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Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma

Abstract

MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.

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References

  1. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  2. Dong JT . Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev 2001; 20: 173–193.

    Article  CAS  Google Scholar 

  3. Testa JR, Liu Z, Feder M, Bell DW, Balsara B, Cheng JQ et al. Advances in the analysis of chromosome alterations in human lung carcinomas. Cancer Genet Cytogenet 1997; 95: 20–32.

    Article  CAS  Google Scholar 

  4. Sato M, Takahashi K, Nagayama K, Arai Y, Ito N, Okada M et al. Identification of chromosome arm 9p as the most frequent target of homozygous deletions in lung cancer. Genes Chromosomes Cancer 2005; 44: 405–414.

    Article  CAS  Google Scholar 

  5. Kohno T, Yokota J . Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: deduction from structural analysis of breakpoints for deletions. DNA Repair (Amst) 2006; 5: 1273–1281.

    Article  CAS  Google Scholar 

  6. Sasaki S, Kitagawa Y, Sekido Y, Minna JD, Kuwano H, Yokota J et al. Molecular processes of chromosome 9p21 deletions in human cancers. Oncogene 2003; 22: 3792–3798.

    Article  CAS  Google Scholar 

  7. Gursky S, Olopade OI, Rowley JD . Identification of a 1.2 Kb cDNA fragment from a region on 9p21 commonly deleted in multiple tumor types. Cancer Genet Cytogenet 2001; 129: 93–101.

    Article  CAS  Google Scholar 

  8. Bartel DP . MicroRNAs: target recognition and regulatory functions. Cell 2009; 136: 215–233.

    Article  CAS  Google Scholar 

  9. Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.

    Article  CAS  Google Scholar 

  10. Nakano H, Miyazawa T, Kinoshita K, Yamada Y, Yoshida T . Functional screening identifies a microRNA, miR-491 that induces apoptosis by targeting Bcl-X(L) in colorectal cancer cells. Int J Cancer 2010; 127: 1072–1080.

    Article  CAS  Google Scholar 

  11. Yan W, Zhang W, Sun L, Liu Y, You G, Wang Y et al. Identification of MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiforme. Brain Res 2011; 1411: 108–115.

    Article  CAS  Google Scholar 

  12. Parker BC, Annala MJ, Cogdell DE, Granberg KJ, Sun Y, Ji P et al. The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma. J Clin Invest 2013; 123: 855–865.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Moore LM, Kivinen V, Liu Y, Annala M, Cogdell D, Liu X et al. Transcriptome and small RNA deep sequencing reveals deregulation of miRNA biogenesis in human glioma. J Pathol 2013; 229: 449–459.

    Article  CAS  Google Scholar 

  14. Fuxe J, Akusjarvi G, Goike HM, Roos G, Collins VP, Pettersson RF . Adenovirus-mediated overexpression of p15INK4B inhibits human glioma cell growth, induces replicative senescence, and inhibits telomerase activity similarly to p16INK4A. Cell Growth Differ 2000; 11: 373–384.

    CAS  PubMed  Google Scholar 

  15. Kim BN, Yamamoto H, Ikeda K, Damdinsuren B, Sugita Y, Ngan CY et al. Methylation and expression of p16INK4 tumor suppressor gene in primary colorectal cancer tissues. Int J Oncol 2005; 26: 1217–1226.

    CAS  PubMed  Google Scholar 

  16. Zhang W, Fuller G . IGFBP2 as a brain tumor oncogene. Cancer Biol Ther 2007; 6: 995–996.

    Article  Google Scholar 

  17. Fukushima T, Tezuka T, Shimomura T, Nakano S, Kataoka H . Silencing of insulin-like growth factor-binding protein-2 in human glioblastoma cells reduces both invasiveness and expression of progression-associated gene CD24. J Biol Chem 2007; 282: 18634–18644.

    Article  CAS  Google Scholar 

  18. Lee EJ, Mircean C, Shmulevich I, Wang H, Liu J, Niemisto A et al. Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion. Mol Cancer 2005; 4: 7.

    Article  Google Scholar 

  19. Wang H, Wang H, Shen W, Huang H, Hu L, Ramdas L et al. Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res 2003; 63: 4315–4321.

    CAS  PubMed  Google Scholar 

  20. Das S, Srikanth M, Kessler JA . Cancer stem cells and glioma. Nat Clin Pract Neurol 2008; 4: 427–435.

    Article  CAS  Google Scholar 

  21. Hsieh D, Hsieh A, Stea B, Ellsworth R . IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochem Biophys Res Commun 2010; 397: 367–372.

    Article  CAS  Google Scholar 

  22. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006; 9: 391–403.

    Article  CAS  Google Scholar 

  23. Griffero F, Daga A, Marubbi D, Capra MC, Melotti A, Pattarozzi A et al. Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors. J Biol Chem 2009; 284: 7138–7148.

    Article  CAS  Google Scholar 

  24. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63: 5821–5828.

    CAS  Google Scholar 

  25. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.

    Article  CAS  Google Scholar 

  26. Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN et al. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci USA 2007; 104: 11736–11741.

    Article  CAS  Google Scholar 

  27. Jin X, Yin J, Kim SH, Sohn YW, Beck S, Lim YC et al. EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res 2011; 71: 7125–7134.

    Article  CAS  Google Scholar 

  28. Mirimanoff RO . High-grade gliomas: reality and hopes. Chin J Cancer 2014; 33: 1–3.

    Article  CAS  Google Scholar 

  29. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010; 17: 98–110.

    Article  CAS  Google Scholar 

  30. Cancer Genome Atlas Research N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455: 1061–1068.

    Article  Google Scholar 

  31. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004; 22: 133–142.

    Article  CAS  Google Scholar 

  32. Hegi ME, Diserens AC, Bady P, Kamoshima Y, Kouwenhoven MC, Delorenzi M et al. Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib—a phase II trial. Mol Cancer Ther 2011; 10: 1102–1112.

    Article  CAS  Google Scholar 

  33. Moore LM, Holmes KM, Smith SM, Wu Y, Tchougounova E, Uhrbom L et al. IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas. Proc Natl Acad Sci USA 2009; 106: 16675–16679.

    Article  CAS  Google Scholar 

  34. Wang GK, Hu L, Fuller GN, Zhang W . An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility. J Biol Chem 2006; 281: 14085–14091.

    Article  CAS  Google Scholar 

  35. Png KJ, Halberg N, Yoshida M, Tavazoie SF . A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 2012; 481: 190–194.

    Article  CAS  Google Scholar 

  36. Feng J, Kim ST, Liu W, Kim JW, Zhang Z, Zhu Y et al. An integrated analysis of germline and somatic, genetic and epigenetic alterations at 9p21.3 in glioblastoma. Cancer 2012; 118: 232–240.

    Article  CAS  Google Scholar 

  37. Holmes KM, Annala M, Chua CY, Dunlap SM, Liu Y, Hugen N et al. Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-kappaB network. Proc Natl Acad Sci USA 2012; 109: 3475–3480.

    Article  CAS  Google Scholar 

  38. Brockschmidt A, Trost D, Peterziel H, Zimmermann K, Ehrler M, Grassmann H et al. KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas. Brain 2012; 135: 1027–1041.

    Article  Google Scholar 

  39. Soeda A, Inagaki A, Oka N, Ikegame Y, Aoki H, Yoshimura S et al. Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem 2008; 283: 10958–10966.

    Article  CAS  Google Scholar 

  40. Ayuso-Sacido A, Moliterno JA, Kratovac S, Kapoor GS, O'Rourke DM, Holland EC et al. Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells. J Neurooncol 2010; 97: 323–337.

    Article  CAS  Google Scholar 

  41. Beukelaers P, Vandenbosch R, Caron N, Nguyen L, Belachew S, Moonen G et al. Cdk6-dependent regulation of G(1) length controls adult neurogenesis. Stem Cells 2011; 29: 713–724.

    Article  CAS  Google Scholar 

  42. Zhou Z, Sun L, Wang Y, Wu Z, Geng J, Miu W et al. Bone morphogenetic protein 4 inhibits cell proliferation and induces apoptosis in glioma stem cells. Cancer Biother Radiopharm 2011; 26: 77–83.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  44. Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D et al. microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 2010; 9: 1031–1036.

    Article  CAS  Google Scholar 

  45. Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, Dugas JC, Gill RM, Huillard E et al. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 2012; 31: 1884–1895.

    Article  CAS  Google Scholar 

  46. Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M et al. microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res 2008; 68: 3566–3572.

    Article  CAS  Google Scholar 

  47. Hai C, Jin YM, Jin WB, Han ZZ, Cui MN, Piao XZ et al. Application of mesenchymal stem cells as a vehicle to deliver replication-competent adenovirus for treating malignant glioma. Chin J Cancer 2012; 31: 233–240.

    Article  CAS  Google Scholar 

  48. Bexell D, Svensson A, Bengzon J . Stem cell-based therapy for malignant glioma. Cancer Treat Rev 2013; 39: 358–365.

    Article  CAS  Google Scholar 

  49. Yin J, Kim JK, Moon JH, Beck S, Piao D, Jin X et al. hMSC-mediated concurrent delivery of endostatin and carboxylesterase to mouse xenografts suppresses glioma initiation and recurrence. Mol Ther 2011; 19: 1161–1169.

    Article  CAS  Google Scholar 

  50. Hwang do W, Son S, Jang J, Youn H, Lee S, Lee D et al. A brain-targeted rabies virus glycoprotein-disulfide linked PEI nanocarrier for delivery of neurogenic microRNA. Biomaterials 2011; 32: 4968–4975.

    Article  Google Scholar 

  51. Jiang H, Gomez-Manzano C, Aoki H, Alonso MM, Kondo S, McCormick F et al. Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J Natl Cancer Inst 2007; 99: 1410–1414.

    Article  CAS  Google Scholar 

  52. He H, Nilsson CL, Emmett MR, Marshall AG, Kroes RA, Moskal JR et al. Glycomic and transcriptomic response of GSC11 glioblastoma stem cells to STAT3 phosphorylation inhibition and serum-induced differentiation. J Proteome Res 2010; 9: 2098–2108.

    Article  CAS  Google Scholar 

  53. Chao DT, Linette GP, Boise LH, White LS, Thompson CB, Korsmeyer SJ . Bcl-XL and Bcl-2 repress a common pathway of cell death. J Exp Med 1995; 182: 821–828.

    Article  CAS  Google Scholar 

  54. van den Heuvel S, Harlow E . Distinct roles for cyclin-dependent kinases in cell cycle control. Science 1993; 262: 2050–2054.

    Article  CAS  Google Scholar 

  55. Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G et al. Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res 2007; 67: 11612–11620.

    Article  CAS  Google Scholar 

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Acknowledgements

We appreciate Xinna Zhang at the MicroRNA Core Facility for help with miRNA hybridization experiments, Zhimin Lu at the Department of Neuro-Oncology-Research for helpful comments, and Kathryn L Hale at the Department of Scientific Publications at MD Anderson Cancer Center for manuscript editing. This work was supported by grants from the National Institutes of Health (CA098503 to WZ and IS, CA141432 and CA143835 to WZ and CA115729 and CA127001 to FFL), IVY, Elias and Broach Foundations, the Gene Pennebaker Brain Cancer Fund, and the Academy of Finland (grant 259038 to KG); Xia Li was supported by a fellowship from The Fourth Military Medical University (4138C4IA1Z). Lynette Moore was supported by a fellowship from the American Cancer Society.

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Li, X., Liu, Y., Granberg, K. et al. Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma. Oncogene 34, 1619–1628 (2015). https://doi.org/10.1038/onc.2014.98

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