MicroRNAs in clear cell renal cell carcinoma: biological functions and applications

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Gianluca Aguiari


MicroRNA, renal cell carcinoma, kidney cancer, VHL


MicroRNAs (miRs) are small noncoding RNAs that govern many biological processes. They frequently acquire a gain or a loss of function in cancer and hence play a causative role in the development and progression of neoplasms. They could be used as biomarkers to improve our knowledge on diagnosis, prognosis and drug resistance, and to attempt therapeutic approaches in several types of cancer including clear cell renal cell carcinoma (ccRCC). ccRCC is the most predominant subtype of RCC that accounts for about 90% of all renal cancers. Since ccRCC is generally asymptomatic until very late, it is difficult to diagnose early. Moreover, in the absence of preventive treatments for metastatic ccRCC after surgical resection of the primary cancer, predictive prognostic biomarkers are needed in order to achieve appropriate therapies. Herein the role of miRs in the biology of ccRCC and the potential applications of these molecules are discussed. Moreover, future applications in the diagnostic and prognostic field, as well as their impact on drug response and therapeutic targets are also explored. Their use in clinical practice as molecular biomarkers alone, or in combination with other biological markers could accelerate progress, help design personalized therapies, limit side effects, and improve quality of life of ccRCC patients.

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1. Cairns P. Renal cell carcinoma. Cancer Biomark. 2010;9:461-473. PMid:22112490.
2. Mangolini A, Bonon A, Volinia S, Lanza G, Gambari R, Pinton P, Russo GR, Del Senno L, Dell'Atti L, Aguiari G. Differential expression of microRNA501-5p affects the aggressiveness of clear cell renal carcinoma. FEBS Open Bio. 2014;4:952-65. http://dx.doi.org/10.1016/j.fob.2014.10.016 PMid:25426415 PMCid:PMC4241533.
3. Ljungberg B et al. EAU Guidelines on Renal Cell Carcinoma: 2014 Update. Eur Urol. 2015;67(5):913-24. http://dx.doi.org/10.1016/j.eururo.2015.01.005 PMid:25616710.
4. Baldewijns MM, van Vlodrop IJ, Schouten LJ, Soetekouw PM, de Bruine AP, van Engeland M. Genetics and epigenetics of renal cell cancer. Biochim Biophys Acta. 2008;1785(2):133-55. http://dx.doi.org/10.1016/j.bbcan.2007.12.002
5. Montironi R, Mazzucchelli R, Scarpelli M, Lopez-Beltran A, Cheng L. Update on selected renal cell tumors with clear cell features. With emphasis on multilocular cystic clear cell renal cell carcinoma. Histol Histopathol. 2013;28(12):1555-66. PMid:23893851.
6. Milowsky MI, Nanus DM. Chemotherapeutic strategies for renal cell carcinoma. Urol Clin North Am 2003;30:601-609. http://dx.doi.org/10.1016/S0094-0143(03)00031-4
7. Jonasch E et al. State of the science: an update on renal cell carcinoma. Mol Cancer Res. 2012;10(7):859-80. http://dx.doi.org/10.1158/1541-7786.MCR-12-0117 PMid:22638109 PMCid:PMC3399969.
8. Brugarolas J. Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol. 2014;32(18):1968-76. http://dx.doi.org/10.1200/JCO.2012.45.2003 PMid:24821879 PMCid:PMC4050206.
9. Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2015;15(1):55-64. http://dx.doi.org/10.1038/nrc3844 PMid:25533676.
10. Gudas LJ, Fu L, Minton DR, Mongan NP, Nanus DM. The role of HIF1α in renal cell carcinoma tumorigenesis. J Mol Med (Berl). 2014;92(8):825-36. http://dx.doi.org/10.1007/s00109-014-1180-z
PMid:24916472 PMCid:PMC41195.
11. Audenet F, Yates DR, Cancel-Tassin G, Cussenot O, Roupret M. Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. BJU Int. 2012;109(12):1864-70. http://dx.doi.org/10.1111/j.1464-410X.2011.10661.x PMid:22035299.
12. Srinivasan R, Ricketts CJ, Sourbier C, Linehan WM. New strategies in renal cell carcinoma: targeting the genetic and metabolic basis of disease. Clin Cancer Res. 2015;21(1):10-7. http://dx.doi.org/10.1158/1078-0432.CCR-13-2993 PMid:25564569.
13. Badal SS, Danesh FR. MicroRNAs and their applications in kidney diseases. Pediatr Nephrol. 2015;30(5):727-40. http://dx.doi.org/10.1007/s00467-014-2867-7 PMid:24928414.
14. Romero-Cordoba SL, Salido-Guadarrama I, Rodriguez-Dorantes M, Hidalgo-Miranda A. miRNA biogenesis: biological impact in the development of cancer. Cancer Biol Ther. 2014;15(11):1444-55. http://dx.doi.org/10.4161/15384047.2014.955442 PMid:25482951.
15. Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003;17:3011-6. http://dx.doi.org/10.1101/gad.1158803 PMid:14681208 PMCid:PMC305252.
16. Reddy KB. MicroRNA (miRNA) in cancer. Cancer Cell Int. 2015;15:38. http://dx.doi.org/10.1186/s12935-015-0185-1 PMid:25960691 PMCid:PMC4424445.
17. Iorio MV, Croce CM. Causes and consequences of microRNA dysregulation. Cancer J. 2012; 18(3):215-22. http://dx.doi.org/10.1097/PPO.0b013e318250c001 PMid:22647357 PMCid:PMC3528102
18. Chan B, Manley J, Lee J, Singh SR. The emerging roles of microRNAs in cancer metabolism. Cancer Lett. 2015;356(2 Pt A):301-8. http://dx.doi.org/10.1016/j.canlet.2014.10.011 PMid:25451319.
19. Chow TF, Youssef YM, Lianidou E, Romaschin AD, Honey RJ, Stewart R, Pace KT, Yousef GM. Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin Biochem. 2010;43(1-2):150-8. http://dx.doi.org/10.1016/j.clinbiochem.2009.07.020 PMid:19646430.
20. Valera VA, Walter BA, Linehan WM, Merino MJ. Regulatory Effects of microRNA-92 (miR-92) on VHL Gene Expression and the Hypoxic Activation of miR-210 in Clear Cell Renal Cell Carcinoma. J Cancer. 2011;2:515-26. http://dx.doi.org/10.7150/jca.2.515 PMid:22043236 PMCid:PMC3204400.
21. Chow TF et al. The miR-17-92 cluster is over expressed in and has an oncogenic effect on renal cell carcinoma. J Urol. 2010;183(2):743-51. http://dx.doi.org/10.1016/j.juro.2009.09.086 PMid:20022054.
22. Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 2013;20(12):1603-14. http://dx.doi.org/10.1038/cdd.2013.125 PMid:24212931 PMCid:PMC3824591.
23. Hell MP, Thoma CR, Fankhauser N, Christinat Y, Weber TC, Krek W. miR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation. Cancer Res. 2014;74(9):2432-43. http://dx.doi.org/10.1158/0008-5472.CAN-13-2041 PMid:24491803.
24. Neal CS, Michael MZ, Rawlings LH, Van der Hoek MB, Gleadle JM. The VHL-dependent regulation of microRNAs in renal cancer. BMC Med. 2010;8:64. http://dx.doi.org/10.1186/1741-7015-8-64 PMid:20964835 PMCid:PMC2978113.
25. Nallamshetty S, Chan SY, Loscalzo J. Hypoxia: a master regulator of microRNA biogenesis and activity. Free Radic Biol Med. 2013;64:20-30. http://dx.doi.org/10.1016/j.freeradbiomed.2013.05.022 PMid:23712003 PMCid:PMC3762925.
26. Dey N, Das F, Ghosh-Choudhury N, Mandal CC, Parekh DJ, Block K, Kasinath BS, Abboud HE, Choudhury GG. microRNA-21 governs TORC1 activation in renal cancer cell proliferation and invasion. PLoS One. 2012;7(6):e37366. http://dx.doi.org/10.1371/journal.pone.0037366 PMid:22685542 PMCid:PMC3368259.
27. Bera A, Das F, Ghosh-Choudhury N, Kasinath BS, Abboud HE, Choudhury GG. microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion. Exp Cell Res. 2014;328(1):99-117. http://dx.doi.org/10.1016/j.yexcr.2014.06.022 PMid:25016284.
28. Zaman MS et al. Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer. PLoS One. 2012;7(11):e50203. http://dx.doi.org/10.1371/journal.pone.0050203 PMid:23189187 PMCid:PMC3506541.
29. Khella HW, Bakhet M, Allo G, Jewett MA, Girgis AH, Latif A, Girgis H, Von Both I, Bjarnason GA, Yousef GM. miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma. Carcinogenesis. 2013;34(10):2231-9. http://dx.doi.org/10.1093/carcin/bgt184 PMid:23715501.
30. Ueno K, Hirata H, Shahryari V, Chen Y, Zaman MS, Singh K, Tabatabai ZL, Hinoda Y, Dahiya R. Tumour suppressor microRNA-584 directly targets oncogene Rock-1 and decreases invasion ability in human clear cell renal cell carcinoma. Br J Cancer. 2011;104(2):308-15. http://dx.doi.org/10.1038/sj.bjc.6606028 PMid:21119662 PMCid:PMC3031891.
31. Yamada Y, Hidaka H, Seki N, Yoshino H, Yamasaki T, Itesako T, Nakagawa M, Enokida H. Tumor-suppressive microRNA-135a inhibits cancer cell proliferation by targeting the c-MYC oncogene in renal cell carcinoma. Cancer Sci. 2013;104(3):304-12. http://dx.doi.org/10.1111/cas.12072 PMid:23176581.
32. Majid S et al. MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer. Cancer Res. 2011;71(7):2611-21. http://dx.doi.org/10.1158/0008-5472.CAN-10-3666
PMid:21330408 PMCid:PMC3940352.
33. Saini S, Yamamura S, Majid S, Shahryari V, Hirata H, Tanaka Y, Dahiya R. MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells. Cancer Res. 2011;71(19):6208-19. http://dx.doi.org/10.1158/0008-5472.CAN-11-0073 PMid:21852381 PMCid:PMC3940359.
34. Hirata H, Hinoda Y, Ueno K, Nakajima K, Ishii N, Dahiya R. MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer. Carcinogenesis. 2012;33(3):501-8. http://dx.doi.org/10.1093/carcin/bgr302 PMid:22180573 PMCid:PMC3291860.
35. Wu C, Jin B, Chen L, Zhuo D, Zhang Z, Gong K, Mao Z. MiR-30d induces apoptosis and is regulated by the Akt/FOXO pathway in renal cell carcinoma. Cell Signal. 2013;25(5):1212-21. http://dx.doi.org/10.1016/j.cellsig.2013.01.028 PMid:23416459.
36. Ma X et al. MicroRNA-185 inhibits cell proliferation and induces cell apoptosis by targeting VEGFA directly in von Hippel-Lindau-inactivated clear cell renal cell carcinoma. Urol Oncol. 2015;33(4):169.e1-169.e11. http://dx.doi.org/10.1016/j.urolonc.2015.01.003. PMid:25700976.
37. Czyzyk-Krzeska MF, Meller J, Plas DR. Not all autophagy is equal. Autophagy. 2012; 8(7):1155-6. http://dx.doi.org/10.4161/auto.20650 PMid:22647376 PMCid:PMC3429557.
38. Mikhaylova O et al. VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer Cell. 2012;21(4):532-546. http://dx.doi.org/10.1016/j.ccr.2012.02.019 PMid:22516261 PMCid:PMC3331999.
39. Zheng B, Zhu H, Gu D, Pan X, Qian L, Xue B, Yang D, Zhou J, Shan Y. MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib. Biochem Biophys Res Commun. 2015;459(2):234-9. http://dx.doi.org/10.1016/j.bbrc.2015.02.084 PMid:25712526.
40. Redova M, Svoboda M. and Slaby O. MicroRNAs and their target gene networks in renal cell carcinoma. Biochem. Biophys. Res. Commun. 2011;405:153-156. http://dx.doi.org/10.1016/j.bbrc.2011.01.019 PMid:21232526.
41. Petillo D, Kort EJ, Anema J, Furge KA, Yang XJ, Teh BT. MicroRNA profiling of human kidney cancer subtypes. Int J Oncol. 2009;35(1):109-14. http://dx.doi.org/10.3892/ijo_00000318 PMid:19513557.
42. Youssef YM, White NM, Grigull J, Krizova A, Samy C, Mejia-Guerrero S, Evans A, Yousef GM. Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur Urol. 2011;59(5):721-30. http://dx.doi.org/10.1016/j.eururo.2011.01.004 PMid:21272993.
43. Spector Y, Fridman E, Rosenwald S, Zilber S, Huang Y, Barshack I, Zion O, Mitchell H, Sanden M, Meiri E. Development and validation of a microRNA-based diagnostic assay for classification of renal cell carcinomas. Mol Oncol. 2013;7(3):732-8. http://dx.doi.org/10.1016/j.molonc.2013.03.002 PMid:23587442.
44. Iwamoto H, Kanda Y, Sejima T, Osaki M, Okada F, Takenaka A. Serum miR-210 as a potential biomarker of early clear cell renal cell carcinoma. Int J Oncol. 2014;44(1):53-8. PMid:24212760.
45. Zhao A, Li G, Peoch M, Genin C, Gigante M. Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp Mol Pathol. 2013;94(1):115-20. http://dx.doi.org/10.1016/j.yexmp.2012.10.005 PMid:23064048.
46. Redova M, Poprach A, Nekvindova J, Iliev R, Radova L, Lakomy R, Svoboda M, Vyzula R, Slaby O. Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J Transl Med. 2012;10:55. http://dx.doi.org/10.1186/1479-5876-10-55 PMid:22440013 PMCid:PMC3340316.
47. Wulfken LM et al. MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS One. 2011;6(9):e25787. http://dx.doi.org/10.1371/journal.pone.0025787 PMid: 21984948 PMCid:PMC3184173.
48. Wang C et al. A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma. Sci Rep. 2015;5:7610. http://dx.doi.org/10.1038/srep07610 PMid:25556603.
49. McCormick RI, Blick C, Ragoussis J, Schoedel J, Mole DR, Young AC, Selby PJ, Banks RE, Harris AL. miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis. Br J Cancer. 2013;108(5):1133-42. http://dx.doi.org/10.1038/bjc.2013.56 PMid:23449350 PMCid:PMC3619073.
50. Samaan S et al. miR-210 is a prognostic marker in clear cell renal cell carcinoma. J Mol Diagn. 2015;17(2):136-44. http://dx.doi.org/10.1016/j.jmoldx.2014.10.005 PMid:25555365.
51. Khella HW et al. Low expression of miR-126 is a prognostic marker for metastatic clear cell renal cell carcinoma. Am J Pathol. 2015;185(3):693-703. http://dx.doi.org/10.1016/j.ajpath.2014.11.017 PMid:25572155.
52. Vergho D, Kneitz S, Rosenwald A, Scherer C, Spahn M, Burger M, Riedmiller H, Kneitz B. Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma. BMC Cancer. 2014;14:25. http://dx.doi.org/10.1186/1471-2407-14-25 PMid:24428907 PMCid:PMC3897948.
53. Fu Q, Liu Z, Pan D, Zhang W, Xu L, Zhu Y, Liu H, Xu J. Tumor miR-125b predicts recurrence and survival of patients with clear-cell renal cell carcinoma after surgical resection. Cancer Sci. 2014;105(11):1427-34. http://dx.doi.org/10.1111/cas.12507 PMid:25155155.
54. Fritz HK, Lindgren D, Ljungberg B, Axelson H, Dahlback B. The miR(21/10b) ratio as a prognostic marker in clear cell renal cell carcinoma. Eur J Cancer. 2014;50(10):1758-65. http://dx.doi.org/10.1016/j.ejca.2014.03.281 PMid:24793999.
55. Heinzelmann J, Unrein A, Wickmann U, Baumgart S, Stapf M, Szendroi A, Grimm MO, Gajda MR, Wunderlich H, Junker K. MicroRNAs with prognostic potential for metastasis in clear cell renal cell carcinoma: a comparison of primary tumors and distant metastases. Ann Surg Oncol. 2014;21(3):1046-54. http://dx.doi.org/10.1245/s10434-013-3361-3 PMid:24242678.
56. Gowrishankar B, Ibragimova I, Zhou Y, Slifker MJ, Devarajan K, Al-Saleem T, Uzzo RG, Cairns P. MicroRNA expression signatures of stage, grade, and progression in clear cell RCC. Cancer Biol Ther. 2014;15(3):329-41. http://dx.doi.org/10.4161/cbt.27314 PMid:24351440 PMCid:PMC3974834.
57. Ge YZ et al. A tumor-specific microRNA signature predicts survival in clear cell renal cell carcinoma. J Cancer Res Clin Oncol. 2015;141(7):1291-9. http://dx.doi.org/10.1007/s00432-015-1927-0
58. Chang I et al. Loss of miR-200c up-regulates CYP1B1 and confers docetaxel resistance in renal cell carcinoma. Oncotarget. 2015;6(10):7774-87. PMid:25860934 PMCid:PMC4480715.
59. Gao C, Peng FH, Peng LK. MiR-200c sensitizes clear-cell renal cell carcinoma cells to sorafenib and imatinib by targeting heme oxygenase-1. Neoplasma. 2014;61(6):680-9. http://dx.doi.org/10.4149/neo_2014_083 PMid:25150313.
60. Prior C et al. Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma. PLoS One. 2014;9(1):e86263. http://dx.doi.org/10.1371/journal.pone.0086263 PMid:24475095 PMCid:PMC3901669.
61. Berkers J et al. A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance. J Urol. 2013;189(5):1930-8. http://dx.doi.org/10.1016/j.juro.2012.11.133 PMid:23206420.
62. Gamez-Pozo A et al. MicroRNA expression profiling of peripheral blood samples predicts resistance to first-line sunitinib in advanced renal cell carcinoma patients. Neoplasia. 2012 Dec;14(12):1144-52. http://dx.doi.org/10.1593/neo.12734 PMid:23308047 PMCid:PMC3541518.
63. Pecot CV et al. Tumour angiogenesis regulation by the miR-200 family. Nat Commun. 2013;4:2427. http://dx.doi.org/10.1038/ncomms3427
64. Cui L et al. MicroRNA-99a induces G1-phase cell cycle arrest and suppresses tumorigenicity in renal cell carcinoma. BMC Cancer. 2012;12:546. http://dx.doi.org/10.1186/1471-2407-12-546
65. Ben-Shushan D, Markovsky E, Gibori H, Tiram G, Scomparin A, Satchi-Fainaro R. Overcoming obstacles in microRNA delivery towards improved cancer therapy. Drug Deliv Transl Res. 2014;4(1):38-49. http://dx.doi.org/10.1007/s13346-013-0160-0
66. Maroto P, Rini B. Molecular biomarkers in advanced renal cell carcinoma. Clin Cancer Res. 2014;20(8):2060-71. http://dx.doi.org/10.1158/1078-0432.CCR-13-1351 PMid:24526734.