013; 19: 611–9.
    OpenUrlCrossRefPubMed
  211. 211.↵
    2. Sun G,
    3. Hou YB,
    4. Jia HY,
    5. Bi XH,
    6. Yu L,
    7. Chen D.
    miR-370 promotes cell death of liver cancer cells by Akt/FoxO3a signalling pathway. Eur Rev Med Pharmacol Sci. 2016; 20: 2011–9.
    OpenUrl
  212. 212.↵
    2. Zhou X,
    3. Zhu HQ,
    4. Ma CQ,
    5. Li HG,
    6. Liu FF,
    7. Chang H, et al.
    MiR-1180 promoted the proliferation of hepatocellular carcinoma cells by repressing TNIP2 expression. Biomed Pharmacother. 2016; 79: 315–20.
    OpenUrl
  213. 213.↵
    2. Sun SC.
    CYLD: A tumor suppressor deubiquitinase regulating NF-κB activation and diverse biological processes. Cell Death Differ. 2010; 17: 25–34.
    OpenUrlCrossRefPubMed
  214. 214.↵
    2. Zhang XY,
    3. Liu SR,
    4. Hu TS,
    5. Liu SP,
    6. He Y,
    7. Sun SH.
    Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology. 2009; 50: 490–9.
    OpenUrlCrossRefPubMed
  215. 215.↵
    2. Scisciani C,
    3. Vossio S,
    4. Guerrieri F,
    5. Schinzari V,
    6. De Iaco R,
    7. De Meo PD, et al.
    Transcriptional regulation of miR-224 upregulated in human HCCs by NFκB inflammatory pathways. J Hepatol. 2012; 56: 855–61.
    OpenUrlCrossRefPubMed
  216. 216.
    2. Zhang K,
    3. Chen J,
    4. Chen DQ,
    5. Huang JY,
    6. Feng B,
    7. Han SQ, et al.
    Aurora-a promotes chemoresistance in hepatocelluar carcinoma by targeting NF-kappaB/microRNA-21/pten signaling pathway. Oncotarget. 2014; 5: 12916–35.
    OpenUrl
  217. 217.
    2. Zhang N,
    3. Duan WD,
    4. Leng JJ,
    5. Zhou L,
    6. Wang X,
    7. Xu YZ, et al.
    STAT3 regulates the migration and invasion of a stem-like subpopulation through microRNA-21 and multiple targets in hepatocellular carcinoma. Oncol Rep. 2015; 33: 1493–8.
    OpenUrl
  218. 218.↵
    2. Wang B,
    3. Hsu SH,
    4. Frankel W,
    5. Ghoshal K,
    6. Jacob ST.
    Stat3-mediated activation of miRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by downr-egulating Glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology. 2012; 56: 186–97.
    OpenUrlCrossRefPubMed
  219. 219.↵
    2. Lotze MT,
    3. Tracey KJ.
    High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005; 5: 331–42.
    OpenUrlCrossRefPubMed
  220. 220.↵
    2. Agresti A,
    3. Lupo R,
    4. Bianchi M,
    5. Müller S.
    HMGB1 interacts differentially with members of the Rel family of transcription factors. Biochem Biophys Res Commun. 2003; 302: 421–46.
    OpenUrlCrossRefPubMed
  221. 221.↵
    2. Chen M,
    3. Liu Y,
    4. Varley P,
    5. Chang Y,
    6. He XX,
    7. Huang H, et al.
    High-mobility group box 1 promotes hepatocellular carcinoma progression through miR-21-mediated matrix metalloproteinase activity. Cancer Res. 2015; 75: 1645–56.
    OpenUrlAbstract/FREE Full Text
  222. 222.↵
    2. Zhong W,
    3. Qin S,
    4. Zhu B,
    5. Pu M,
    6. Liu F,
    7. Wang L, et al.
    Oxysterol-binding protein-related protein 8 (ORP8) increases sensitivity of hepatocellular carcinoma cells to Fas-mediated apoptosis. J Biol Chem. 2015; 290: 8876–87.
    OpenUrlAbstract/FREE Full Text
  223. 223.↵
    2. Zhang ZQ,
    3. Meng H,
    4. Wang N,
    5. Liang LN,
    6. Liu LN,
    7. Lu SM, et al.
    Serum microRNA 143 and microRNA 215 as potential biomarkers for the diagnosis of chronic hepatitis and hepatocellular carcinoma. Diagn Pathol. 2014; 9: 135.
    OpenUrlCrossRefPubMed
  224. 224.↵
    2. Zhuang LP,
    3. Meng ZQ.
    Serum miR-224 reflects stage of hepatocellular carcinoma and predicts survival. Biomed Res Int. 2015; 2015: 731781.
  225. 225.↵
    2. Li Q,
    3. Ding CC,
    4. Chen C,
    5. Zhang ZM,
    6. Xiao H,
    7. Xie F, et al.
    miR-224 promotion of cell migration and invasion by targeting homeobox D 10 gene in human hepatocellular carcinoma. J Gastroenterol Hepatol. 2014; 29: 835–42.
    OpenUrlCrossRefPubMed
  226. 226.↵
    2. An F,
    3. Olaru AV,
    4. Mezey E,
    5. Xie Q,
    6. Li L,
    7. Piontek KB, et al.
    MicroRNA-224 induces G1/S checkpoint release in liver cancer. J Clin Med. 2015; 4: 1713–28.
    OpenUrl
  227. 227.↵
    2. Liu YM,
    3. Berthier-Schaad Y,
    4. Fallin MD,
    5. Fink NE,
    6. Tracy RP,
    7. Klag MJ, et al.
    IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort. J Am Soc Nephrol. 2006; 17: 863–70.
    OpenUrlAbstract/FREE Full Text
  228. 228.↵
    2. Huang SL,
    3. He XH,
    4. Ding J,
    5. Liang LH,
    6. Zhao YJ,
    7. Zhang ZF, et al.
    Upregulation of miR-23a~27a~24 decreases transforming growth factor-beta-induced tumor-suppressive activities in human hepatocellular carcinoma cells. Int J Cancer. 2008; 123: 972–8.
    OpenUrlCrossRefPubMed
  229. 229.↵
    2. Krützfeldt J,
    3. Rajewsky N,
    4. Braich R,
    5. Rajeev KG,
    6. Tuschl T,
    7. Manoharan M, et al.
    Silencing of microRNAs in vivo with 'antagomirs'. Nature. 2005; 438: 685–9.
    OpenUrlCrossRefPubMed
  230. 230.↵
    2. He XD,
    3. Li JJ,
    4. Guo WD,
    5. Liu W,
    6. Yu J,
    7. Song W, et al.
    Targeting the microRNA-21/AP1 axis by 5-fluorouracil and pirarubicin in human hepatocellular carcinoma. Oncotarget. 2014; 6: 2302–14.
    OpenUrl
  231. 231.↵
    2. Yu W,
    3. Fang H.
    Clinical trials with oncolytic adenovirus in china. Curr Cancer Drug Targets. 2007; 7: 141–8.
    OpenUrlCrossRefPubMed
  232. 232.↵
    2. Callegari E,
    3. Elamin BK,
    4. D'Abundo L,
    5. Falzoni S,
    6. Donvito G,
    7. Moshiri F, et al.
    Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. PLoS One. 2013; 8: e73964.
  233. 233.↵
    2. Ghosh AS,
    3. Tergaonkar V.
    Telomeres and inflammation: Rap1 joins the ends? Cell Cycle. 2010; 9: 3834–5.
    OpenUrlCrossRefPubMed
  234. 234.↵
    2. Zha Y,
    3. Gan P,
    4. Yao Q,
    5. Ran FM,
    6. Tan J.
    Downregulation of Rap1 promotes 5-fluorouracil-induced apoptosis in hepatocellular carcinoma cell line HepG2. Oncol Rep. 2014; 31: 1691–8.
    OpenUrl
  235. 235.↵
    2. Egeblad M,
    3. Nakasone ES,
    4. Werb Z.
    Tumors as organs: Complex tissues that interface with the entire organism. Dev Cell. 2010; 18: 884–901.
    OpenUrlCrossRefPubMed
  236. 236.↵
    2. Eggert T,
    3. McGlynn KA,
    4. Duffy A,
    5. Manns MP,
    6. Greten TF,
    7. Altekruse SF.
    Epidemiology of fibrolamellar hepatocellular carcinoma in the USA, 2000-10. Gut. 2013; 62: 1667–8.
    OpenUrlFREE Full Text
  237. 237.↵
    2. Lin XJ,
    3. Chong YT,
    4. Guo ZW,
    5. Xie C,
    6. Yang XJ,
    7. Zhang Q, et al.
    A serum microRNA classifier for early detection of hepatocellular carcinoma: A multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol. 2015; 16: 804–15.
    OpenUrlPubMed
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