miR‑410 regulates apoptosis by targeting Bak1 in human colorectal cancer cells

Liu,Chunyuan; Zhang,Aihong; Cheng,Lei; Gao,Yang

doi:10.3892/mmr.2016.5271

miR‑410 regulates apoptosis by targeting Bak1 in human colorectal cancer cells

Authors:
- Chunyuan Liu
- Aihong Zhang
- Lei Cheng
- Yang Gao
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Affiliations: Department of General Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China
Published online on: May 13, 2016 https://doi.org/10.3892/mmr.2016.5271
Pages: 467-473

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Abstract

MicroRNAs (miRs) are essential in the pathogenesis of colorectal cancer (CRC). Previous studies have demonstrated that miR‑410 exerts multiple effects on tumors, however, whether it affects the apoptosis of CRC cells remains to be elucidated. In the present study, to demonstrate the role of miR-410 in CRC, miR-410 expression was detected in CRC tissues and cell lines, and the miR-410 level was manipulated by transfection with an miR-410 or miR-410 inhibitor in CRC cells. Cell growth and apoptosis was tested using an MTT assay, western blot and cytochrome C assay. Target validation was conducted by luciferase assay. It was found that miR‑410 was upregulated in CRC tissues and cell lines. The overexpression of miR‑410 resulted in an increase in growth activity and decrease in the extent of apoptosis. By contrast, the inhibition of endogenous miR‑410 activated the apoptotic machinery. Western blot analysis and a luciferase activity assay showed that Bak1 was directly targeted by miR‑410, and that knockdown of Bak1 attenuated the pro‑apoptotic effect of miR‑410 inhibition. In addition, it was shown that the expression of Bak1 was downregulated in CRC tumor tissues and was reversely correlated with the expression of miR‑410, which provided further support that Bak1 was regulated by miR‑410. The results of the present study suggested that miR‑410 may function as an oncogenic miR by suppressing the basal level of apoptosis. These findings may assist in understanding the molecular mechanisms of cancer development.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Hagan S, Orr MC and Doyle B: Targeted therapies in colorectal cancer-an integrative view by PPPM. EPMA J. 4:32013. View Article : Google Scholar : PubMed/NCBI
3	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
4	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
5	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
6	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
7	Kloosterman WP and Plasterk RH: The diverse functions of microRNAs in animal development and disease. Dev Cell. 11:441–450. 2006. View Article : Google Scholar : PubMed/NCBI
8	Schetter AJ, Okayama H and Harris CC: The role of microRNAs in colorectal cancer. Cancer J. 18:244–252. 2012. View Article : Google Scholar : PubMed/NCBI
9	Nieminen AI, Eskelinen VM, Haikala HM, Tervonen TA, Yan Y, Partanen JI and Klefström J: Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosis. Proc Natl Acad Sci USA. 110:E1839–E1848. 2013. View Article : Google Scholar : PubMed/NCBI
10	Shimizu S, Narita M and Tsujimoto Y: Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature. 399:483–487. 1999. View Article : Google Scholar : PubMed/NCBI
11	Pryczynicz A, Gryko M, Niewiarowska K, Cepowicz D, Ustymowicz M, Kemona A and Guzińska-Ustymowicz K: Bax protein may influence the invasion of colorectal cancer. World J Gastroenterol. 20:1305–1310. 2014. View Article : Google Scholar : PubMed/NCBI
12	García-Flórez LJ, Gómez-Álvarez G, Frunza AM, Barneo-Serra L, Martínez-Alonso C and Fresno-Forcelledo MF: Predictive markers of response to neoadjuvant therapy in rectal cancer. J Surg Res. 194:120–126. 2015. View Article : Google Scholar
13	Xin M, Li R, Xie M, Park D, Owonikoko TK, Sica GL, Corsino PE, Zhou J, Ding C, White MA, et al: Small-molecule Bax agonists for cancer therapy. Nat Commun. 5:49352014. View Article : Google Scholar : PubMed/NCBI
14	Ogura E, Senzaki H, Yamamoto D, Yoshida R, Takada H, Hioki K and Tsubura A: Prognostic significance of Bcl-2, Bcl-xL/S, Bax and Bak expressions in colorectal carcinomas. Oncol Rep. 6:365–369. 1999.PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar
16	Naghdi S, Varnai P and Hajnoczky G: Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis. Proc Natl Acad Sci USA. 112:E5590–E5599. 2015. View Article : Google Scholar : PubMed/NCBI
17	Michael MZ, O' Connor SM, van Holst Pellekaan NG, Young GP and James RJ: Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 1:882–891. 2003.PubMed/NCBI
18	Luo X, Burwinkel B, Tao S and Brenner H: MicroRNA signatures: Novel biomarker for colorectal cancer? Cancer Epidemiol Biomarkers Prev. 20:1272–1286. 2011. View Article : Google Scholar : PubMed/NCBI
19	Akao Y, Nakagawa Y, Hirata I, Iio A, Itoh T, Kojima K, Nakashima R, Kitade Y and Naoe T: Role of anti-oncomirs miR-143 and -145 in human colorectal tumors. Cancer Gene Ther. 17:398–408. 2010. View Article : Google Scholar : PubMed/NCBI
20	Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S and Allgayer H: MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 27:2128–2136. 2008. View Article : Google Scholar
21	Peacock O, Lee AC, Cameron F, Tarbox R, Vafadar-Isfahani N, Tufarelli C and Lund JN: Inflammation and MiR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer. PloS One. 9:e1102672014. View Article : Google Scholar : PubMed/NCBI
22	Lin PL, Wu DW, Huang CC, He TY, Chou MC, Sheu GT and Lee H: MicroRNA-21 promotes tumour malignancy via increased nuclear translocation of β-catenin and predicts poor outcome in APC-mutated but not in APC-wild-type colorectal cancer. Carcinogenesis. 35:2175–2182. 2014. View Article : Google Scholar : PubMed/NCBI
23	Shen J, Niu W, Zhou M and Zhang H, Ma J, Wang L and Zhang H: MicroRNA-410 suppresses migration and invasion by targeting MDM2 in gastric cancer. PloS One. 9:e1045102014. View Article : Google Scholar : PubMed/NCBI
24	Chen N, Wang J, Hu Y, Cui B, Li W, Xu G, Liu L and Liu S: MicroRNA-410 reduces the expression of vascular endothelial growth factor and inhibits oxygen-induced retinal neovascularization. PloS One. 9:e956652014. View Article : Google Scholar : PubMed/NCBI
25	Choi SW, Kim JJ, Seo MS, Park SB, Kang TW, Lee JY, Lee BC, Kang I, Shin TH, Kim HS, et al: miR-410 inhibition induces RPE differentiation of amniotic epithelial stem cells via overexpression of OTX2 and RPE65. Stem Cell Rev. 11:376–386. 2015. View Article : Google Scholar
26	Chien WW, Domenech C, Catallo R, Kaddar T, Magaud JP, Salles G and Ffrench M: Cyclin-dependent kinase 1 expression is inhibited by p16(INK4a) at the post-transcriptional level through the microRNA pathway. Oncogene. 30:1880–1891. 2011. View Article : Google Scholar
27	Chen L, Zhang J, Feng Y, Li R, Sun X, Du W, Piao X, Wang H, Yang D, Sun Y, et al: MiR-410 regulates MET to influence the proliferation and invasion of glioma. Int J Biochem Cell Biol. 44:1711–1717. 2012. View Article : Google Scholar : PubMed/NCBI
28	Wang Y, Fu J, Jiang M, Zhang X, Cheng L, Xu X, Fan Z, Zhang J, Ye Q and Song H: MiR-410 is overexpressed in liver and colorectal tumors and enhances tumor cell growth by silencing FHL1 via a direct/indirect mechanism. PloS One. 9:e1087082014. View Article : Google Scholar : PubMed/NCBI
29	Liu Y and Bodmer WF: Analysis of P53 mutations and their expression in 56 colorectal cancer cell lines. Proc Natl Acad Sci USA. 103:976–981. 2006. View Article : Google Scholar : PubMed/NCBI
30	Oden-Gangloff A, Di Fiore F, Bibeau F, Lamy A, Bougeard G, Charbonnier F, Blanchard F, Tougeron D, Ychou M, Boissière F, et al: TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy. Br J Cancer. 100:1330–1335. 2009. View Article : Google Scholar : PubMed/NCBI
31	Luo HY and Xu RH: Predictive and prognostic biomarkers with therapeutic targets in advanced colorectal cancer. World J Gastroenterol. 20:3858–3874. 2014. View Article : Google Scholar : PubMed/NCBI
32	Baltaziak M, Koda M, Wincewicz A, Sulkowska M, Kanczuga-Koda L and Sulkowski S: Relationships of P53 and Bak with EPO and EPOR in human colorectal cancer. Anticancer Res. 29:4151–4156. 2009.PubMed/NCBI
33	Kondo S, Shinomura Y, Miyazaki Y, Kiyohara T, Tsutsui S, Kitamura S, Nagasawa Y, Nakahara M, Kanayama S and Matsuzawa Y: Mutations of the bak gene in human gastric and colorectal cancers. Cancer research. 60:4328–4330. 2000.PubMed/NCBI
34	Krajewska M, Moss SF, Krajewski S, Song K, Holt PR and Reed JC: Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas. Cancer Res. 56:2422–2427. 1996.PubMed/NCBI
35	Chen X, Liu J, Feng WK, Wu X and Chen SY: MiR-125b protects against ethanol-induced apoptosis in neural crest cells and mouse embryos by targeting Bak 1 and PUMA. Exp Neurol. 271:104–111. 2015. View Article : Google Scholar : PubMed/NCBI
36	Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, et al: Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 26:745–752. 2007. View Article : Google Scholar : PubMed/NCBI
37	Gao J, Li N, Dong Y, Li S, Xu L, Li X, Li Y, Li Z, Ng SS, Sung JJ, et al: miR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer. Oncogene. 34:4142–4152. 2015. View Article : Google Scholar
38	Rokavec M, Öner MG, Li H, Jackstadt R, Jiang L, Lodygin D, Kaller M, Horst D, Ziegler PK, Schwitalla S, et al: IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 124:1853–1867. 2014. View Article : Google Scholar : PubMed/NCBI
39	Talotta F, Cimmino A, Matarazzo MR, Casalino L, De Vita G, D'Esposito M, Di Lauro R and Verde P: An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation. Oncogene. 28:73–84. 2009. View Article : Google Scholar