miR-451 suppresses bladder cancer cell migration and invasion via directly targeting c-Myc

Wang,Jun; Zhao,Xiaomei; Shi,Jianhua; Pan,Yiwei; Chen,Qinghai; Leng,Pengfei; Wang,Yan

doi:10.3892/or.2016.5040

miR-451 suppresses bladder cancer cell migration and invasion via directly targeting c-Myc

Authors:
- Jun Wang
- Xiaomei Zhao
- Jianhua Shi
- Yiwei Pan
- Qinghai Chen
- Pengfei Leng
- Yan Wang
View Affiliations

Affiliations: Department of Urology, The First Clinical Medical School of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Surgery, The People Hospital of Arun Banner, Hulun Buir, Inner Mongolia 162750, P.R. China
Published online on: August 25, 2016 https://doi.org/10.3892/or.2016.5040
Pages: 2049-2058

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

MicroRNA (miRNA) expression is shown dysregulated in tumors. It has been reported that miR-451 alters gene expression and regulates tumorigenesis in various cancer tissues. However, its underlying biological significance in bladder cancer remains to be clarified. In the present study, we investigated the function and molecular mechanism of miR-451 involved in bladder cancer cell migration and invasion. Our results showed that miR-451 was downregulated in clinical bladder carcinoma tissues compared with adjacent bladder tissues. Overexpression of miR-451 significantly retarded the proliferation, migration and invasion of bladder cancer T24 and 5637 cells in vitro. Moreover, the attenuated cell migration and invasion by miR-451 was correlated with increased apoptosis. However, our dual-luciferase reporter assay validated that c-Myc, an oncogene in many tumors, was a direct target gene of miR-451 in bladder cancer. The expression of c-Myc was repressed by miR-451 in bladder cancer cells, and knockdown of c-Myc mimicked the effects of miR-451 overexpression. This discovery suggested that miR-451 is a tumor suppressor modulating bladder cancer cell migration and invasion by directly targeting c-Myc. In addition, apoptosis promoted by miR-451 may participates in this biological behavior. Therefore, target miR-451 may be a novel therapeutic intervention for bladder cancer.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Zuiverloon TC, Nieuweboer AJ, Vékony H, Kirkels WJ, Bangma CH and Zwarthoff EC: Markers predicting response to bacillus Calmette-Guérin immunotherapy in high-risk bladder cancer patients: A systematic review. Eur Urol. 61:128–145. 2012. View Article : Google Scholar
3	Luke C, Tracey E, Stapleton A and Roder D: Exploring contrary trends in bladder cancer incidence, mortality and survival: Implications for research and cancer control. Intern Med J. 40:357–362. 2010. View Article : Google Scholar
4	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
5	Lages E, Ipas H, Guttin A, Nesr H, Berger F and Issartel JP: MicroRNAs: Molecular features and role in cancer. Front Biosci. 17:2508–2540. 2012. View Article : Google Scholar
6	Xiu Y, Liu Z, Xia S, Jin C, Yin H, Zhao W and Wu Q: Micro-RNA-137 upregulation increases bladder cancer cell proliferation and invasion by targeting PAQR3. PLoS One. 9:e1097342014. View Article : Google Scholar
7	Price C and Chen J: MicroRNAs in cancer biology and therapy: Current status and perspectives. Genes Dis. 1:53–63. 2014. View Article : Google Scholar : PubMed/NCBI
8	Tölle A, Ratert N and Jung K: miRNA panels as biomarkers for bladder cancer. Biomarkers Med. 8:733–746. 2014. View Article : Google Scholar
9	Pan X, Wang R and Wang ZX: The potential role of miR-451 in cancer diagnosis, prognosis, and therapy. Mol Cancer Ther. 12:1153–1162. 2013. View Article : Google Scholar : PubMed/NCBI
10	Fukumoto I, Kinoshita T, Hanazawa T, Kikkawa N, Chiyomaru T, Enokida H, Yamamoto N, Goto Y, Nishikawa R, Nakagawa M, et al: Identification of tumour suppressive microRNA-451a in hypopharyngeal squamous cell carcinoma based on microRNA expression signature. Br J Cancer. 111:386–394. 2014. View Article : Google Scholar : PubMed/NCBI
11	Yin P, Peng R, Peng H, Yao L, Sun Y, Wen L, Wu T, Zhou J and Zhang Z: MiR-451 suppresses cell proliferation and metastasis in A549 lung cancer cells. Mol Biotechnol. 57:1–11. 2015. View Article : Google Scholar
12	Lv G, Hu Z, Tie Y, Du J, Fu H, Gao X and Zheng X: MicroRNA-451 regulates activating transcription factor 2 expression and inhibits liver cancer cell migration. Oncol Rep. 32:1021–1028. 2014.PubMed/NCBI
13	Xu H, Mei Q, Shi L, Lu J, Zhao J and Fu Q: Tumor-suppressing effects of miR451 in human osteosarcoma. Cell Biochem Biophys. 69:163–168. 2014. View Article : Google Scholar
14	Godlewski J, Nowicki MO, Bronisz A, Nuovo G, Palatini J, De Lay M, Van Brocklyn J, Ostrowski MC, Chiocca EA and Lawler SE: MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol Cell. 37:620–632. 2010. View Article : Google Scholar : PubMed/NCBI
15	Chen MB, Wei MX, Han JY, Wu XY, Li C, Wang J, Shen W and Lu PH: MicroRNA-451 regulates AMPK/mTORC1 signaling and fascin1 expression in HT-29 colorectal cancer. Cell Signal. 26:102–109. 2014. View Article : Google Scholar
16	Eble JN, Sauter G, Epstein JI and Sesterhenn IA: World Health Organization classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARC Press; Lyon: 2004
17	Kawahara T, Kashiwagi E, Ide H, Li Y, Zheng Y, Miyamoto Y, Netto GJ, Ishiguro H and Miyamoto H: Cyclosporine A and tacrolimus inhibit bladder cancer growth through down-regulation of NFATc1. Oncotarget. 6:1582–1593. 2015. View Article : Google Scholar : PubMed/NCBI
18	Mehlen P and Puisieux A: Metastasis: A question of life or death. Nat Rev Cancer. 6:449–458. 2006. View Article : Google Scholar : PubMed/NCBI
19	Raghavan A and Shah ZA: Withania somnifera improves ischemic stroke outcomes by attenuating PARP1-AIF-mediated caspase-independent apoptosis. Mol Neurobiol. 52:1093–1105. 2015. View Article : Google Scholar
20	Hwang HW and Mendell JT: MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 94:776–780. 2006. View Article : Google Scholar : PubMed/NCBI
21	Costa PM and Pedroso de Lima MC: MicroRNAs as molecular targets for cancer therapy: On the modulation of microRNA expression. Pharmaceuticals. 6:1195–1220. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wu CT, Lin WY, Chang YH, Lin PY, Chen WC and Chen MF: DNMT1-dependent suppression of microRNA424 regulates tumor progression in human bladder cancer. Oncotarget. 6:24119–24131. 2015. View Article : Google Scholar : PubMed/NCBI
23	Itesako T, Seki N, Yoshino H, Chiyomaru T, Yamasaki T, Hidaka H, Yonezawa T, Nohata N, Kinoshita T, Nakagawa M, et al: The microRNA expression signature of bladder cancer by deep sequencing: The functional significance of the miR-195/497 cluster. PLoS One. 9:e843112014. View Article : Google Scholar : PubMed/NCBI
24	Li X, Sanda T, Look AT, Novina CD and von Boehmer H: Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL. J Exp Med. 208:663–675. 2011. View Article : Google Scholar : PubMed/NCBI
25	Kovalchuk O, Filkowski J, Meservy J, Ilnytskyy Y, Tryndyak VP, Chekhun VF and Pogribny IP: Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 7:2152–2159. 2008. View Article : Google Scholar : PubMed/NCBI
26	Zeng T, Peng L, Chao C, Fu B, Wang G, Wang Y and Zhu X: miR-451 inhibits invasion and proliferation of bladder cancer by regulating EMT. Int J Clin Exp Pathol. 7:7653–7662. 2014.
27	Hofmann UB, Houben R, Bröcker EB and Becker JC: Role of matrix metalloproteinases in melanoma cell invasion. Biochimie. 87:307–314. 2005. View Article : Google Scholar : PubMed/NCBI
28	Strand S, Vollmer P, van den Abeelen L, Gottfried D, Alla V, Heid H, Kuball J, Theobald M, Galle PR and Strand D: Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells. Oncogene. 23:3732–3736. 2004. View Article : Google Scholar : PubMed/NCBI
29	Abraham R, Schäfer J, Rothe M, Bange J, Knyazev P and Ullrich A: Identification of MMP-15 as an anti-apoptotic factor in cancer cells. J Biol Chem. 280:34123–34132. 2005. View Article : Google Scholar : PubMed/NCBI
30	Perron MP and Provost P: Protein interactions and complexes in human microRNA biogenesis and function. Front Biosci. 13:2537–2547. 2008. View Article : Google Scholar
31	Chen BJ, Wu YL, Tanaka Y and Zhang W: Small molecules targeting c-Myc oncogene: Promising anti-cancer therapeutics. Int J Biol Sci. 10:1084–1096. 2014. View Article : Google Scholar : PubMed/NCBI
32	Dang CV: MYC on the path to cancer. Cell. 149:22–35. 2012. View Article : Google Scholar : PubMed/NCBI
33	Seo HK, Ahn KO, Jung NR, Shin JS, Park WS, Lee KH, Lee SJ and Jeong KC: Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer. Oncotarget. 5:326–337. 2014. View Article : Google Scholar : PubMed/NCBI
34	Lin F, Ding R, Zheng S, Xing D, Hong W, Zhou Z and Shen J: Decreased expression of microRNA-744 promotes cell proliferation by targeting c-Myc in human hepatocellular carcinoma. Cancer Cell Int. 14:582014. View Article : Google Scholar
35	Liu Z, Zhang G, Li J, Liu J and Lv P: The tumor-suppressive microRNA-135b targets c-myc in osteoscarcoma. PLoS One. 9:e1026212014. View Article : Google Scholar : PubMed/NCBI
36	Yang X, Cai H, Liang Y, Chen L, Wang X, Si R, Qu K, Jiang Z, Ma B, Miao C, et al: Inhibition of c-Myc by let-7b mimic reverses mutidrug resistance in gastric cancer cells. Oncol Rep. 33:1723–1730. 2015.PubMed/NCBI
37	Lü M, Ding K, Zhang G, Yin M, Yao G, Tian H, Lian J, Liu L, Liang M, Zhu T, et al: MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRγ. Sci Rep. 5:87352015. View Article : Google Scholar