MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP-2 expression

Shin,Seung-Shick; Park,Sung-Soo; Hwang,Byungdoo; Kim,Won Tae; Choi,Yung Hyun; Kim,Wun-Jae; Moon,Sung-Kwon

doi:10.3892/or.2016.5015

MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP-2 expression

Authors:
- Seung-Shick Shin
- Sung-Soo Park
- Byungdoo Hwang
- Won Tae Kim
- Yung Hyun Choi
- Wun-Jae Kim
- Sung-Kwon Moon
View Affiliations

Affiliations: Department of Food Science and Nutrition, Jeju National University, Jeju 63243, Republic of Korea, Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea, Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-052, Republic of Korea
Published online on: August 11, 2016 https://doi.org/10.3892/or.2016.5015
Pages: 2421-2429

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Despite the clinical significance of tumorigenesis, little is known about the cellular signaling networks of microRNAs (miRs). Here we report a new finding that mir‑106a regulates the proliferation, migration, and invasion of bladder cancer cells. Basal expression levels of mir‑106a were significantly lower in bladder cancer cells than in normal urothelial cells. Overexpression of mir‑106a suppressed the proliferation of bladder cancer cell line EJ. Transient transfection of mir‑106a into EJ cells led to downregulation of ERK phosphorylation and upregulation of p38 and JNK phosphorylation over their levels in the control. Flow cytometry analysis revealed that mir‑106a-transfected cells accumulated in the G1-phase of the cell cycle, and cyclin D1 and CDK6 were significantly downregulated. This G1-phase cell cycle arrest was due in part to the upregulation of p21CIP1/WAF1. In addition, mir‑106a overexpression blocked the wound-healing migration and invasion of EJ cells. Furthermore, mir‑106a transfection resulted in decreased expression of MMP-2 and diminished binding activity of transcription factor Ets-1 in EJ cells. Collectively, we report the novel mir‑106a-mediated molecular signaling networks that regulate the proliferation, migration, and invasion of bladder cancer cells, suggesting that mir‑106a may be a therapeutic target for treating advanced bladder tumors.

View Figures

View References

1	Hayes J, Peruzzi PP and Lawler S: MicroRNAs in cancer: Biomarkers, functions and therapy. Trends Mol Med. 20:460–469. 2014. View Article : Google Scholar : PubMed/NCBI
2	Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, et al: Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 99:15524–15529. 2002. View Article : Google Scholar
3	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
4	Koturbash I, Zemp FJ, Pogribny I and Kovalchuk O: Small molecules with big effects: The role of the microRNAome in cancer and carcinogenesis. Mutat Res. 722:94–105. 2011. View Article : Google Scholar
5	Zhang B, Pan X, Cobb GP and Anderson TA: microRNAs as oncogenes and tumor suppressors. Dev Biol. 302:1–12. 2007. View Article : Google Scholar
6	Eissa S, Ali-Labib R, Swellam M, Bassiony M, Tash F and El-Zayat TM: Noninvasive diagnosis of bladder cancer by detection of matrix metalloproteinases (MMP-2 and MMP-9) and their inhibitor (TIMP-2) in urine. Eururol. 52:1388–1396. 2007.
7	Jiang X, Du L, Wang L, Li J, Liu Y, Zheng G, Qu A, Zhang X, Pan H, Yang Y, et al: Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer. Int J Cancer. 136:854–862. 2015. View Article : Google Scholar
8	Ratert N, Meyer HA, Jung M, Lioudmer P, Mollenkopf HJ, Wagner I, Miller K, Kilic E, Erbersdobler A, Weikert S, et al: miRNA profiling identifies candidate mirnas for bladder cancer diagnosis and clinical outcome. J Mol Diagn. 15:695–705. 2013. View Article : Google Scholar : PubMed/NCBI
9	Puerta-Gil P, García-Baquero R, Jia AY, Ocaña S, Alvarez-Múgica M, Alvarez-Ossorio JL, Cordon-Cardo C, Cava F and Sánchez-Carbayo M: miR-143, miR-222, and miR-452 are useful as tumor stratification and noninvasive diagnostic biomarkers for bladder cancer. Am J Pathol. 180:1808–1815. 2012. View Article : Google Scholar : PubMed/NCBI
10	Wang XL, Xie HY, Zhu CD, Zhu XF, Cao GX, Chen XH and Xu HF: Increased miR-141 expression is associated with diagnosis and favorable prognosis of patients with bladder cancer. Tumour Biol. 36:877–883. 2015. View Article : Google Scholar
11	Rouanne M, Loriot Y, Lebret T and Soria JC: Novel therapeutic targets in advanced urothelial carcinoma. Crit Rev Oncol Hematol. 98:106–115. 2016. View Article : Google Scholar
12	Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, et al: Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 31:3133–3140. 2013. View Article : Google Scholar : PubMed/NCBI
13	Park SL, Cho TM, Won SY, Song JH, Noh DH, Kim WJ and Moon SK: MicroRNA-20b inhibits the proliferation, migration and invasion of bladder cancer EJ cells via the targeting of cell cycle regulation and Sp-1-mediated MMP-2 expression. Oncol Rep. 34:1605–1612. 2015.PubMed/NCBI
14	Yun SJ, Jeong P, Kim WT, Kim TH, Lee YS, Song PH, Choi YH, Kim IY, Moon SK and Kim WJ: Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer. Int J Oncol. 41:1871–1878. 2012.PubMed/NCBI
15	Moon SK, Jung SY, Choi YH, Lee YC, Patterson C and Kim CH: PDTC, metal chelating compound, induces G1 phase cell cycle arrest in vascular smooth muscle cells through inducing p21Cip1 expression: Involvement of p38 mitogen activated protein kinase. J Cell Physiol. 198:310–323. 2004. View Article : Google Scholar
16	Lee SJ, Cho SC, Lee EJ, Kim S, Lee SB, Lim JH, Choi YH, Kim WJ and Moon SK: Interleukin-20 promotes migration of bladder cancer cells through extracellular signal-regulated kinase (ERK)-mediated MMP-9 protein expression leading to nuclear factor (NF-χB) activation by inducing the up-regulation of p21(WAF1) protein expression. J Biol Chem. 288:5539–5552. 2013. View Article : Google Scholar
17	American Cancer Society: Cancer Facts and Figures 2015. American Cancer Society; Atlanta, GA: 2015, http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdfurisimplewww.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf.
18	Wang F, Zheng Z, Guo J and Ding X: Correlation and quantitation of microRNA aberrant expression in tissues and sera from patients with breast tumor. Gynecol Oncol. 119:586–593. 2010. View Article : Google Scholar : PubMed/NCBI
19	Feng B, Dong TT, Wang LL, Zhou HM, Zhao HC, Dong F and Zheng MH: Colorectal cancer migration and invasion initiated by microRNA-106a. PLoS One. 7:e434522012. View Article : Google Scholar : PubMed/NCBI
20	Wang Z, Liu M, Zhu H, Zhang W, He S, Hu C, Quan L, Bai J and Xu N: miR-106a is frequently upregulated in gastric cancer and inhibits the extrinsic apoptotic pathway by targeting FAS. Mol Carcinog. 52:634–646. 2013. View Article : Google Scholar
21	Díaz R, Silva J, García JM, Lorenzo Y, García V, Peña C, Rodríguez R, Muñoz C, García F, Bonilla F, et al: Deregulated expression of miR-106a predicts survival in human colon cancer patients. Genes Chromosomes Cancer. 47:794–802. 2008. View Article : Google Scholar : PubMed/NCBI
22	Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
23	Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al: Mutations of the BRAF gene in human cancer. Nature. 417:949–954. 2002. View Article : Google Scholar : PubMed/NCBI
24	Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, et al: A landscape of driver mutations in melanoma. Cell. 150:251–263. 2012. View Article : Google Scholar : PubMed/NCBI
25	Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Palmer AA, Zhang XD, Thompson JF, Bron LP and Hersey P: Activation of the extracellular signal regulated kinase (ERK) pathway in human melanoma. J Clin Pathol. 58:1163–1169. 2005. View Article : Google Scholar : PubMed/NCBI
26	Smalley KS: A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer. 104:527–532. 2003. View Article : Google Scholar : PubMed/NCBI
27	Yayon A, Ma YS, Safran M, Klagsbrun M and Halaban R: Suppression of autocrine cell proliferation and tumorigenesis of human melanoma cells and fibroblast growth factor transformed fibroblasts by a kinase-deficient FGF receptor 1: Evidence for the involvement of Src-family kinases. Oncogene. 14:2999–3009. 1997. View Article : Google Scholar : PubMed/NCBI
28	Wu GS: Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer. Cancer Metastasis Rev. 26:579–585. 2007. View Article : Google Scholar : PubMed/NCBI
29	Eissa S, Ahmed MI, Said H, Zaghlool A and El-Ahmady O: Cell cycle regulators in bladder cancer: Relationship to schistosomiasis. IUBMB Life. 56:557–564. 2004. View Article : Google Scholar : PubMed/NCBI
30	Shan G and Tang T: Expression of cyclin D1 and cyclin E in urothelial bladder carcinoma detected in tissue chips using a quantum dot immunofluorescence technique. Oncol Lett. 10:1271–1276. 2015.PubMed/NCBI
31	Zang WQ, Yang X, Wang T, Wang YY, Du YW, Chen XN, Li M and Zhao GQ: MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. World J Gastroenterol. 21:5867–5876. 2015.PubMed/NCBI
32	Takahashi Y, Forrest AR, Maeno E, Hashimoto T, Daub CO and Yasuda J: MiR-107 and MiR-185 can induce cell cycle arrest in human non small cell lung cancer cell lines. PLoS One. 4:e66772009. View Article : Google Scholar : PubMed/NCBI
33	Zhao X, Li J, Huang S, Wan X, Luo H and Wu D: MiRNA-29c regulates cell growth and invasion by targeting CDK6 in bladder cancer. Am J Transl Res. 7:1382–1389. 2015.PubMed/NCBI
34	Liu L, Zhao X, Zhu X, Zhong Z, Xu R, Wang Z, Cao J and Hou Y: Decreased expression of miR-430 promotes the development of bladder cancer via the upregulation of CXCR7. Mol Med Rep. 8:140–146. 2013.PubMed/NCBI
35	Qin H, Sun Y and Benveniste EN: The transcription factors Sp1, Sp3, and AP-2 are required for constitutive matrix metalloproteinase-2 gene expression in astroglioma cells. J Biol Chem. 274:29130–29137. 1999. View Article : Google Scholar : PubMed/NCBI