Abstract
Renal cell cancer (RCC) remains one of the most lethal types of cancer in adults. MicroRNAs (miRNAs) play key roles in the pathogenesis of RCC. The role of miR-206 in RCC has not been fully understood. The purpose of this study was to examine the role of miR-206 in the regulation of proliferation and metastasis of RCC and the possible mechanism. miR-206 expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in RCC cell lines (786-O and OS-RC-2 cells) and clinical samples. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] method, colony formation and transwell assay were used to detect the tumor-suppressing ability of miR-206 in RCC. Luciferase assay was performed to verify the precise target of miR-206. The results showed that the expression of miR-206 was significantly down-regulated in RCC tissues and cells. The expression level of cyclin G-associated kinase (GAK), a master regulator of tumor proliferation and metastasis, was up-regulated with the decrease in miR-206 in RCC tissues as well as RCC cell lines. In addition, the miR-206 inhibitor promoted the proliferation, migration and invasion of 786-O and OS-RC-2 cells. Bioinformatics combined with luciferase and Western blot assays revealed that miR-206 inhibited the expression of GAK. Moreover, miR-206 regulates RCC cell growth partly through targeting GAK. Our study indicated that miR-206 functions as a tumor suppressor in regulating the proliferation, migration and invasion of RCC by directly targeting GAK, and it holds promises as a potential therapeutic target for RCC.
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References
Akhavan A, Richards M, Shnorhavorian M, et al. Renal cell carcinoma in children, adolescents and young adults: a National Cancer Database study. J urol, 2015,193(4):1336–1341
Kapoor A. What’s new in renal cell cancer research? Highlights of GU-ASCO 2015. Can Urol Assoc J, 2015,9(5-6Suppl3):S154–S155
White NM, Yousef GM. MicroRNAs: exploring a new dimension in the pathogenesis of kidney cancer. BMC Med, 2010,8:65
Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol, 2001,166(5):1611–1623
Qin X, Zhang H, Ye D, et al. B7-H3 is a new cancer-specific endothelial marker in clear cell renal cell carcinoma. Onco Targets Ther, 2013,6:1667–1673
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell, 2009,136(2):215–233
Li WY, Chen XM, Xiong W, et al. Detection of microvesicle miRNA expression in ALL subtypes and analysis of their functional roles. J Huazhong Univ Sci Technolog Med Sci, 2014,34(5):640–645
Zhang Y, Kim J, Mueller AC, et al. Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma. Cell Death Differ, 2014,21(5):720–734
Yin J, Park G, Lee JE, et al. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain, 2015,138(Pt 9):2553–2570
Li X, Liu Y, Granberg KJ, et al. Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma. Oncogene, 2015,34(13):1619–1628
Dai S, Wang X, Li X, et al. MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme. Biochem Biophys Res Commun, 2015,467(2):204–210
Sun P, Sun D, Wang X, et al. miR-206 is an independent prognostic factor and inhibits tumor invasion and migration in colorectal cancer. Cancer Biomark, 2015,15(4):391–396
Ge X, Lyu P, Cao Z, et al. Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting. Biochem Biophys Res Commun, 2015,463(4):1115–1121
Panwalkar P, Moiyadi A, Goel A, et al. MiR-206, a cerebellum enriched miRNA is downregulated in all medulloblastoma subgroups and its overexpression is necessary for growth inhibition of medulloblastoma cells. J Mol Neurosci, 2015,56(3):673–680
Yu WF, Wang HM, Lu BC, et al. miR-206 inhibits human laryngeal squamous cell carcinoma cell growth by regulation of cyclinD2. Eur Rev Med Pharmacol Sci, 2015,19(14):2697–2702
Zhang L, Xia L, Zhao L, et al. Activation of PAX3-MET pathways due to miR-206 loss promotes gastric cancer metastasis. Carcinogenesis, 2015,36(3):390–399
Kanaoka Y, Kimura SH, Okazaki I, et al. GAK: a cyclin G associated kinase contains a tensin/auxilin-like domain. FEBS Lett, 1997,402(1):73–80
Greener T, Zhao X, Nojima H, et al. Role of cyclin G-associated kinase in uncoating clathrin-coated vesicles from non-neuronal cells. J Biol Chem, 2000,275(2):1365–1370
Zhang CX, Engqvist-Goldstein AE, Carreno S, et al. Multiple roles for cyclin G-associated kinase in clathrin-mediated sorting events. Traffic, 2005,6(12):1103–1113
Sakurai MA, Ozaki Y, Okuzaki D, et al. Gefitinib and luteolin cause growth arrest of human prostate cancer PC-3 cells via inhibition of cyclin G-associated kinase and induction of miR-630. PLoS One, 2014,9(6):e100124
Sun W, Lv W, Lv H, et al. Genome-wide haplotype association analysis identifies SERPINB9, SERPINE2, GAK, and HSP90B1 as novel risk genes for oral squamous cell carcinoma. Tumour Biol, 2016,37(2):1845–1851
Susa M, Choy E, Liu X, et al. Cyclin G-associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. Mol Cancer Ther, 2010,9(12):3342–3350
Zoni E, van der Horst G, van de Merbel AF, et al. miR-25 modulates invasiveness and dissemination of human prostate cancer cells via regulation of alphav-and alpha6-integrin expression. Cancer Res, 2015,75(11):2326–2336
Que T, Song Y, Liu Z, et al. Decreased miRNA-637 is an unfavorable prognosis marker and promotes glioma cell growth, migration and invasion via direct targeting Akt1. Oncogene, 2015,34(38):4952–4963
Du M, Shi D, Yuan L, et al. Circulating miR-497 and miR-663b in plasma are potential novel biomarkers for bladder cancer. Sci Rep, 2015,5:10437
Zhang YJ, Xu F, Zhang YJ, et al. miR-206 inhibits non small cell lung cancer cell proliferation and invasion by targeting SOX9. Int J Clin Exp Med, 2015,8(6):9107–9113
Chen QY, Jiao DM, Wang J, et al. miR-206 regulates cisplatin resistance and EMT in human lung adenocarcinoma cells partly by targeting MET. Oncotarget, 2016,21:8229
Wang XW, Xi XQ, Wu J, et al. MicroRNA-206 attenuates tumor proliferation and migration involving the downregulation of NOTCH3 in colorectal cancer. Oncol Rep, 2015,33(3):1402–1410
Kimura SH, Tsuruga H, Yabuta N, et al. Structure, expression, and chromosomal localization of human GAK. Genomics, 1997,44(2):179–187
Ahle S, Ungewickell E. Auxilin, a newly identified clathrin-associated protein in coated vesicles from bovine brain. J Cell Biol, 1990,111(1):19–29
Ray MR, Wafa LA, Cheng H, et al. Cyclin G-associated kinase: a novel androgen receptor-interacting transcriptional coactivator that is overexpressed in hormone refractory prostate cancer. Int J Cancer, 2006,118(5):1108–1119
Garzon R, Pichiorri F, Palumbo T, et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene 2007,26:4148–4157
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Wei, C., Wang, S., Ye, Zq. et al. miR-206 inhibits renal cell cancer growth by targeting GAK. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 36, 852–858 (2016). https://doi.org/10.1007/s11596-016-1674-8
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DOI: https://doi.org/10.1007/s11596-016-1674-8