Abstract
MicroRNAs play critical roles in the development and progression of human cancers. Although it has been reported that miR-106a* is downregulated in follicular lymphoma, its role in renal cell carcinoma (RCC) remains unknown. This study investigated the expression and role of miR-106a* in human RCC. Our results showed that the miR-106a* expression decreased dramatically in clinical RCC tissues and cell lines. In vitro, overexpression of miR-106a* suppressed RCC cell proliferation and S/G2 transition, whereas inhibition of miR-106a* promoted cell proliferation and S/G2 transition. It was also found that miR-106a* expression was inversely correlated with the expression of insulin receptor substrate 2 (IRS-2). IRS-2 was determined to be a direct target of miR-106a* by a luciferase reporter assay. Importantly, silencing IRS-2 resulted in the same biologic effects as those of miR-106a* overexpression in RCC cells, including inhibition of RCC cell proliferation and triggering of S/G2 cell cycle arrest with inhibition of the PI3K/Akt signaling pathway. These results indicate that miR-106a* affects RCC progression by targeting IRS-2 with suppression of the PI3K/Akt signaling pathway in RCC cells. The findings suggest miR-106a* as a novel strategy for RCC treatment.
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References
Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin. 2013;63(1):11–30.
Yang FQ, Yang FP, Li W, Liu M, Wang GC, Che JP, et al. Foxl1 inhibits tumor invasion and predicts outcome in human renal cancer. Int J Clin Exp Pathol. 2013;7(1):110–22.
Russo P. Renal cell carcinoma: presentation, staging, and surgical treatment. Semin Oncol. 2000;27(2):160–76.
Motzer RJ, Molina AM. Targeting renal cell carcinoma. J Clin Oncol. 2009;27(20):3274–6.
Zhang H, Cheng Y, Jia C, Yu S, Xiao Y, Chen J. MicroRNA-29s could target AKT2 to inhibit gastric cancer cells invasion ability. Med Oncol. 2015;32(1):342.
Zhang Z, Zheng W, Hai J. MicroRNA-148b expression is decreased in hepatocellular carcinoma and associated with prognosis. Med Oncol. 2014;31(6):984.
Esquela-Kerscher A, Slack FJ. Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69.
Su Z, Ni L, Yu W, Yu Z, Chen D, Zhang E, et al. MicroRNA-451a is associated with cell proliferation, migration and apoptosis in renal cell carcinoma. Mol Med Rep. 2015;11(3):2248–54.
Chen Z, Tang ZY, He Y, Liu LF, Li DJ, Chen X. miRNA-205 is a candidate tumor suppressor that targets ZEB2 in renal cell carcinoma. Oncol Res Treat. 2014;37(11):658–64.
Wang W, Corrigan-Cummins M, Hudson J, Maric I, Simakova O, Neelapu SS, et al. MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response. Haematologica. 2012;97(4):586–94.
Cai D, Dhe-Paganon S, Melendez PA, Lee J, Shoelson SE. Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem. 2003;278(28):25323–30.
Lee YH, White MF. Insulin receptor substrate proteins and diabetes. Arch Pharm Res. 2004;27(4):361–70.
Gibson SL, Ma Z, Shaw LM. Divergent roles for IRS-1 and IRS-2 in breast cancer metastasis. Cell Cycle. 2007;6(6):631–7.
White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 2002;283(3):E413–22.
Zhao XM, Chen J, Yang L, Luo X, Xu LL, Liu DX, et al. Association between IRS-2 G1057D polymorphism and risk of gastric cancer. World J Gastrointest Oncol. 2012;4(1):9–15.
Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang X, et al. Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol Cell Biol. 2006;26(24):9302–14.
Hu G, Lai P, Liu M, Xu L, Guo Z, Liu H, et al. miR-203a regulates proliferation, migration, and apoptosis by targeting glycogen synthase kinase-3β in human renal cell carcinoma. Tumour Biol. 2014;35(11):11443–53.
Gopalan V, Pillai S, Ebrahimi F, Salajegheh A, Lam TC, Le TK, et al. Regulation of microRNA-1288 in colorectal cancer: altered expression and its clinicopathological significance. Mol Carcinog. 2013;53:E36–44.
Lang Q, Ling C. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun. 2012;426(2):247–52.
Poudel S, Song J, Jin EJ, Song K. Sulfuretin-induced miR-30C selectively downregulates cyclin D1 and D2 and triggers cell death in human cancer cell lines. Biochem Biophys Res Commun. 2013;431(3):572–8.
Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, et al. Identification of metastasis related microRNAs in hepatocellular carcinoma. Hepatology. 2008;47(3):897–907.
Zhao LY, Yao Y, Han J, Yang J, Wang XF, Tong DD, et al. miR-638 suppresses cell proliferation in gastric cancer by targeting Sp2. Dig Dis Sci. 2014;59(8):1743–53.
Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48(6):2047–63.
Rossi JJ. New hope for a microRNA therapy for liver cancer. Cell. 2009;137(6):990–2.
Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D. Downregulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer. 2000;89(6):506–13.
Sisci D, Morelli C, Garofalo C, Romeo F, Morabito L, Casaburi F, et al. Expression of nuclear insulin receptor substrate 1 (IRS-1) in breast cancer. J Clin Pathol. 2007;60(6):633–41.
Han CH, Cho JY, Moon JT, Kim HJ, Kim SK, Shin DH, et al. Clinical significance of insulin receptor substrate-I down-regulation in non-small cell lung cancer. Oncol Rep. 2006;16(6):1205–10.
Mardilovich K, Pankratz SL, Shaw LM. Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun Signal. 2009;7:14.
Kwon J, Stephan S, Mukhopadhyay A, Muders MH, Dutta SK, Lau JS, et al. Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. Cancer Res. 2009;69(4):1350–7.
Byron S, Horwitz K, Richer J, Lange C, Zhang X, Yee D. Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells. Br J Cancer. 2006;95(9):1220–8.
Day E, Poulogiannis G, McCaughan F, Mulholland S, Arends MJ, Ibrahim AE, et al. IRS-2 is a candidate driver oncogene on 13q34 in colorectal cancer. Int J Exp Pathol. 2013;94(3):203–11.
Chan BT, Lee AV. Insulin receptor substrates (IRSs) and breast tumorigenesis. J Mammary Gland Biol Neoplasia. 2008;13(4):415–22.
Porter HA, Perry A, Kingsley C, Tran NL, Keegan AD. IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy, while IRS2 is highly expressed in invasive breast tumors. Cancer Lett. 2013;338(2):239–48.
Gao L, Wang X, Wang X, Zhang L, Qiang C, Chang S, et al. IGF-1R, a target of let-7b, mediates crosstalk between IRS- 2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma. Oncotarget. 2014;5(9):2562–74.
Boissan M, Beurel E, Wendum D, Rey C, Lecluse Y, Housset C, et al. Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. Am J Pathol. 2005;167(3):869–77.
Briaud I, Dickson LM, Lingohr MK, McCuaig JF, Lawrence JC, Rhodes CJ. Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells. J Biol Chem. 2005;280(3):2282–93.
Ando K, Fujita T. Role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the development of hypertensive organ damage. Clin Exp Nephrol. 2004;8(3):178–82.
Neid M, Datta K, Stephan S, Khanna I, Pal S, Shaw L, et al. Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. J Biol Chem. 2004;279(6):3941–8.
Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol. 2004;24(22):9726–35.
Kim B, Feldman EL. Insulin receptor substrate (IRS)-2, not IRS-1, protects human neuroblastoma cells against apoptosis. Apoptosis. 2009;14(5):665–73.
Szabolcs M, Keniry M, Simpson L, Reid LJ, Koujak S, Schiff SC, et al. Irs2 inactivation suppresses tumor progression in Pten +/- mice. Am J Pathol. 2009;174(1):276–86.
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The authors would like to thank Professor Qi Chen for polishing the language in this manuscript.
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Ma, Y., Zhang, H., He, X. et al. miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2. Tumor Biol. 36, 8389–8398 (2015). https://doi.org/10.1007/s13277-015-3605-x
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DOI: https://doi.org/10.1007/s13277-015-3605-x