miR-15a and miR-16-1 downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma

Cai,Cheng-Kui; Zhao,Guang-Yi; Tian,Li-Ying; Liu,Lie; Yan,Kang; Ma,Yun-Lei; Ji,Zhen-Wei; Li,Xiao-Xiang; Han,Kang; Gao,Jie; Qiu,Xiu-Chun; Fan,Qing-Yu; Yang,Tong-Tao; Ma,Bao-An

doi:10.3892/or.2012.1995

miR-15a and miR-16-1 downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma

Authors:
- Cheng-Kui Cai
- Guang-Yi Zhao
- Li-Ying Tian
- Lie Liu
- Kang Yan
- Yun-Lei Ma
- Zhen-Wei Ji
- Xiao-Xiang Li
- Kang Han
- Jie Gao
- Xiu-Chun Qiu
- Qing-Yu Fan
- Tong-Tao Yang
- Bao-An Ma
View Affiliations

Affiliations: Department of Orthopedic Surgery Center and Orthopedic Oncology Institute of People's Liberation Army, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China , Department of Orthopedics, Baoji Center Hospital, Baoji, Shaanxi 710038, P.R. China
Published online on: August 24, 2012 https://doi.org/10.3892/or.2012.1995
Pages: 1764-1770

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

Osteosarcoma, the most common primary tumor of the bones, causes many deaths due to its rapid proliferation and drug resistance. Recent studies have shown that cyclin D1 plays a key regulatory role during cell proliferation, and non-coding microRNAs (miRNAs) act as crucial modulators of cyclin D1 (CCND1). The aim of the current study was to determine the role of miRNAs in controlling CCND1 expression and inducing cell apoptosis. CCND1 has been found to be a target of miR-15a and miR-16-1 through analysis of complementary sequences between microRNAs and CCND1 mRNA. The upregulation of miR-15a and miR-16-1 in the cell line SOSP-9607 induces apoptosis and cell cycle arrest. Osteosarcoma cells transfected with miR-15a and miR-16-1 show slower proliferation curves. Moreover, the transcription of CCND1 is suppressed by miR-15a and miR-16-1 via direct binding to the CCND1 3'-untranslated region (3'-UTR). The data presented here demonstrate that the CCND1 contributes to osteosarcoma cell proliferation, suggesting that repression of CCND1 by miR-15a and miR-16-1 could be used for osteosarcoma therapy.

View Figures

View References

1	Kosacka M, Piesiak P, Porebska I, et al: The cyclin A, B1, D1, and E expression in advanced non-small cell lung cancer - stages IIIB-IV (preliminary report). Pol Merkur Lekarski. 30:253–258. 2011.(in Polish).
2	Chen RW, Bemis LT, Amato CM, et al: Truncation in CCND1 mRNA alters miR-16-1 regulation in mantel cell lymphoma. Blood. 112:822–829. 2008. View Article : Google Scholar : PubMed/NCBI
3	Miska EA: How microRNAs control cell division, diffentiation and death. Curr Opin Genet Dev. 15:563–568. 2005. View Article : Google Scholar : PubMed/NCBI
4	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
5	Carè A, Catalucci D, Felicetti F, et al: MicroRNA-133 controls cardiac hypertrophy. Nat Med. 13:613–618. 2007.
6	Bandi N, Zbinden S, Gugger M, et al: miR-15a and miR-16-1 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
7	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
8	Guo CJ, Pan Q, Jiang B, Chen GY and Li DG: Effects of upregulated expression of microRNA-16 on biological properties of culture-activated hepatic stellate cells. Apoptosis. 14:1331–1340. 2009. View Article : Google Scholar : PubMed/NCBI
9	Xu F, Zhang X, Lei Y, et al: Loss of repression of HuR translation by miR-16 may be responsible for the elevation of HuR in human breast carcinoma. J Cell Biochem. 111:727–734. 2010. View Article : Google Scholar : PubMed/NCBI
10	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
11	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
12	Xia L, Zhang DX, Du R, et al: miR-15b and miR-16-1 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 123:372–379. 2008. View Article : Google Scholar : PubMed/NCBI
13	Bottoni A, Piccin D, Tagliati F, et al: miR-15a and miR-16-1 down-regulation in pituitary adenomas. J Cell Physiol. 204:280–285. 2005. View Article : Google Scholar : PubMed/NCBI
14	Nedelcu T, Kubista B, Koller A, et al: Livin and Bcl-2 expression in high-grade osteosarcoma. J Cancer Res Clin Oncol. 134:237–244. 2008. View Article : Google Scholar : PubMed/NCBI
15	Gao J, Yang TT, Qiu XC, et al: Cloning and identification of microRNA from human osteosarcoma cell line SOSP-9607. Ai Zheng. 26:561–565. 2007.(In Chinese).
16	Tsang TY, Tang WY, Chan JY, et al: P-glycoprotein enhances radiation-induced apoptotic cell death through the regulation of miR-16 and Bcl-2 expressions in hepatocellar carcinoma cells. Apoptosis. 16:524–535. 2011. View Article : Google Scholar : PubMed/NCBI
17	Cimmino A, Calin GA, Fabbri M, et al: miR-15 and miR-16 induce apoptosis by targeting BCL-2. Proc Natl Acad Sci USA. 102:13944–13949. 2005. View Article : Google Scholar : PubMed/NCBI
18	Lerner M, Harada M, Lovén J, et al: DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1. Exp Cell Res. 315:2941–2952. 2009. View Article : Google Scholar : PubMed/NCBI
19	Shan LQ, Ma S, Qiu XC, et al: A novel recombinant immune-tBid with a furin site effectively suppresses the growth of HER2-positive osteosarcoma cells in vitro. Oncol Rep. 25:325–331. 2011.PubMed/NCBI
20	Wang LF, Zhou Y, Xu YM, et al: A caspase-6 and anti-HER2 antibody chimeric tumor-targeted proapoptotic molecule decreased metastasis of human osteosarcoma. Cancer Invest. 27:774–780. 2009. View Article : Google Scholar : PubMed/NCBI
21	Chen X, Yang TT, Wang W, et al: Establishment and characterization of human osteosarcoma cell lines with different pulmonary metastatic potentials. Cytotechnology. 61:37–44. 2009. View Article : Google Scholar : PubMed/NCBI
22	Sherr CJ: D-type cyclins. Trends Biochem Sci. 20:187–190. 1995. View Article : Google Scholar
23	Motokura T, Bloom T, Kim HG, et al: A novel cyclin encoded by a bell-linked candidate oncogene. Nature. 350:512–515. 1991. View Article : Google Scholar : PubMed/NCBI
24	Liu Q, Fu H, Sun F, et al: miR-16-1 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res. 36:5391–5404. 2008. View Article : Google Scholar : PubMed/NCBI
25	Iaquinta PJ and Lees JA: Life and death decisions by the E2F transcription factors. Curr Opin Cell Biol. 19:649–657. 2007. View Article : Google Scholar : PubMed/NCBI
26	Wu X and Levine AJ: p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci USA. 91:3602–3606. 1994. View Article : Google Scholar : PubMed/NCBI
27	Han EK, Ng SC, Arber N, Begemann M and Weinstein IB: Roles of cyclin D1 and related genes in growth inhibition, senescence and apoptosis. Apoptosis. 4:213–219. 1999. View Article : Google Scholar : PubMed/NCBI
28	Moroni MC, Hickman ES, Lazzerini Denchi E, et al: Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol. 3:552–558. 2001. View Article : Google Scholar : PubMed/NCBI
29	Han J, Flemington C, Houghton AB, et al: Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA. 98:11318–11323. 2001. View Article : Google Scholar : PubMed/NCBI
30	Nakano K and Vousden KH: PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 7:683–694. 2001. View Article : Google Scholar : PubMed/NCBI
31	Oda E, Ohki R, Murasawa H, et al: Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 288:1053–1058. 2000. View Article : Google Scholar : PubMed/NCBI
32	Fortin A, MacLaurin JG, Arbour N, et al: The proapoptotic gene SIVA is a direct transcriptional target for the tumor suppressors p53 and E2F1. J Biol Chem. 279:28706–28714. 2004. View Article : Google Scholar : PubMed/NCBI
33	Hershko T and Ginsberg D: Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem. 279:8627–8634. 2004. View Article : Google Scholar : PubMed/NCBI
34	Polager S and Ginsberg D: P53 and E2f: partners in life and death. Nat Rev Cancer. 9:738–748. 2009. View Article : Google Scholar : PubMed/NCBI