Integrated analysis of miRNA landscape and cellular networking pathways in stage-specific prostate cancer

Autoři: Shiv Verma aff001;  Mitali Pandey aff001;  Girish C. Shukla aff003;  Vaibhav Singh aff004;  Sanjay Gupta aff001
Působiště autorů: Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH, United States of America aff001;  The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States of America aff002;  Center of Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH, United States of America aff003;  Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States of America aff004;  Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States of America aff005;  Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH, United States of America aff006;  Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States of America aff007
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224071


Dysregulation of miRNAs has been demonstrated in several human malignancies including prostate cancer. Due to tissue limitation and variable disease progression, stage-specific miRNAs changes in prostate cancer is unknown. Using chip-based microarray, we investigated global miRNA expression in human prostate cancer LNCaP, PC3, DU145 and 22Rv1 cells representing early-stage, advanced-stage and castration resistant prostate cancer in comparison with normal prostate epithelial cells. A total of 292 miRNAs were differentially expressed with 125 upregulated and 167 downregulated. These miRNAs were involved in pathways including drug resistance drug-efflux, adipogenesis, epithelial-to-mesenchymal transition, bone metamorphosis, and Th1/Th2 signaling. Regulation of miRNAs were interlinked with upstream regulators such as Argonaut 2 (AGO2), Double-Stranded RNA-Specific Endoribonuclease (DICER1), Sjogren syndrome antigen B (SSB), neurofibromatosis 2 (NF2), and peroxisome proliferator activated receptor alpha (PPARA), activated during stage-specific disease progression. Candidate target genes and pathways dysregulated in stage-specific prostate cancer were identified using CS-miRTar database and confirmed in clinical specimens. Integrative network analysis suggested some genes targeted by miRNAs include miR-17, let7g, miR-146, miR-204, miR-205, miR-221, miR-301 and miR-520 having a major effect on their dysregulation in prostate cancer. MiRNA-microarray analysis further identified miR-130a, miR-181, miR-328, miR146 and miR-200 as a panel of novel miRNAs associated with drug resistance drug-efflux and epithelial-to-mesenchymal transition in prostate cancer. Our findings provide evidence on miRNA dysregulation and its association with key functional components in stage-specific prostate cancer.

Klíčová slova:

Androgens – DU145 cells – Gene expression – Gene regulation – MicroRNAs – Prostate cancer – Prostate gland – Regulator genes


1. Brawley OW. Trends in prostate cancer in the United States. Journal of the National Cancer Institute Monographs. 2012;45:152–6. Epub 09/14. doi: 10.1093/jncimonographs/lgs035 PubMed PMID: 23271766.

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;69(1):7–34. doi: 10.3322/caac.21551 30620402

3. Loeb S, Peskoe SB, Joshu CE, Huang W-Y, Hayes RB, Carter HB, et al. Do Environmental Factors Modify the Genetic Risk of Prostate Cancer? Cancer Epidemiology Biomarkers & Prevention. 2015;24(1):213–20. doi: 10.1158/1055-9965.epi-14-0786-t 25342390

4. Pienta KJ, Bradley D. Mechanisms Underlying the Development of Androgen-Independent Prostate Cancer. Clinical Cancer Research. 2006;12(6):1665. doi: 10.1158/1078-0432.CCR-06-0067 16551847

5. Tindall DJ, Huang H, Grossmann ME. Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer. JNCI: Journal of the National Cancer Institute. 2001;93(22):1687–97. doi: 10.1093/jnci/93.22.1687 11717329

6. Brawer MK. Androgen deprivation therapy: a cornerstone in the treatment of advanced prostate cancer. Reviews in urology. 2004;6 Suppl 8(Suppl 8):S3–S9. 16985918.

7. Cinar B, Koeneman KS, Edlund M, Prins GS, Zhau HE, Chung LWK. Androgen Receptor Mediates the Reduced Tumor Growth, Enhanced Androgen Responsiveness, and Selected Target Gene Transactivation in a Human Prostate Cancer Cell Line. Cancer Research. 2001;61(19):7310. 11585771

8. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32(49):5501–11. Epub 06/10. doi: 10.1038/onc.2013.206 23752182.

9. Nevedomskaya E, Baumgart SJ, Haendler B. Recent Advances in Prostate Cancer Treatment and Drug Discovery. International journal of molecular sciences. 2018;19(5):1359. doi: 10.3390/ijms19051359 29734647.

10. Macfarlane L-A, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Current genomics. 2010;11(7):537–61. doi: 10.2174/138920210793175895 21532838.

11. Wei JS, Johansson P, Chen Q-R, Song YK, Durinck S, Wen X, et al. microRNA profiling identifies cancer-specific and prognostic signatures in pediatric malignancies. Clinical cancer research: an official journal of the American Association for Cancer Research. 2009;15(17):5560–8. Epub 08/25. doi: 10.1158/1078-0432.CCR-08-3287 19706822.

12. Tang W, Wan S, Yang Z, Teschendorff AE, Zou Q. Tumor origin detection with tissue-specific miRNA and DNA methylation markers. Bioinformatics. 2017;34(3):398–406. doi: 10.1093/bioinformatics/btx622 29028927

13. Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67(13):6130–5. Epub 2007/07/10. doi: 10.1158/0008-5472.CAN-07-0533 17616669.

14. Macha MA, Seshacharyulu P, Krishn SR, Pai P, Rachagani S, Jain M, et al. MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers. Current pharmaceutical design. 2014;20(33):5287–97. doi: 10.2174/1381612820666140128213117 24479799.

15. Lan H, Lu H, Wang X, Jin H. MicroRNAs as potential biomarkers in cancer: opportunities and challenges. BioMed research international. 2015;2015:125094–. Epub 03/22. doi: 10.1155/2015/125094 25874201.

16. Singh S, Zheng Y, Jagadeeswaran G, Ebron JS, Sikand K, Gupta S, et al. Deep sequencing of small RNA libraries from human prostate epithelial and stromal cells reveal distinct pattern of microRNAs primarily predicted to target growth factors. Cancer Lett. 2016;371(2):262–73. Epub 2015/12/15. doi: 10.1016/j.canlet.2015.10.038 26655274.

17. Zhau HYE, Chang S-M, Chen B-Q, Wang Y, Zhang H, Kao C, et al. Androgen-repressed phenotype in human prostate cancer. Proceedings of the National Academy of Sciences. 1996;93(26):15152–7. doi: 10.1073/pnas.93.26.15152 8986779

18. Tai S, Sun Y, Squires JM, Zhang H, Oh WK, Liang C-Z, et al. PC3 is a cell line characteristic of prostatic small cell carcinoma. The Prostate. 2011;71(15):1668–79. Epub 03/22. doi: 10.1002/pros.21383 21432867.

19. Stone KR, Mickey DD, Wunderli H, Mickey GH, Paulson DF. Isolation of a human prostate carcinoma cell line (DU 145). Int J Cancer. 1978;21(3):274–81. Epub 1978/03/15. doi: 10.1002/ijc.2910210305 631930.

20. Sramkoski RM, Pretlow TG 2nd, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 1999;35(7):403–9. Epub 1999/08/26. doi: 10.1007/s11626-999-0115-4 10462204.

21. Wu WS, Tu BW, Chen TT, Hou SW, Tseng JT. CSmiRTar: Condition-Specific microRNA targets database. PLoS One. 2017;12(7):e0181231. Epub 2017/07/14. doi: 10.1371/journal.pone.0181231 28704505; PubMed Central PMCID: PMC5509330.

22. Kolluru V, Chandrasekaran B, Tyagi A, Dervishi A, Ankem M, Yan X, et al. miR-301a expression: Diagnostic and prognostic marker for prostate cancer. Urol Oncol. 2018;36(11):503.e9–.e15. Epub 2018/09/10. doi: 10.1016/j.urolonc.2018.07.014 30195463.

23. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cellular and molecular life sciences: CMLS. 2008;65(10):1566–84. doi: 10.1007/s00018-008-7440-8 18259690.

24. van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, et al. Molecular characterization of human prostate carcinoma cell lines. Prostate. 2003;57(3):205–25. Epub 2003/10/01. doi: 10.1002/pros.10290 14518029.

25. Traish AM, Morgentaler A. Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth. Br J Cancer. 2009;101(12):1949–56. Epub 2009/11/06. doi: 10.1038/sj.bjc.6605376 19888222; PubMed Central PMCID: PMC2795439.

26. Gan Y, Shi C, Inge L, Hibner M, Balducci J, Huang Y. Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells. Oncogene. 2010;29(35):4947–58. Epub 2010/06/22. doi: 10.1038/onc.2010.240 20562913.

27. Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers. 2017;9(5):52. doi: 10.3390/cancers9050052 28513565.

28. Damodaran C, Das TP, Papu John AMS, Suman S, Kolluru V, Morris TJ, et al. miR-301a expression: A prognostic marker for prostate cancer. Urologic oncology. 2016;34(8):336.e13–.e3.36E20. Epub 04/26. doi: 10.1016/j.urolonc.2016.03.009 27133223.

29. Xu B, Huang Y, Niu X, Tao T, Jiang L, Tong N, et al. Hsa-miR-146a-5p modulates androgen-independent prostate cancer cells apoptosis by targeting ROCK1. Prostate. 2015;75(16):1896–903. Epub 2015/08/27. doi: 10.1002/pros.23068 26306811.

30. Xu B, Wang N, Wang X, Tong N, Shao N, Tao J, et al. MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer. Prostate. 2012;72(11):1171–8. Epub 2011/12/14. doi: 10.1002/pros.22466 22161865.

31. Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013;335(1):201–4. Epub 2013/02/20. doi: 10.1016/j.canlet.2013.02.019 23419525; PubMed Central PMCID: PMC3665755.

32. Srivastava A, Goldberger H, Dimtchev A, Ramalinga M, Chijioke J, Marian C, et al. MicroRNA Profiling in Prostate Cancer—The Diagnostic Potential of Urinary miR-205 and miR-214. PLOS ONE. 2013;8(10):e76994. doi: 10.1371/journal.pone.0076994 24167554

33. Verdoodt B, Neid M, Vogt M, Kuhn V, Liffers ST, Palisaar RJ, et al. MicroRNA-205, a novel regulator of the anti-apoptotic protein Bcl2, is downregulated in prostate cancer. Int J Oncol. 2013;43(1):307–14. Epub 2013/04/25. doi: 10.3892/ijo.2013.1915 23612742.

34. Lin Y, Fukuchi J, Hiipakka RA, Kokontis JM, Xiang J. Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. Cell Res. 2007;17(6):531–6. Epub 2007/04/04. doi: 10.1038/cr.2007.12 17404601.

35. Suer I, Guzel E, Karatas OF, Creighton CJ, Ittmann M, Ozen M. MicroRNAs as prognostic markers in prostate cancer. The Prostate. 2019;79(3):265–71. doi: 10.1002/pros.23731 30345533

36. Sun T, Wang X, He HH, Sweeney CJ, Liu SX, Brown M, et al. MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene. 2014;33(21):2790–800. Epub 2013/06/19. doi: 10.1038/onc.2013.230 23770851; PubMed Central PMCID: PMC3883998.

37. Gui B, Hsieh CL, Kantoff PW, Kibel AS, Jia L. Androgen receptor-mediated downregulation of microRNA-221 and -222 in castration-resistant prostate cancer. PLoS One. 2017;12(9):e0184166. Epub 2017/09/09. doi: 10.1371/journal.pone.0184166 28886115; PubMed Central PMCID: PMC5590894.

38. Sun R, Fu X, Li Y, Xie Y, Mao Y. Global gene expression analysis reveals reduced abundance of putative microRNA targets in human prostate tumours. BMC Genomics. 2009;10(1):93. doi: 10.1186/1471-2164-10-93 19245699

39. Raffo AJ, Perlman H, Chen MW, Day ML, Streitman JS, Buttyan R. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res. 1995;55(19):4438–45. Epub 1995/10/01. 7671257.

40. Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, et al. Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene. 2010;29(6):811–21. Epub 2009/11/17. doi: 10.1038/onc.2009.389 19915614; PubMed Central PMCID: PMC2820596.

41. Luk SU, Xue H, Cheng H, Lin D, Gout PW, Fazli L, et al. The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis. Oncotarget. 2014;5(16):6896–908. Epub 2014/07/30. doi: 10.18632/oncotarget.2229 25071009; PubMed Central PMCID: PMC4196171.

42. Wang Z, Yuan H, Roth M, Stark JM, Bhatia R, Chen WY. SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene. 2013;32(5):589–98. Epub 2012/03/14. doi: 10.1038/onc.2012.83 22410779; PubMed Central PMCID: PMC3376246.

43. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303(5666):2011–5. Epub 2004/02/21. doi: 10.1126/science.1094637 14976264.

44. Jung-Hynes B, Nihal M, Zhong W, Ahmad N. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J Biol Chem. 2009;284(6):3823–32. Epub 2008/12/17. doi: 10.1074/jbc.M807869200 19075016; PubMed Central PMCID: PMC2635052.

45. Paolillo C, Mu Z, Rossi G, Schiewer MJ, Nguyen T, Austin L, et al. Detection of Activating Estrogen Receptor Gene (ESR1) Mutations in Single Circulating Tumor Cells. Clin Cancer Res. 2017;23(20):6086–93. Epub 2017/07/07. doi: 10.1158/1078-0432.CCR-17-1173 28679775; PubMed Central PMCID: PMC5641250.

46. Jain P, Di Croce L. Mutations and deletions of PRC2 in prostate cancer. Bioessays. 2016;38(5):446–54. Epub 2016/03/24. doi: 10.1002/bies.201500162 27000413.

47. Zhu H, Han C, Lu D, Wu T. miR-17-92 cluster promotes cholangiocarcinoma growth: evidence for PTEN as downstream target and IL-6/Stat3 as upstream activator. The American journal of pathology. 2014;184(10):2828–39. doi: 10.1016/j.ajpath.2014.06.024 25239565.

48. Li L, Shi B, Chen J, Li C, Wang S, Wang Z, et al. An E2F1/MiR-17-92 Negative Feedback Loop mediates proliferation of Mouse Palatal Mesenchymal Cells. Scientific Reports. 2017;7(1):5148. doi: 10.1038/s41598-017-05479-7 28698574

49. Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME. The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer. 2010;17(1):F19–36. Epub 2009/09/26. doi: 10.1677/ERC-09-0184 19779035.

50. Nadiminty N, Tummala R, Lou W, Zhu Y, Shi X-B, Zou JX, et al. MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. PloS one. 2012;7(3):e32832–e. doi: 10.1371/journal.pone.0032832 22479342.

51. Gottesman MM, Ambudkar SV. Overview: ABC transporters and human disease. J Bioenerg Biomembr. 2001;33(6):453–8. Epub 2002/01/24. doi: 10.1023/a:1012866803188 11804186.

52. Yang W-J, Ma P-F, Li S-P, Su H, Liu Y-J. MicroRNA-146a contributes to CD4(+) T lymphocyte differentiation in patients with thyroid ophthalmopathy. American journal of translational research. 2017;9(4):1801–9. 28469785

53. Sadeghi M, Ranjbar B, Ganjalikhany MR, M Khan F, Schmitz U, Wolkenhauer O, et al. MicroRNA and Transcription Factor Gene Regulatory Network Analysis Reveals Key Regulatory Elements Associated with Prostate Cancer Progression. PloS one. 2016;11(12):e0168760–e. doi: 10.1371/journal.pone.0168760 28005952.

Článek vyšel v časopise


2019 Číslo 11