microRNA-16 represses colorectal cancer cell growth in vitro by regulating the p53/survivin signaling pathway

Ma,Qunying; Wang,Xinying; Li,Zhao; Li,Bingsheng; Ma,Fengli; Peng,Liang; Zhang,Yu; Xu,Angao; Jiang,Bo

doi:10.3892/or.2013.2262

microRNA-16 represses colorectal cancer cell growth in vitro by regulating the p53/survivin signaling pathway

Authors:
- Qunying Ma
- Xinying Wang
- Zhao Li
- Bingsheng Li
- Fengli Ma
- Liang Peng
- Yu Zhang
- Angao Xu
- Bo Jiang
View Affiliations

Affiliations: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Huizhou Medicine Institute, Huizhou First Hospital, Huizhou 516001, P.R. China
Published online on: January 31, 2013 https://doi.org/10.3892/or.2013.2262
Pages: 1652-1658

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

Dysregulated expression of microRNAs (miRNA) is a hallmark of cancer. miR-16 has been reported to be downregulated and to act as a tumor suppressor in different cancer types. In the present study, we sought to investigate the possible roles and mechanisms of miR-16 and its relationship with p53 and survivin in CRC cells. We showed that miR-16 was downregulated in 67% of CRC tissues and was correlated with the degree of histological differentiation. Experiments in vitro showed that overexpression of miR-16 inhibited the proliferation and induced apoptosis of CRC cells through the intrinsic apoptosis pathway. We further showed that miR-16 repressed survivin expression at both the mRNA and protein levels and the survivin gene was a direct target of miR-16. In addition, miR-16 reduced p53 expression and p53 increased miR-16 levels, with downregulation of miR-16 targets survivin, cyclin D1 and CDK6. Our findings suggest that miR-16 represses colorectal cancer cell growth in vitro by regulating the p53/survivin signaling pathway. Our findings provide further evidence for the involvement of dysregulated miRNAs in CRC, and miR-16 could serve as a molecular target for CRC therapy.

View Figures

View References

1	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
2	Friedman RC, Farh KK, Burge CB and Bartel DP: Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19:92–105. 2009. View Article : Google Scholar : PubMed/NCBI
3	Calin GA, Dumitru CD, Shimizu M, 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 : PubMed/NCBI
4	Bandi N, Zbinden S, Gugger M, et al: miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res. 69:5553–5559. 2009. View Article : Google Scholar : PubMed/NCBI
5	Bhattacharya R, Nicoloso M, Arvizo R, et al: miR-15a and miR-16 control Bmi-1 expression in ovarian cancer. Cancer Res. 69:9090–9095. 2009. View Article : Google Scholar : PubMed/NCBI
6	Bonci D, Coppola V, Musumeci M, et al: The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med. 14:1271–1277. 2008. View Article : Google Scholar : PubMed/NCBI
7	Aqeilan RI, Calin GA and Croce CM: miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ. 17:215–220. 2010. View Article : Google Scholar : PubMed/NCBI
8	Cimmino A, Calin GA, Fabbri M, et al: miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 102:13944–13949. 2005. View Article : Google Scholar : PubMed/NCBI
9	Tsang WP and Kwok TT: Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis in human cancer cells. J Nutr Biochem. 21:140–146. 2010. View Article : Google Scholar : PubMed/NCBI
10	Boominathan L: The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex. PLoS One. 5:e106152010. View Article : Google Scholar : PubMed/NCBI
11	Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S and Miyazono K: Modulation of microRNA processing by p53. Nature. 460:529–533. 2009. View Article : Google Scholar : PubMed/NCBI
12	Alexander D, Jhala N, Chatla C, et al: High-grade tumor differentiation is an indicator of poor prognosis in African Americans with colonic adenocarcinomas. Cancer. 103:2163–2170. 2005. View Article : Google Scholar : PubMed/NCBI
13	Feng S, Cong S, Zhang X, et al: MicroRNA-192 targeting retinoblastoma 1 inhibits cell proliferation and induces cell apoptosis in lung cancer cells. Nucleic Acids Res. 39:6669–6678. 2011. View Article : Google Scholar : PubMed/NCBI
14	Fabbri M, Bottoni A, Shimizu M, et al: Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA. 305:59–67. 2011. View Article : Google Scholar : PubMed/NCBI
15	Bottoni A, Piccin D, Tagliati F, Luchin A, Zatelli MC and degli Uberti EC: miR-15a and miR-16-1 down-regulation in pituitary adenomas. J Cell Physiol. 204:280–285. 2005. View Article : Google Scholar : PubMed/NCBI
16	Yip KW, Shi W, Pintilie M, et al: Prognostic significance of the Epstein-Barr virus, p53, Bcl-2, and survivin in nasopharyngeal cancer. Clin Cancer Res. 12:5726–5732. 2006. View Article : Google Scholar : PubMed/NCBI
17	Shen W, Wang CY, Wang XH and Fu ZX: Oncolytic adenovirus mediated Survivin knockdown by RNA interference suppresses human colorectal carcinoma growth in vitro and in vivo. J Exp Clin Cancer Res. 28:812009. View Article : Google Scholar
18	Ambrosini G, Adida C and Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 3:917–921. 1997. View Article : Google Scholar : PubMed/NCBI
19	Kawasaki H, Toyoda M, Shinohara H, et al: Expression of survivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis. Cancer. 91:2026–2032. 2001. View Article : Google Scholar : PubMed/NCBI
20	Lynch CJ and Milner J: Loss of one p53 allele results in four-fold reduction of p53 mRNA and protein: a basis for p53 haplo-insufficiency. Oncogene. 25:3463–3470. 2006. View Article : Google Scholar : PubMed/NCBI
21	Vegran F, Boidot R, Oudin C, Defrain C, Rebucci M and Lizard-Nacol S: Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer. Oncogene. 26:290–297. 2007. View Article : Google Scholar : PubMed/NCBI
22	Hoffman WH, Biade S, Zilfou JT, Chen J and Murphy M: Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem. 277:3247–3257. 2002. View Article : Google Scholar : PubMed/NCBI
23	Murphy M, Ahn J, Walker KK, et al: Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13:2490–2501. 1999. View Article : Google Scholar : PubMed/NCBI
24	Mirza A, McGuirk M, Hockenberry TN, et al: Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene. 21:2613–2622. 2002. View Article : Google Scholar : PubMed/NCBI
25	Raj D, Liu T, Samadashwily G, Li F and Grossman D: Survivin repression by p53, Rb and E2F2 in normal human melanocytes. Carcinogenesis. 29:194–201. 2008. View Article : Google Scholar : PubMed/NCBI
26	Yang X, Xiong G, Chen X, et al: Survivin expression in esophageal cancer: correlation with p53 mutations and promoter polymorphism. Dis Esophagus. 22:223–230. 2009. View Article : Google Scholar : PubMed/NCBI
27	Suh SO, Chen Y, Zaman MS, et al: MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. Carcinogenesis. 32:772–778. 2011. View Article : Google Scholar : PubMed/NCBI