MicroRNA-148b enhances proliferation and apoptosis in human renal cancer cells via directly targeting MAP3K9

Nie,Fang; Liu,Tianming; Zhong,Liang; Yang,Xianggui; Liu,Yunhong; Xia,Hongwei; Liu,Xiaoqiang; Wang,Xiaoyan; Liu,Zhicheng; Zhou,Li; Mao,Zhaomin; Zhou,Qin; Chen,Tingmei

doi:10.3892/mmr.2015.4555

MicroRNA-148b enhances proliferation and apoptosis in human renal cancer cells via directly targeting MAP3K9

Authors:
- Fang Nie
- Tianming Liu
- Liang Zhong
- Xianggui Yang
- Yunhong Liu
- Hongwei Xia
- Xiaoqiang Liu
- Xiaoyan Wang
- Zhicheng Liu
- Li Zhou
- Zhaomin Mao
- Qin Zhou
- Tingmei Chen
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Affiliations: Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China, Department of Medical Oncology and Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: November 11, 2015 https://doi.org/10.3892/mmr.2015.4555
Pages: 83-90
Copyright: © Nie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Increasing evidence revealed that miRNAs, the vital regulators of gene expression, are involved in various cellular processes, including cell growth, differentiation, apoptosis and progression. In addition, miRNAs act as oncogenes and/or tumor suppressors. The present study aimed to verify the potential roles of miR148b in human renal cancer cells. miR‑148b was found to be downregulated in human renal cancel tissues and human renal cancer cell lines. Functional studies demonstrated that plasmid‑mediated overexpression of miR‑148b promoted cell proliferation, increased the S‑phase population of the cell cycle and enhanced apoptosis in the 786‑O and OS‑RC‑2 renal cancer cell lines, while it did not appear to affect the total number of viable cells according to a Cell Counting Kit‑8 assay. Subsequently, a luciferase reporter assay verified that miR148b directly targeted mitogen‑activated protein kinase (MAPK) kinase kinase 9 (MAP3K9), an upstream activator of MAPK kinase/c‑Jun N‑terminal kinase (JNK) signaling, suppressing the protein but not the mRNA levels. Furthermore, western blot analysis indicated that overexpression of miR148b in renal cancer cells inhibited MAPK/JNK signaling by decreasing the expression of phosphorylated (p)JNK. In addition, overexpression of MAP3K9 and pJNK was detected in clinical renal cell carcinoma specimens compared with that in their normal adjacent tissues. The present study therefore suggested that miR‑148b exerts an oncogenic function by enhancing the proliferation and apoptosis of renal cancer cells by inhibiting the MAPK/JNK pathway.

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1	Falebita OA, Mancini S, Kiely E and Comber H: Rising incidence of renal cell carcinoma in Ireland. Int Urol Nephrol. 41:7–12. 2009. View Article : Google Scholar
2	Störkel S and van den Berg E: Morphological classification of renal cancer. World J Urol. 13:153–158. 1995. View Article : Google Scholar : PubMed/NCBI
3	Bukowski RM, Negrier S and Elson P: Prognostic factors in patients with advanced renal cell carcinoma: Development of an international kidney cancer working group. Clin Cancer Res. 10:S6310–S6314. 2004. View Article : Google Scholar
4	Heinzelmann J, Henning B, Sanjmyatav J, Posorski N, Steiner T, Wunderlich H, Gajda MR and Junker K: Specific miRNA signatures are associated with metastasis and poor prognosis in clear cell renal cell carcinoma. World J Urol. 29:367–373. 2011. View Article : Google Scholar : PubMed/NCBI
5	An J, Liu H, Magyar CE, Guo Y, Veena MS, Srivatsan ES, Huang J and Rettig MB: Hyperactivated JNK is a therapeutic target in pVHL-deficient renal cell carcinoma. Cancer Res. 73:1374–1385. 2013. View Article : Google Scholar : PubMed/NCBI
6	Zeng L, Bai M, Mittal AK, El-Jouni W, Zhou J, Cohen DM, Zhou MI and Cohen HT: Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. Cancer Res. 73:5371–5380. 2013. View Article : Google Scholar : PubMed/NCBI
7	Pal SK, He M, Tong T, Wu H, Liu X, Lau C, Wang JH, Warden C, Wu X, Signoretti S, et al: RNA-seq reveals aurora kinase driven-mTOR pathway activation in patients with sarcomatoid metastatic renal cell carcinoma. Mol Cancer Res. 13:130–137. 2015. View Article : Google Scholar
8	Von Schulz-Hausmann SA, Schmeel LC, Schmeel FC and Schmidt-Wolf IG: Targeting the Wnt/beta-catenin pathway in renal cell carcinoma. Anticancer Res. 34:4101–4108. 2014.PubMed/NCBI
9	Schütte U, Bisht S, Heukamp LC, Kebschull M, Florin A, Haarmann J, Hoffmann P, Bendas G, Buettner R, Brossart P and Feldmann G: Hippo signaling mediates proliferation, invasiveness, and metastatic potential of clear cell renal cell carcinoma. Transl Oncol. 7:309–321. 2014. View Article : Google Scholar : PubMed/NCBI
10	Huang D, Ding Y, Luo WM, Bender S, Qian CN, Kort E, Zhang ZF, VandenBeldt K, Duesbery NS, Resau JH and Teh BT: Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo. Cancer Res. 68:81–88. 2008. View Article : Google Scholar : PubMed/NCBI
11	Zhan YH, Liu J, Qu XJ, Hou KZ, Wang KF, Liu YP and Wu B: β-Elemene induces apoptosis in human renal-cell carcinoma 786-0 cells through inhibition of MAPK/ERK and PI3K/Akt/mTOR signalling pathways. Asian Pac J Cancer Prev. 13:2739–2744. 2012. View Article : Google Scholar
12	Du HF, Ou LP, Song XD, Fan YR, Yang X, Tan B, Quan Z, Luo CL and Wu XH: Nuclear factor-kB signaling pathway is involved in phospholipase Cε-regulated proliferation in human renal cell carcinoma cells. Mol Cell Biochem. 389:265–275. 2014. View Article : Google Scholar : PubMed/NCBI
13	Munshi A and Ramesh R: Mitogen-activated protein kinases and their role in radiation response. Genes Cancer. 4:401–408. 2013. View Article : Google Scholar : PubMed/NCBI
14	Liu J and Lin A: Role of JNK activation in apoptosis: A double-edged sword. Cell Res. 15:36–42. 2005. View Article : Google Scholar : PubMed/NCBI
15	Cimino D, De Pittà C, Orso F, Zampini M, Casara S, Penna E, Quaglino E, Forni M, Damasco C, Pinatel E, et al: miR148b is a major coordinator of breast cancer progression in a relapse-associated microRNA signature by targeting ITGA5, ROCK1, PIK3CA, NRAS and CSF1. FASEB J. 27:1223–1235. 2013. View Article : Google Scholar
16	Liu GL, Liu X, Lv XB, Wang XP, Fang XS and Sang Y: miR-148b functions as a tumor suppressor in non-small cell lung cancer by targeting carcinoembryonic antigen (CEA). Int J Clin Exp Med. 7:1990–1999. 2014.PubMed/NCBI
17	Zhang Z, Zheng W and Hai J: MicroRNA-148b expression is decreased in hepatocellular carcinoma and associated with prognosis. Med Oncol. 31:9842014. View Article : Google Scholar : PubMed/NCBI
18	Zhao G, Zhang JG, Liu Y, Qin Q, Wang B, Tian K, Liu L, Li X, Niu Y, Deng SC and Wang CY: miR-148b functions as a tumor suppressor in pancreatic cancer by targeting AMPKα1. Mol Cancer Ther. 12:83–93. 2013. View Article : Google Scholar
19	Song YX, Yue ZY, Wang ZN, Xu YY, Luo Y, Xu HM, Zhang X, Jiang L, Xing CZ and Zhang Y: MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation. Mol Cancer. 10:12011. View Article : Google Scholar : PubMed/NCBI
20	Song Y, Xu Y, Wang Z, Chen Y, Yue Z, Gao P, Xing C and Xu H: MicroRNA-148b suppresses cell growth by targeting cholecystokinin-2 receptor in colorectal cancer. Int J Cancer. 131:1042–1051. 2012. View Article : Google Scholar
21	Fawdar S, Trotter EW, Li Y, Stephenson NL, Hanke F, Marusiak AA, Edwards ZC, Ientile S, Waszkowycz B, Miller CJ and Brognard J: Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer. Proc Natl Acad Sci USA. 110:12426–12431. 2013. View Article : Google Scholar : PubMed/NCBI
22	Ribeiro J, Marinho-Dias J, Monteiro P, Loureiro J, Baldaque I, Medeiros R and Sousa H: miR-34a and miR-125b expression in HPV infection and cervical cancer development. Biomed Res Int. 2015:3045842015. View Article : Google Scholar : PubMed/NCBI
23	Lyu Z, Mao Z, Wang H, Fang Y, Chen T, Wan Q, Wang M, Wang N, Xiao J, Wei H, et al: MiR-181b targets Six2 and inhibits the proliferation of metanephric mesenchymal cells in vitro. Biochem Biophys Res Commun. 440:495–501. 2013. View Article : Google Scholar : PubMed/NCBI
24	Grange C, Collino F, Tapparo M and Camussi G: Oncogenic micro-RNAs and renal cell carcinoma. Front Oncol. 4:492014. View Article : Google Scholar : PubMed/NCBI
25	Durkin JT, Holskin BP, Kopec KK, Reed MS, Spais CM, Steffy BM, Gessner G, Angeles TS, Pohl J, Ator MA and Meyer SL: Phosphoregulation of mixed-lineage kinase 1 activity by multiple phosphorylation in the activation loop. Biochemistry. 43:16348–16355. 2004. View Article : Google Scholar : PubMed/NCBI
26	Stronach B, Lennox AL and Garlena RA: Domain specificity of MAP3K family members, MLK and Tak1, for JNK signaling in drosophila. Genetics. 197:497–513. 2014. View Article : Google Scholar : PubMed/NCBI
27	Bisson N, Tremblay M, Robinson F, Kaplan DR, Trusko SP and Moss T: Mice lacking both mixed-lineage kinase genes Mlk1 and Mlk2 retain a wild type phenotype. Cell Cycle. 7:909–916. 2008. View Article : Google Scholar : PubMed/NCBI
28	Dhanasekaran DN and Reddy EP: JNK signaling in apoptosis. Oncogene. 27:6245–6251. 2008. View Article : Google Scholar : PubMed/NCBI