MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma

Chen,Ren; Li,Xiaohai; He,Bin; Hu,Wei

doi:10.3892/mmr.2017.6149

MicroRNA-410 regulates autophagy-related gene ATG16L1 expression and enhances chemosensitivity via autophagy inhibition in osteosarcoma

Authors:
- Ren Chen
- Xiaohai Li
- Bin He
- Wei Hu
View Affiliations

Affiliations: Department of Spine Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: January 26, 2017 https://doi.org/10.3892/mmr.2017.6149
Pages: 1326-1334
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteosarcoma, which is the most common type of primary bone tumor in adolescents, is characterized by complex genetic alterations and frequent resistance to conventional treatments. MicroRNAs (miRs) have emerged as fundamental regulators in gene expression through their ability to silence gene expression at post-transcriptional and translational levels. The present study investigated the role of miR‑410 in the progression of osteosarcoma. The results demonstrated that the expression of miR‑410 was markedly downregulated in human osteosarcoma tissues, and U2OS and MG‑63 osteosarcoma cell lines. Clinicopathological significance suggested that miR‑410 may be a potential biomarker for chemotherapy‑resistant osteosarcoma. Furthermore, overexpression of miR‑410 exhibited a limited effect on cell viability in U2OS and MG‑63 cells. Target prediction algorithms (TargetScan and miRanda) indicated that autophagy related 16‑like 1 (ATG16L1) was a potential target gene of miR‑410. A luciferase reporter assay demonstrated that miR‑410 directly decreased ATG16L1 expression by targeting its 3'‑untranslated region. In addition, the results revealed that miR‑410 was able to markedly inhibit autophagy. Accordingly, autophagy was activated as a protective mechanism when osteosarcoma cells were exposed to three common anticancer drugs, including rapamycin, doxorubicin and cisplatin. Furthermore, the autophagy inhibitor 3‑methyladenine and miR‑410 expression were able to improve the therapeutic response of the cells to chemotherapy drugs (rapamycin, doxorubicin and cisplatin), thus indicating that miR‑410 enhanced chemosensitivity through autophagy inhibition in osteosarcoma cells. In conclusion, studies regarding the function of miR‑410 on autophagy provided insight into the biological function of miR‑410 in osteosarcoma and may offer a promising approach for the treatment of osteosarcoma.

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1	Tsai YC, Wu CT and Hong RL: Response of refractory osteosarcoma to thalidomide and celecoxib. Lancet Oncol. 6:997–999. 2005. View Article : Google Scholar : PubMed/NCBI
2	Zhang W, Li Q, Song C and Lao L: Knockdown of autophagy-related protein 6, Beclin-1, decreases cell growth, invasion, and metastasis and has a positive effect on chemotherapy-induced cytotoxicity in osteosarcoma cells. Tumour Biol. 36:2531–2539. 2015. View Article : Google Scholar : PubMed/NCBI
3	Xie Z, Xie Y, Xu Y, Zhou H, Xu W and Dong Q: Bafilomycin A1 inhibits autophagy and induces apoptosis in MG63 osteosarcoma cells. Mol Med Rep. 10:1103–1107. 2014.PubMed/NCBI
4	Kim HJ, Lee SG, Kim YJ, Park JE, Lee KY, Yoo YH and Kim JM: Cytoprotective role of autophagy during paclitaxel-induced apoptosis in Saos-2 osteosarcoma cells. Int J Oncol. 42:1985–1992. 2013.PubMed/NCBI
5	Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI
6	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
7	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
8	Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M and Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 101:2999–3004. 2004. View Article : Google Scholar : PubMed/NCBI
9	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
10	Labialle S, Marty V, Bortolin-Cavaillé ML, Hoareau-Osman M, Pradère JP, Valet P, Martin PG and Cavaillé J: The miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 domain controls neonatal metabolic adaptation. EMBO J. 33:2216–2230. 2014. View Article : Google Scholar : PubMed/NCBI
11	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
12	Huang J, Ni J, Liu K, Yu Y, Xie M, Kang R, Vernon P, Cao L and Tang D: HMGB1 promotes drug resistance in osteosarcoma. Cancer Res. 72:230–238. 2012. View Article : Google Scholar : PubMed/NCBI
13	Lambert LA, Qiao N, Hunt KK, Lambert DH, Mills GB, Meijer L and Keyomarsi K: Autophagy: A novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model. Cancer Res. 68:7966–7974. 2008. View Article : Google Scholar : PubMed/NCBI
14	Zhao Z, Tao L, Shen C, Liu B, Yang Z and Tao H: Silencing of Barkor/ATG14 sensitizes osteosarcoma cells to cisplatin-induced apoptosis. Int J Mol Med. 33:271–276. 2014.PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Cadwell K, Patel KK, Komatsu M, Virgin HW IV and Stappenbeck TS: A common role for Atg16L1, Atg5 and Atg7 in small intestinal Paneth cells and Crohn disease. Autophagy. 5:250–252. 2009. View Article : Google Scholar : PubMed/NCBI
17	Zhao D, Yuan H, Yi F, Meng C and Zhu Q: Autophagy prevents doxorubicin-induced apoptosis in osteosarcoma. Mol Med Rep. 9:1975–1981. 2014.PubMed/NCBI
18	Mu Y, Zhang H, Che L and Li K: Clinical significance of microRNA-183/Ezrin axis in judging the prognosis of patients with osteosarcoma. Med Oncol. 31:8212014. View Article : Google Scholar : PubMed/NCBI
19	Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F, et al: Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 465:942–946. 2010. View Article : Google Scholar : PubMed/NCBI
20	Behrends C, Sowa ME, Gygi SP and Harper JW: Network organization of the human autophagy system. Nature. 466:68–76. 2010. View Article : Google Scholar : PubMed/NCBI
21	Yao F, Wang G, Wei W, Tu Y, Tong H and Sun S: An autophagy inhibitor enhances the inhibition of cell proliferation induced by a proteasome inhibitor in MCF-7 cells. Mol Med Rep. 5:84–88. 2012.PubMed/NCBI
22	Yang C and Han LO: Knockdown of Beclin 1 inhibits vitamin K3-induced autophagy, but promotes apoptosis of human hepatoma SMMC-7721 cells. Mol Med Rep. 3:801–807. 2010.PubMed/NCBI
23	Apel A, Herr I, Schwarz H, Rodemann HP and Mayer A: Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 68:1485–1494. 2008. View Article : Google Scholar : PubMed/NCBI
24	Zhang J, Yan YG, Wang C, Zhang SJ, Yu XH and Wang WJ: MicroRNAs in osteosarcoma. Clin Chim Acta. 444:9–17. 2015. View Article : Google Scholar : PubMed/NCBI
25	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
26	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
27	Chen L, Jiang K, Jiang H and Wei P: miR-155 mediates drug resistance in osteosarcoma cells via inducing autophagy. Exp Ther Med. 8:527–532. 2014.PubMed/NCBI
28	Li X, Wang S, Chen Y, Liu G and Yang X: miR-22 targets the 3′ UTR of HMGB1 and inhibits the HMGB1-associated autophagy in osteosarcoma cells during chemotherapy. Tumour Biol. 35:6021–6028. 2014. View Article : Google Scholar : PubMed/NCBI
29	Shen C, Wang W, Tao L, Liu B, Yang Z and Tao H: Chloroquine blocks the autophagic process in cisplatin-resistant osteosarcoma cells by regulating the expression of p62/SQSTM1. Int J Mol Med. 32:448–456. 2013.PubMed/NCBI
30	Wu W, Li W, Zhou Y and Zhang C: Inhibition of beclin1 affects the chemotherapeutic sensitivity of osteosarcoma. Int J Clin Exp Pathol. 7:7114–7122. 2014.PubMed/NCBI