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Stage-dependent differential expression of microRNAs in colorectal cancer: potential role as markers of metastatic disease

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Abstract

MicroRNAs (miRs) are short non-coding RNAs that bind complementary sequences in mRNA resulting in translation repression and/or mRNA degradation. We investigated expression of the reported metastasis-associated miRs-335, 206, 135a, 146a, 146b, 10b, 21, let7a and let7b in normal mucosa, non-metastatic and metastatic colorectal cancer (CRC). Expression of target miRs in micro-dissected paraffin embedded tissues was evaluated in 15 primary tumours with adjacent normal tissue from patients that were disease-free at 4 years (cohort A) and 19 paired primary tumours with corresponding liver metastases (cohort B) by quantitative real-time PCR. Increased expression of miR-21, mir-135a and miR-335 was associated with clinical progression of CRC, while miR-206 demonstrated an opposite trend. The levels of mir-21 did not associate with the expression of PTEN, an important tumour suppressor in CRC and one of many putative targets of miR-21, but interestingly was associated with stage of disease in the PTEN expressing tumours. Surprisingly, let7a, a KRAS-targeting miR, showed elevated expression in metastatic disease compared to normal mucosa or non-metastatic disease, and only in KRAS mutation positive tumors. Finally, a prognostic signature of miR 21,135a, 335, 206 and let-7a for detecting the presence of metastases had a specificity of 87% and sensitivity of 76% for the presence of metastases. In summary, we have shown stage-associated differential expression of five out of nine tested metastasis-associated miRs. We have further found that an analysis of these five miRs expression levels in primary tumors significantly correlates with the presence of metastatic disease, making this a potential clinically useful prognostic tool.

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Abbreviations

miR:

MicroRNA

CRC:

Colorectal cancer

APC:

Adenomatous polyposis coli

FFPE:

Formalin fixed paraffin embedded

DFS:

Disease free survival

LM:

Liver metastasis

LCM:

Laser-capture-micro dissection

RFS:

Recurrence free survival

SNP:

Single nucleotide polymorphism

PTEN:

Phosphatase and tensin homolog

References

  1. Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108

    Article  PubMed  Google Scholar 

  2. Kurkjian C, Murgo AJ, Kummar S (2008) Treatment of recurrent metastatic colon cancer in the age of modern adjuvant therapy. Clin Colorectal Cancer 7(5):321–324

    Article  PubMed  CAS  Google Scholar 

  3. Eccles SA, Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369(9574):1742–1757

    Article  PubMed  CAS  Google Scholar 

  4. Iorio MV, Croce CM (2009) MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol 27(34):5848–5856

    Article  PubMed  CAS  Google Scholar 

  5. Williams AE (2008) Functional aspects of animal microRNAs. Cell Mol Life Sci 65(4):545–562

    Article  PubMed  CAS  Google Scholar 

  6. Kulda V, Pesta M, Topolcan O et al (2010) Relevance of miR-21 and miR-143 expression in tissue samples of colorectal carcinoma and its liver metastases. Cancer Genet Cytogenet 200(2):154–160

    Article  PubMed  CAS  Google Scholar 

  7. Nielsen BS, Jorgensen S, Fog JU et al (2011) High levels of microRNA-21 in the stroma of colorectal cancers predict short disease-free survival in stage II colon cancer patients. Clin Exp Metastasis 28(1):27–38

    Article  PubMed  CAS  Google Scholar 

  8. Schee K, Fodstad O, Flatmark K (2010) MicroRNAs as biomarkers in colorectal cancer. Am J Pathol 177(4):1592–1599

    Article  PubMed  CAS  Google Scholar 

  9. Wang P, Zou F, Zhang X et al (2009) microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res 69(20):8157–8165

    Article  PubMed  CAS  Google Scholar 

  10. Schetter AJ, Leung SY, Sohn JJ et al (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299(4):425–436

    Article  PubMed  CAS  Google Scholar 

  11. Nagel R, le Sage C, Diosdado B et al (2008) Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res 68(14):5795–5802

    Article  PubMed  CAS  Google Scholar 

  12. Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120(5):635–647

    Article  PubMed  CAS  Google Scholar 

  13. Hurst DR, Edmonds MD, Welch DR (2009) Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res 69(19):7495–7498

    Article  PubMed  CAS  Google Scholar 

  14. Asangani IA, Rasheed SA, Nikolova DA et al (2008) MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27(15):2128–2136

    Article  PubMed  CAS  Google Scholar 

  15. Tavazoie SF, Alarcon C, Oskarsson T et al (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451(7175):147–152

    Article  PubMed  CAS  Google Scholar 

  16. Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449(7163):682–688

    Article  PubMed  CAS  Google Scholar 

  17. Zhang W, Winder T, Ning Y et al (2011) A let-7 microRNA-binding site polymorphism in 3′-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy. Ann Oncol 22(1):104–109

    Article  PubMed  CAS  Google Scholar 

  18. King CE, Wang L, Winograd R et al (2011) LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene 30(40):4185–4193

    Article  PubMed  CAS  Google Scholar 

  19. Rossi L, Bonmassar E, Faraoni I (2007) Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro. Pharmacol Res 56(3):248–253

    Article  PubMed  CAS  Google Scholar 

  20. Peltier HJ, Latham GJ (2008) Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. RNA 14(5):844–852

    Article  PubMed  CAS  Google Scholar 

  21. Chang GJ, Rodriguez-Bigas MA, Skibber JM et al (2007) Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst 99(6):433–441

    Article  PubMed  Google Scholar 

  22. Negrini M, Calin GA (2008) Breast cancer metastasis: a microRNA story. Breast Cancer Res 10(2):203

    Article  PubMed  Google Scholar 

  23. Slaby O, Svoboda M, Fabian P et al (2007) Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 72(5–6):397–402

    Article  PubMed  CAS  Google Scholar 

  24. Meng F, Henson R, Lang M et al (2006) Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 130(7):2113–2129

    Article  PubMed  CAS  Google Scholar 

  25. De Roock W, Jonker DJ, Di Nicolantonio F et al (2010) Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304(16):1812–1820

    Article  PubMed  Google Scholar 

  26. Chin LJ, Ratner E, Leng S et al (2008) A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk. Cancer Res 68(20):8535–8540

    Article  PubMed  CAS  Google Scholar 

  27. Christensen BC, Moyer BJ, Avissar M et al (2009) A let-7 microRNA-binding site polymorphism in the KRAS 3′ UTR is associated with reduced survival in oral cancers. Carcinogenesis 30(6):1003–1007

    Article  PubMed  CAS  Google Scholar 

  28. Koga Y, Yasunaga M, Takahashi A et al (2010) MicroRNA expression profiling of exfoliated colonocytes isolated from feces for colorectal cancer screening. Cancer Prev Res (Phila) 3(11):1435–1442

    Article  Google Scholar 

  29. Song G, Zhang Y, Wang L (2009) MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation. J Biol Chem 284(46):31921–31927

    Article  PubMed  CAS  Google Scholar 

  30. Adams BD, Cowee DM, White BA (2009) The role of miR-206 in the epidermal growth factor (EGF) induced repression of estrogen receptor-alpha (ERalpha) signaling and a luminal phenotype in MCF-7 breast cancer cells. Mol Endocrinol 23(8):1215–1230

    Article  PubMed  CAS  Google Scholar 

  31. Yan D, Dong Xda E, Chen X et al (2009) MicroRNA-1/206 targets c-Met and inhibits rhabdomyosarcoma development. J Biol Chem 284(43):29596–29604

    Article  PubMed  CAS  Google Scholar 

  32. Gabriely G, Wurdinger T, Kesari S et al (2008) MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28(17):5369–5380

    Article  PubMed  CAS  Google Scholar 

  33. Zhang JG, Wang JJ, Zhao F et al (2010) MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta 411(11–12):846–852

    Article  PubMed  CAS  Google Scholar 

  34. Zhu S, Si ML, Wu H et al (2007) MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282(19):14328–14336

    Article  PubMed  CAS  Google Scholar 

  35. Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532

    Article  PubMed  CAS  Google Scholar 

  36. Hu X, Schwarz JK, Lewis JS Jr et al (2010) A microRNA expression signature for cervical cancer prognosis. Cancer Res 70(4):1441–1448

    Article  PubMed  CAS  Google Scholar 

  37. Hu Z, Chen X, Zhao Y et al (2010) Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol 28(10):1721–1726

    Article  PubMed  Google Scholar 

  38. Juan D, Alexe G, Antes T et al (2010) Identification of a microRNA panel for clear-cell kidney cancer. Urology 75(4):835–841

    Article  PubMed  Google Scholar 

  39. Li X, Zhang Y, Ding J et al (2010) Survival prediction of gastric cancer by a seven-microRNA signature. Gut 59(5):579–585

    Article  PubMed  CAS  Google Scholar 

  40. Yanaihara N, Caplen N, Bowman E et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3):189–198

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Research support from the Canadian Institute of Health Research (J.D.), the Ontario Institute for Cancer Research (J.D.) and Ortho-Biotech Canada (J.D.) is greatly appreciated. The authors would like to thank Ms. Colleen Crane for her technical support. Presented in part at the 2010 European Society of Medical Oncology Meeting, Milan, Italy.

Conflict of Interest

All authors declare no conflict of interests with respect to the contents of this manuscript.

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Author notes

  1. Michael M. Vickers

    Present address: Department of Oncology, Tom Baker Cancer Centre, 1331 29th Street, NW, Calgary, AB, T2N 4N2, Canada

Authors and Affiliations

  1. Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 503 Smyth Road, Third Floor, Ottawa, ON, K1H 1C4, Canada

    Michael M. Vickers, Jair Bar, Ivan Gorn-Hondermann, Manijeh Daneshmand, Jennifer E. L. Hanson, Christina L. Addison, Ian A. J. Lorimer & Jim Dimitroulakos

  2. Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada

    Michael M. Vickers, Jair Bar, Nirit Yarom, Timothy R. Asmis, Derek J. Jonker, Jean Maroun & Glenwood D. Goss

  3. Department of Medicine, University of Ottawa, Ottawa, ON, Canada

    Christina L. Addison, Timothy R. Asmis, Derek J. Jonker, Jean Maroun, Ian A. J. Lorimer, Glenwood D. Goss & Jim Dimitroulakos

  4. Department Biochemistry, University of Ottawa, Ottawa, ON, Canada

    Christina L. Addison, Ian A. J. Lorimer & Jim Dimitroulakos

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  1. Michael M. Vickers
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Corresponding author

Correspondence to Jim Dimitroulakos.

Additional information

First two authors contributed equally to this study.

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Vickers, M.M., Bar, J., Gorn-Hondermann, I. et al. Stage-dependent differential expression of microRNAs in colorectal cancer: potential role as markers of metastatic disease. Clin Exp Metastasis 29, 123–132 (2012). https://doi.org/10.1007/s10585-011-9435-3

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  • DOI: https://doi.org/10.1007/s10585-011-9435-3

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