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MiR-135a functions as a selective killer of malignant glioma

Abstract

Glioma is the most common and fatal primary brain tumor. Thus far, therapeutic strategies to efficiently and specifically antagonize glioma are limited and poorly developed. Here we report that glia-enriched miR-135a, a microRNA that is dramatically downregulated in malignant glioma and correlated with the pathological grading, is capable of inducing mitochondria-dependent apoptosis of malignant glioma by regulating various genes including STAT6, SMAD5 and BMPR2, as well as affecting the signaling pathway downstream. Moreover, this lethal effect is selectively towards malignant glioma cells, but not neurons and glial cells, through a novel mechanism. Our findings suggest an important role of miR-135a in glioma etiology and provide a potential candidate for malignant glioma therapy.

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References

  • Altieri DC . (2008). Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8: 61–70.

    Article  CAS  Google Scholar 

  • Beduneau A, Saulnier P, Benoit JP . (2007). Active targeting of brain tumors using nanocarriers. Biomaterials 28: 4947–4967.

    Article  CAS  Google Scholar 

  • Bomben VC, Sontheimer H . (2010). Disruption of transient receptor potential canonical channel 1 causes incomplete cytokinesis and slows the growth of human malignant gliomas. Glia 58: 1145–1156.

    Article  Google Scholar 

  • Budihardjo I, Oliver H, Lutter M, Luo X, Wang XD . (1999). Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Bi 15: 269–290.

    Article  CAS  Google Scholar 

  • Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C et al. (2007). Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67: 2456–2468.

    Article  CAS  Google Scholar 

  • Girard M, Jacquemin E, Munnich A, Lyonnet S, Henrion-Caude A . (2008). miR-122, a paradigm for the role of microRNAs in the liver. J Hepatol 48: 648–656.

    Article  CAS  Google Scholar 

  • Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G et al. (2008). Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 68: 9125–9130.

    Article  CAS  Google Scholar 

  • Hammell CM, Lubin I, Boag PR, Blackwell TK, Ambros V . (2009). nhl-2 modulates microRNA activity in Caenorhabditis elegans. Cell 136: 926–938.

    Article  CAS  Google Scholar 

  • Hsu SD, Chu CH, Tsou AP, Chen SJ, Chen HC, Hsu PW et al. (2008). miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes. Nucleic Acids Res 36: D165–D169.

    Article  CAS  Google Scholar 

  • Jiang Q, Wang Y, Hao Y, Juan L, Teng M, Zhang X et al. (2009). miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Res 37: D98–D104.

    Article  CAS  Google Scholar 

  • Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP et al. (2009). Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 36: 487–499.

    Article  CAS  Google Scholar 

  • Kota J, Chivukula RR, O'Donnell KA, Wentzel EA, Montgomery CL, Hwang HW et al. (2009). Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137: 1005–1017.

    Article  CAS  Google Scholar 

  • Kumar B, Hovland AR, Prasad JE, Clarkson E, Cole WC, Nahreini P et al. (2001). Establishment of human embryonic brain cell lines. In Vitro Cell Dev Biol Anim 37: 259–262.

    Article  CAS  Google Scholar 

  • Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T . (2002). Identification of tissue-specific microRNAs from mouse. Curr Biol 12: 735–739.

    Article  CAS  Google Scholar 

  • Lewis BP, Burge CB, Bartel DP . (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

    Article  CAS  Google Scholar 

  • Li KK, Pang JC, Ching AK, Wong CK, Kong X, Wang Y et al. (2009). miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1. Hum Pathol 40: 1234–1243.

    Article  CAS  Google Scholar 

  • Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM et al. (2008). A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A 105: 13906–13911.

    Article  CAS  Google Scholar 

  • Lim M, Zhong C, Yang S, Bell AM, Cohen MB, Roy-Burman P . (2010). Runx2 regulates survivin expression in prostate cancer cells. Lab Invest 90: 222–233.

    Article  CAS  Google Scholar 

  • Liu Z, Shen J, Pu K, Katus HA, Ploger F, Tiefenbacher CP et al. (2009). GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. Biochim Biophys Acta 1793: 1819–1827.

    Article  CAS  Google Scholar 

  • Malzkorn B, Wolter M, Liesenberg F, Grzendowski M, Stuhler K, Meyer HE et al. (2010). Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. Brain Pathol 20: 539–550.

    Article  CAS  Google Scholar 

  • Maragkakis M, Reczko M, Simossis VA, Alexiou P, Papadopoulos GL, Dalamagas T et al. (2009). DIANA-microT web server: elucidating microRNA functions through target prediction. Nucleic Acids Res 37(Suppl. S): W273–W276.

    Article  CAS  Google Scholar 

  • Masuda A, Matsuguchi T, Yamaki K, Hayakawa T, Yoshikai Y . (2001). Interleukin-15 prevents mouse mast cell apoptosis through STAT6-mediated Bcl-xL expression. J Biol Chem 276: 26107–26113.

    Article  CAS  Google Scholar 

  • Nagel R, le Sage C, Diosdado B, van der Waal M, Oude VJ, Bolijn A et al. (2008). Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer. Cancer Res 68: 5795–5802.

    Article  CAS  Google Scholar 

  • Nahreini P, Andreatta C, Kumar B, Hanson A, Edwards-Prasad J, Freed CR et al. (2003). Distinct patterns of gene expression induced by viral oncogenes in human embryonic brain cells. Cell Mol Neurobiol 23: 27–42.

    Article  CAS  Google Scholar 

  • Navarro A, Diaz T, Martinez A, Gaya A, Pons A, Gel B et al. (2009). Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma. Blood 114: 2945–2951.

    Article  CAS  Google Scholar 

  • Nilsen TW . (2007). Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet 23: 243–249.

    Article  CAS  Google Scholar 

  • Rebholz-Schuhmann D, Kirsch H, Arregui M, Gaudan S, Riethoven M, Stoehr P . (2007). EBIMed—text crunching to gather facts for proteins from medline. Bioinformatics 23: e237–e244.

    Article  CAS  Google Scholar 

  • Ritchie W, Flamant S, Rasko JE . (2010). mimiRNA: a microRNA expression profiler and classification resource designed to identify functional correlations between microRNAs and their targets. Bioinformatics 26: 223–227.

    Article  CAS  Google Scholar 

  • Schwamborn JC, Berezikov E, Knoblich JA . (2009). The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 136: 913–925.

    Article  CAS  Google Scholar 

  • Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M et al. (2008). miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6: 14.

    Article  Google Scholar 

  • Siomi H, Siomi MC . (2010). Posttranscriptional regulation of microRNA biogenesis in animals. Mol Cell 38: 323–332.

    Article  CAS  Google Scholar 

  • Sun Y, Zhou J, Liao X, Lu Y, Deng C, Huang P et al. (2005). Disruption of Smad5 gene induces mitochondria-dependent apoptosis in cardiomyocytes. Exp Cell Res 306: 85–93.

    Article  CAS  Google Scholar 

  • Wen PY, Kesari S . (2008). Malignant gliomas in adults. N Engl J Med 359: 492–507.

    Article  CAS  Google Scholar 

  • Wurster AL, Rodgers VL, White MF, Rothstein TL, Grusby MJ . (2002). Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL. J Biol Chem 277: 27169–27175.

    Article  CAS  Google Scholar 

  • Yang S, Lim M, Pham LK, Kendall SE, Reddi AH, Altieri DC et al. (2006). Bone morphogenetic protein 7 protects prostate cancer cells from stress-induced apoptosis via both Smad and c-Jun NH2-terminal kinase pathways. Cancer Res 66: 4285–4290.

    Article  CAS  Google Scholar 

  • Yang YL, Li XM . (2000). The IAP family: endogenous caspase inhibitors with multiple biological activities. Cell Res 10: 169–177.

    Article  CAS  Google Scholar 

  • Zhang WJ, Li BH, Yang XZ, Li PD, Yuan Q, Liu XH et al. (2008). IL-4-induced Stat6 activities affect apoptosis and gene expression in breast cancer cells. Cytokine 42: 39–47.

    Article  CAS  Google Scholar 

  • Zhang Y, Chao T, Li R, Liu W, Chen Y, Yan X et al. (2009). MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med 87: 43–51.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Key program, National Natural Science Foundation of China (No. 30830111), Guangzhou Scientific and Technological program (No. 2008Z1-E561) and Guangdong Natural Science Foundation (No. S2011040004371).

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Correspondence to G Yan.

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Wu, S., Lin, Y., Xu, D. et al. MiR-135a functions as a selective killer of malignant glioma. Oncogene 31, 3866–3874 (2012). https://doi.org/10.1038/onc.2011.551

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