Overexpression of miR‑155 in clear‑cell renal cell carcinoma and its oncogenic effect through targeting FOXO3a

Ji,Hong; Tian,Dong; Zhang,Bing; Zhang,Yangyang; Yan,Dongliang; Wu,Shuhua

doi:10.3892/etm.2017.4263

Overexpression of miR‑155 in clear‑cell renal cell carcinoma and its oncogenic effect through targeting FOXO3a

Authors:
- Hong Ji
- Dong Tian
- Bing Zhang
- Yangyang Zhang
- Dongliang Yan
- Shuhua Wu
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Affiliations: Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong 256600, P.R. China, Department of Urology, Binzhou Medical University Hospital, Binzhou, Shandong 256600, P.R. China
Published online on: March 24, 2017 https://doi.org/10.3892/etm.2017.4263
Pages: 2286-2292
Copyright: © Ji et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

MicroRNA-155 (miR-155) is overexpressed in numerous human cancer types and has an oncogenic role. Previous study has revealed that miR‑155 serves an important role in the progression of clear‑cell renal cell carcinoma (ccRCC); however, the underlying mechanism was not completely clarified. The present study aimed to investigate the biological role of miR‑155 in ccRCC and the underlying molecular mechanisms. The expression of miR‑155 in 20 ccRCC and adjacent normal kidney tissues was determined by PCR. After downregulation of miR‑155 expression by miR‑155 inhibitor, cell growth was assessed by MTT and colony formation assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry. Cell invasion and migration was detected by wound healing and Transwell assays. Furthermore, forkhead box O3a (FOXO3a) mRNA and protein expression were detected by PCR and immunoblotting. The expression of FOXO3a in 20 ccRCC tissues was also examined by immunohistochemistry. The expression of miR‑155 was upregulated in ccRCC tissues compared to that in adjacent normal tissues. Inhibition of miR‑155 significantly suppressed the proliferation, colony formation, migration and invasion, and induced G1 arrest and apoptosis of ccRCC cells in vitro. Moreover, inhibition of miR‑155 significantly upregulated FOXO3a expression, and miR‑155 expression was inversely correlated with FOXO3a expression in ccRCC tissues. In conclusion, miR‑155 may have an important role in the genesis of ccRCC through targeting FOXO3a and may be a potential target for ccRCC therapy.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Cohen HT and McGovern FJ: Renal-cell carcinoma. N Engl J Med. 353:2477–2490. 2005. View Article : Google Scholar : PubMed/NCBI
3	Curti BD: Renal cell carcinoma. JAMA. 292:97–100. 2004. View Article : Google Scholar : PubMed/NCBI
4	Ge YZ, Wu R, Xin H, Zhu M, Lu TZ, Liu H, Xu Z, Yu P, Zhao YC, Li MH, et al: A tumor-specific microRNA signature predicts survival in clear cell renal cell carcinoma. J Cancer Res Clin Oncol. 141:1291–1299. 2015. View Article : Google Scholar : PubMed/NCBI
5	Ishihara T, Seki N, Inoguchi S, Yoshino H, Tatarano S, Yamada Y, Itesako T, Goto Y, Nishikawa R, Nakagawa M and Enokida H: Expression of the tumor suppressive miRNA-23b/27b cluster is a good prognostic marker in clear cell renal cell carcinoma. J Urol. 192:1822–1830. 2014. View Article : Google Scholar : PubMed/NCBI
6	Cummins JM and Velculescu VE: Implications of micro-RNA profiling for cancer diagnosis. Oncogene. 25:6220–6227. 2006. View Article : Google Scholar : PubMed/NCBI
7	Alvarez-Garcia I and Miska E: MicroRNA functions in animal development and human disease. Development. 132:4653–4662. 2005. View Article : Google Scholar : PubMed/NCBI
8	Luo M, Shen D, Wang W and Xian J: Aberrant expression of microRNA-26b and its prognostic potential in human cervical cancer. Int J Clin Exp Pathol. 8:5542–5548. 2015.PubMed/NCBI
9	Ha TY: MicroRNAs in human diseases: From cancer to cardiovascular disease. Immune Netw. 11:135–154. 2011. View Article : Google Scholar : PubMed/NCBI
10	Li M, Wang Y, Song Y, Bu R, Yin B, Fei X, Guo Q and Wu B: MicroRNAs in renal cell carcinoma: A systematic review of clinical implications (Review). Oncol Rep. 33:1571–1578. 2015.PubMed/NCBI
11	Calvo E, Schmidinger M, Heng DY, Grünwald V and Escudier B: Improvement in survival end points of patients with metastatic renal cell carcinoma through sequential targeted therapy. Cancer Treat Rev. 50:109–117. 2016. View Article : Google Scholar : PubMed/NCBI
12	O'Connell RM, Taganov KD, Boldin MP, Cheng G and Baltimore D: MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA. 104:1604–1609. 2007. View Article : Google Scholar : PubMed/NCBI
13	Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, et al: Requirement of bic/microRNA-155 for normal immune function. Science. 316:608–611. 2007. View Article : Google Scholar : PubMed/NCBI
14	Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D, Valenzuela D, Kutok JL, et al: Regulation of the germinal center response by microRNA-155. Science. 316:604–608. 2007. View Article : Google Scholar : PubMed/NCBI
15	Tili E, Croce CM and Michaille JJ: miR-155: On the crosstalk between inflammation and cancer. Int Rev Immunol. 28:264–284. 2009. View Article : Google Scholar : PubMed/NCBI
16	Juan D, Alexe G, Antes T, Liu H, Madabhushi A, Delisi C, Ganesan S, Bhanot G and Liou LS: Identification of a microRNA panel for clear-cell kidney cancer. Urology. 75:835–841. 2010. View Article : Google Scholar : PubMed/NCBI
17	Chen CZ: MicroRNAs as oncogenes and tumor suppressors. N Engl J Med. 353:1768–1771. 2005. View Article : Google Scholar : PubMed/NCBI
18	Kumar MS, Lu J, Mercer KL, Golub TR and Jacks T: Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 39:673–677. 2007. View Article : Google Scholar : PubMed/NCBI
19	Hale JS, Nelson LT, Simmons KB and Fink PJ: Bcl-2-interacting mediator of cell death influences autoantigen-driven deletion and TCR revision. J Immunol. 186:799–806. 2011. View Article : Google Scholar : PubMed/NCBI
20	Bouamar H, Jiang D, Wang L, Lin AP, Ortega M and Aguiar RC: MicroRNA 155 control of p53 activity is context dependent and mediated by Aicda and Socs1. Mol Cell Biol. 35:1329–1340. 2015. View Article : Google Scholar : PubMed/NCBI
21	Amente S, Zhang J, Lavadera ML, Lania L, Avvedimento EV and Majello B: Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression. Nucleic Acids Res. 39:9498–9507. 2011. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Cai ZK, Chen Q, Chen YB, Gu M, Zheng DC, Zhou J and Wang Z: microRNA-155 promotes the proliferation of prostate cancer cells by targeting annexin 7. Mol Med Rep. 11:533–538. 2015.PubMed/NCBI
24	Lao G, Liu P, Wu Q, Zhang W, Liu Y, Yang L and Ma C: Mir-155 promotes cervical cancer cell proliferation through suppression of its target gene LKB1. Tumour Biol. 35:11933–11938. 2014. View Article : Google Scholar : PubMed/NCBI
25	Novara G, Ficarra V, Antonelli A, Artibani W, Bertini R, Carini M, Cosciani Cunico S, Imbimbo C, Longo N, Martignoni G, et al: Validation of the 2009 TNM version in a large multi-institutional cohort of patients treated for renal cell carcinoma: Are further improvements needed? Eur Urol. 58:588–595. 2010. View Article : Google Scholar : PubMed/NCBI
26	Dinami R, Ercolani C, Petti E, Piazza S, Ciani Y, Sestito R, Sacconi A, Biagioni F, le Sage C, Agami R, et al: miR-155 drives telomere fragility in human breast cancer by targeting TRF1. Cancer Res. 74:4145–4156. 2014. View Article : Google Scholar : PubMed/NCBI
27	Li T, Yang J, Lv X, Liu K, Gao C, Xing Y and Xi T: miR-155 regulates the proliferation and cell cycle of colorectal carcinoma cells by targeting E2F2. Biotechnol Lett. 36:1743–1752. 2014. View Article : Google Scholar : PubMed/NCBI
28	Kong W, He L, Coppola M, Guo J, Esposito NN, Coppola D and Cheng JQ: MicroRNA-155 regulates cell survival, growth and chemosensitivity by targeting FOXO3a in breast cancer. J Biol Chem. 285:17869–12879. 2010. View Article : Google Scholar : PubMed/NCBI
29	Spinetti G, Cordella D, Fortunato O, Sangalli E, Losa S, Gotti A, Carnelli F, Rosa F, Riboldi S, Sessa F, et al: Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: Implication of the microRNA-155/FOXO3a signaling pathway. Circ Res. 112:510–522. 2013. View Article : Google Scholar : PubMed/NCBI
30	Anderson MJ, Viars CS, Czekay S, Cavenee WK and Arden KC: Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics. 47:187–199. 1998. View Article : Google Scholar : PubMed/NCBI
31	Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, DiStefano PS, Chiang LW and Greenberg ME: DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 296:530–534. 2002. View Article : Google Scholar : PubMed/NCBI
32	Sunters A, de Fernández Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema RH, Coombes RC and Lam EW: FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem. 278:49795–49805. 2003. View Article : Google Scholar : PubMed/NCBI
33	Ni D, Ma X, Li HZ, Gao Y, Li XT, Zhang Y, Ai Q, Zhang P, Song EL, Huang QB, et al: Downregulation of FOXO3a promotes tumor metastasis and is associated with metastasis-free survival of patients with clear cell renal cell carcinoma. Clin Cancer Res. 20:1779–1790. 2014. View Article : Google Scholar : PubMed/NCBI
34	Ling N, Gu J, Lei Z, Li M, Zhao J, Zhang HT and Li X: microRNA-155 regulates cell proliferation and invasion by targeting FOXO3a in glioma. Oncol Rep. 30:2111–2118. 2013.PubMed/NCBI