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C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition

Abstract

Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients’ samples and by in silico analysis on an independent patient cohort from Taylor’s platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients’ risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring.

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References

  1. Haas GP, Delongchamps N, Brawley OW, Wang CY, de la Roza G . The worldwide epidemiology of prostate cancer: perspectives from autopsy studies. Can J Urol 2008; 15: 3866–3871.

    PubMed  PubMed Central  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–130.

    Article  PubMed  Google Scholar 

  3. Isaacs JT, Coffey DS . Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. Cancer Res 1981; 41 (12 Pt 1): 5070–5075.

    CAS  PubMed  Google Scholar 

  4. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–1197.

    CAS  Article  PubMed  Google Scholar 

  6. Balk SP . Androgen receptor as a target in androgen-independent prostate cancer. Urology 2002; 60 (3 Suppl 1): 132–138; discussion 138–139.

    Article  PubMed  Google Scholar 

  7. Feldman BJ, Feldman D . The development of androgen-independent prostate cancer. Nat Rev Cancer 2001; 1: 34–45.

    CAS  Article  PubMed  Google Scholar 

  8. Gelmann EP . Molecular biology of the androgen receptor. J Clin Oncol 2002; 20: 3001–3015.

    CAS  Article  PubMed  Google Scholar 

  9. Matias PM, Carrondo MA, Coelho R, Thomaz M, Zhao XY, Wegg A et al. Structural basis for the glucocorticoid response in a mutant human androgen receptor (AR(ccr)) derived from an androgen-independent prostate cancer. J Med Chem 2002; 45: 1439–1446.

    CAS  Article  PubMed  Google Scholar 

  10. Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 1999; 59: 2511–2515.

    CAS  PubMed  Google Scholar 

  11. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995; 332: 1393–1398.

    CAS  Article  PubMed  Google Scholar 

  12. Taplin ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol 2003; 21: 2673–2678.

    CAS  Article  PubMed  Google Scholar 

  13. Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 1990; 173: 534–540.

    CAS  Article  PubMed  Google Scholar 

  14. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C et al. in vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995; 9: 401–406.

    CAS  Article  PubMed  Google Scholar 

  15. Craft N, Shostak Y, Carey M, Sawyers CL . A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 1999; 5: 280–285.

    CAS  Article  PubMed  Google Scholar 

  16. Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD et al. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem 2002; 277: 29304–29314.

    CAS  Article  PubMed  Google Scholar 

  17. Gregory CW, Johnson Jr RT, Mohler JL, French FS, Wilson EM . Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 2001; 61: 2892–2898.

    CAS  PubMed  Google Scholar 

  18. Li P, Yu X, Ge K, Melamed J, Roeder RG, Wang Z . Heterogeneous expression and functions of androgen receptor co-factors in primary prostate cancer. Am J Pathol 2002; 161: 1467–1474.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Brawn PN, Speights VO . The dedifferentiation of metastatic prostate carcinoma. Br J Cancer 1989; 59: 85–88.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin Mar-Apr 61: 69–90.

    Google Scholar 

  21. Maeda A, Nakashiro K, Hara S, Sasaki T, Miwa Y, Tanji N et al. Inactivation of AR activates HGF/c-Met system in human prostatic carcinoma cells. Biochem Biophys Res Commun 2006; 347: 1158–1165.

    CAS  Article  PubMed  Google Scholar 

  22. Verras M, Lee J, Xue H, Li TH, Wang Y, Sun Z . The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res 2007; 67: 967–975.

    CAS  Article  PubMed  Google Scholar 

  23. Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 2008; 14: 1271–1277.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  25. Esquela-Kerscher A, Slack FJ . Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006; 6: 259–269.

    CAS  Article  PubMed  Google Scholar 

  26. Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A et al. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med Jan 18: 74–82.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM et al. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci USA 2008; 105: 12182–12187.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Tilley WD, Wilson CM, Marcelli M, McPhaul MJ . Androgen receptor gene expression in human prostate carcinoma cell lines. Cancer Res 1990; 50: 5382–5386.

    CAS  PubMed  Google Scholar 

  29. Knudsen BS, Edlund M . Prostate cancer and the met hepatocyte growth factor receptor. Adv Cancer Res 2004; 91: 31–67.

    CAS  Article  PubMed  Google Scholar 

  30. Nguyen HM, Ruppender N, Zhang X, Brown LG, Gross TS, Morrissey C et al. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling. PloS One 2013; 8: e78881.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Varkaris A, Corn PG, Gaur S, Dayyani F, Logothetis CJ, Gallick GE . The role of HGF/c-Met signaling in prostate cancer progression and c-Met inhibitors in clinical trials. Expert Opin Investig Drugs 2011; 20: 1677–1684.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Verhoef EI, Kolijn K, De Herdt MJ, van der Steen B, Hoogland AM, Sleddens HF et al. MET expression during prostate cancer progression. Oncotarget 2016; 7: 31029–31036.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11–22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Dean M, Park M, Kaul K, Blair D, Vande Woude GF . Activation of the met proto-oncogene in a human cell line. Haematol Blood Transfus 1987; 31: 464–468.

    CAS  PubMed  Google Scholar 

  35. Dean M, Park M, Vande Woude GF . Characterization of the rearranged tpr-met oncogene breakpoint. Mol Cell Biol 1987; 7: 921–924.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Li BL, Lu C, Lu W, Yang TT, Qu J, Hong X et al. miR-130b is an EMT-related microRNA that targets DICER1 for aggression in endometrial cancer. Med Oncol 2013; 30: 484.

    Article  PubMed  Google Scholar 

  37. Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST et al. Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open 2012; 2: e000825.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A et al. miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 2010; 7: 694–707.

    CAS  Article  PubMed  Google Scholar 

  39. Nanni S, Priolo C, Grasselli A, D'Eletto M, Merola R, Moretti F et al. Epithelial-restricted gene profile of primary cultures from human prostate tumors: a molecular approach to predict clinical behavior of prostate cancer. Mol Cancer Res 2006; 4: 79–92.

    CAS  Article  PubMed  Google Scholar 

  40. Reisinger K, Kaufmann R, Gille J . Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription. J Cell Sci 2003; 116 (Pt 2): 225–238.

    CAS  Article  PubMed  Google Scholar 

  41. Mueller C, Edmiston KH, Carpenter C, Gaffney E, Ryan C, Ward R et al. One-step preservation of phosphoproteins and tissue morphology at room temperature for diagnostic and research specimens. PloS One 2011; 6: e23780.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Pierobon M, Wulfkuhle J, Liotta L, Petricoin E . Application of molecular technologies for phosphoproteomic analysis of clinical samples. Oncogene 2015; 34: 805–814.

    CAS  Article  PubMed  Google Scholar 

  43. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci USA 2011; 108: 3713–3718.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 2014; 26: 707–721.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F et al. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J Clin Oncol 2014; 32: 768–773.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Federici G, Gao X, Slawek J, Arodz T, Shitaye A, Wulfkuhle JD et al. Systems analysis of the NCI-60 cancer cell lines by alignment of protein pathway activation modules with '-OMIC' data fields and therapeutic response signatures. Mol Cancer Res 2013; 11: 676–685.

    CAS  Article  PubMed  Google Scholar 

  47. Blyth K, Cameron ER, Neil JC . The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer 2005; 5: 376–387.

    CAS  Article  PubMed  Google Scholar 

  48. Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006; 440: 692–696.

    CAS  Article  PubMed  Google Scholar 

  49. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003; 3: 537–549.

    CAS  Article  PubMed  Google Scholar 

  50. Wang J, Loberg R, Taichman RS . The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis. Cancer Metastasis Rev 2006; 25: 573–587.

    CAS  Article  PubMed  Google Scholar 

  51. Adolfsson J . Watchful waiting and active surveillance: the current position. BJU Int 2008; 102: 10–14.

    Article  PubMed  Google Scholar 

  52. D'Amico AV, Chen MH, Roehl KA, Catalona WJ, Preoperative PSA . velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004; 351: 125–135.

    CAS  Article  PubMed  Google Scholar 

  53. D'Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen MH . Prostate specific antigen doubling time as a surrogate end point for prostate cancer specific mortality following radical prostatectomy or radiation therapy. J Urol 2004; 172 (5 Pt 2): S42–S46; discussion S6–7.

    PubMed  Google Scholar 

  54. Colangelo T, Fucci A, Votino C, Sabatino L, Pancione M, Laudanna C et al. MicroRNA-130b promotes tumor development and is associated with poor prognosis in colorectal cancer. Neoplasia 2013; 15: 1218–1231.

    Article  Google Scholar 

  55. Dong P, Karaayvaz M, Jia N, Kaneuchi M, Hamada J, Watari H et al. Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis. Oncogene 2013; 32: 3286–3295.

    CAS  Article  PubMed  Google Scholar 

  56. Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 2010; 467: 986–990.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Zhao G, Zhang JG, Shi Y, Qin Q, Liu Y, Wang B et al. MiR-130b is a prognostic marker and inhibits cell proliferation and invasion in pancreatic cancer through targeting STAT3. PloS One 2013; 8: e73803.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank Giuseppe Loreto and Tania Merlino for their technical support. We thank Alessandra Boe for cytofluorimetric analysis. This manuscript was supported by National Ministry of Health, Under-forty researcher (2012) and Italy-USA microRNA program to DB and the Italian Association for Cancer (AIRC) and Fondazione Roma funding to RDM.

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Correspondence to R De Maria or D Bonci.

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Cannistraci, A., Federici, G., Addario, A. et al. C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition. Oncogene 36, 3718–3728 (2017). https://doi.org/10.1038/onc.2016.505

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