miRNA‑125a‑5p inhibits hepatocellular carcinoma cell proliferation and induces apoptosis by targeting TP53 regulated inhibitor of apoptosis 1 and Bcl‑2‑like‑2 protein

Ming,Ma; Ying,Ma; Ling,Ma

doi:10.3892/etm.2019.7674

miRNA‑125a‑5p inhibits hepatocellular carcinoma cell proliferation and induces apoptosis by targeting TP53 regulated inhibitor of apoptosis 1 and Bcl‑2‑like‑2 protein

Authors:
- Ma Ming
- Ma Ying
- Ma Ling
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830001, P.R. China, Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China, Department of Pharmacy, Xinjiang Uygur Autonomous Region Chest Hospital, Urumqi, Xinjiang 830049, P.R. China
Published online on: June 14, 2019 https://doi.org/10.3892/etm.2019.7674
Pages: 1196-1202
Copyright: © Ming et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

The present study aimed to investigate the role and underlying molecular mechanism of microRNA (miR)‑125a‑5p in hepatocellular carcinoma. The level of miR‑125a‑5p was detected using reverse transcription‑quantitative polymerase chain reaction. TargetScan was used to investigate the association between miR‑125a‑5p and TP53‑regulated inhibitor of apoptosis 1 (TRIAP1)/B cell lymphoma‑2‑like 2 protein (BCL2L2). Dual luciferase reporter assay was used to confirm this prediction. To investigate the role of miR‑125a‑5p in hepatocellular carcinoma (HCC) cells, miR‑125a‑5p was overexpressed in the human HCC cell line PLC/PRF/5 using miR‑125a‑5p mimics. Subsequently, cell proliferation, cell apoptosis and cell migration were studied using MTT assay, flow cytometry analysis and Transwell assay, respectively. Protein expression levels in the present study were measured by western blot analysis. Taken together, the present results suggested that miR‑125a‑5p was markedly downregulated in HCC cells. TRIAP1 and BCL2L2 were direct targets of miR‑125a‑5p and were upregulated in PLC/PRF/5 cells. miR‑125a‑5p upregulation inhibited PLC/PRF/5 cell viability and migration and induced cell apoptosis. In addition, miR‑125a‑5p overexpression increased the expression of caspase9 and apoptotic protease‑activating factor 1. Notably, the present study revealed that all the effects on PLC/PRF/5 cells elicited by miR‑125a‑5p overexpression were eliminated by TRIAP1/BCL2L2 upregulation. In conclusion, miR‑125a‑5p was shown to be downregulated in hepatocellular carcinoma and its upregulation inhibited hepatocellular carcinoma cell growth and metastasis by targeting TRIAP1 and BCL2L2.

View Figures

View References

1	Chiou JF, Tai CJ, Huang MT, Wei PL, Wang YH, An J, Wu CH, Liu TZ and Chang YJ: Glucose-regulated protein 78 is a novel contributor to acquisition of resistance to sorafenib in hepatocellular carcinoma. Ann Surg Oncol. 17:603–612. 2010. View Article : Google Scholar : PubMed/NCBI
2	Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A and Gennari L: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 334:693–699. 1996. View Article : Google Scholar : PubMed/NCBI
3	Bruix J and Sherman M; American Association for the Study of Liver Diseases, : Management of hepatocellular carcinoma: An update. Hepatology. 53:1020–1022. 2011. View Article : Google Scholar : PubMed/NCBI
4	Greten TF and Sangro B: Targets for immunotherapy of liver cancer. J Hepatol. Sep 18–2017.(Epub ahead of print).
5	Anindo MI and Yaqinuddin A: Insights into the potential use of microRNAs as biomarker in cancer. Int J Surg. 10:443–449. 2012. View Article : Google Scholar : PubMed/NCBI
6	Chandrasekaran K, Karolina DS, Sepramaniam S, Armugam A, Wintour EM, Bertram JF and Jeyaseelan K: Role of microRNAs in kidney homeostasis and disease. Kidney Int. 81:617–627. 2012. View Article : Google Scholar : PubMed/NCBI
7	Petrovic N, Ergün S and Isenovic ER: Levels of MicroRNA heterogeneity in cancer biology. Mol Diagn Ther. 21:511–523. 2017. View Article : Google Scholar : PubMed/NCBI
8	Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 133:647–658. 2007. View Article : Google Scholar : PubMed/NCBI
9	Alhoot MA, Wang SM and Sekaran SD: RNA interference mediated inhibition of dengue virus multiplication and entry in HepG2 cells. PLoS One. 7:e340602012. View Article : Google Scholar : PubMed/NCBI
10	Jin Y, Wang J, Han J, Luo D and Sun Z: MiR-122 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Snail1 and Snail2 and suppressing WNT/β-cadherin signaling pathway. Exp Cell Res. 360:210–217. 2017. View Article : Google Scholar : PubMed/NCBI
11	Zhong L, Sun S, Shi J, Cao F, Han X and Chen Z: MicroRNA-125a-5p plays a role as a tumor suppressor in lung carcinoma cells by directly targeting STAT3. Tumour Biol. 39:10104283176975792017. View Article : Google Scholar : PubMed/NCBI
12	Zheng H, Wu J, Shi J, Lu C, Wang Y, Sun Q, Zhang G and Zhao G: miR-125a-5p upregulation suppresses the proliferation and induces the cell apoptosis of lung adenocarcinoma by targeting NEDD9. Oncol Rep. 38:1790–1796. 2017. View Article : Google Scholar : PubMed/NCBI
13	Natalia MA, Alejandro GT, Virginia TJ and Alvarez-Salas LM: MARK1 is a novel target for miR-125a-5p: Implications for cell migration in cervical tumor cells. Microrna. 7:54–61. 2018. View Article : Google Scholar : PubMed/NCBI
14	Cao Y, Tan S, Tu Y, Zhang G, Liu Y, Li D, Xu S, Le Z, Xiong J, Zou W, et al: MicroRNA-125a-5p inhibits invasion and metastasis of gastric cancer cells by targeting BRMS1 expression. Oncol Lett. 15:5119–5130. 2018.PubMed/NCBI
15	Li G, Zhang W, Gong L and Huang X: MicroRNA 125a-5p inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma by downregulation of ErbB3. Oncol Res. 27:449–458. 2019. View Article : Google Scholar : PubMed/NCBI
16	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
17	Fook-Alves VL, de Oliveira MB, Zanatta DB, Strauss BE and Colleoni GW: TP53 regulated inhibitor of apoptosis 1 (TRIAP1) stable silencing increases late apoptosis by upregulation of caspase 9 and APAF1 in RPMI8226 multiple myeloma cell line. Biochim Biophys Acta. 1862:1105–1110. 2016. View Article : Google Scholar : PubMed/NCBI
18	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
19	Shimada K, Sakamoto Y, Esaki M, Kosuge T, Morizane C, Ikeda M, Ueno H, Okusaka T, Arai Y and Takayasu K: Analysis of prognostic factors affecting survival after initial recurrence and treatment efficacy for recurrence in patients undergoing potentially curative hepatectomy for hepatocellular carcinoma. Ann Surg Oncol. 14:2337–2347. 2007. View Article : Google Scholar : PubMed/NCBI
20	Xiao J, Yu W, Hu K, Li M, Chen J and Li Z: miR-92a promotes tumor growth of osteosarcoma by targeting PTEN/AKT signaling pathway. Oncol Rep. 37:2513–2521. 2017. View Article : Google Scholar : PubMed/NCBI
21	Xie F, Yuan Y, Xie L, Ran P, Xiang X, Huang Q, Qi G, Guo X, Xiao C and Zheng S: miRNA-320a inhibits tumor proliferation and invasion by targeting c-Myc in human hepatocellular carcinoma. Onco Targets Ther. 10:885–894. 2017. View Article : Google Scholar : PubMed/NCBI
22	Zhu HR, Huang RZ, Yu XN, Shi X, Bilegsaikhan E, Guo HY, Song GQ, Weng SQ, Dong L, Janssen HLA, et al: Microarray expression profiling of microRNAs reveals potential biomarkers for hepatocellular carcinoma. Tohoku J Exp Med. 245:89–98. 2018. View Article : Google Scholar : PubMed/NCBI
23	Yang T, Thakur A, Chen T, Yang L, Lei G, Liang Y, Zhang S, Ren H and Chen M: MicroRNA-15a induces cell apoptosis and inhibits metastasis by targeting BCL2L2 in non-small cell lung cancer. Tumour Biol. 36:4357–4365. 2015. View Article : Google Scholar : PubMed/NCBI
24	Jin S, Liu MD, Wu H, Pang P, Wang S, Li ZN, Sun CF and Liu FY: Overexpression of hsa-miR-125a-5p enhances proliferation, migration and invasion of head and neck squamous cell carcinoma cell lines by upregulating C-C chemokine receptor type 7. Oncol Lett. 15:9703–9710. 2018.PubMed/NCBI
25	Li Y, Tang X, He Q, Yang X, Ren X, Wen X, Zhang J, Wang Y, Liu N and Ma J: Overexpression of mitochondria mediator gene TRIAP1 by miR-320b loss is associated with progression in nasopharyngeal carcinoma. PLoS Genet. 12:e10061832016. View Article : Google Scholar : PubMed/NCBI
26	Tiedt S, Prestel M, Malik R, Schieferdecker N, Duering M, Kautzky V, Stoycheva I, Böck J, Northoff BH, Klein M, et al: RNA-Seq identifies circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as potential biomarkers for acute ischemic stroke. Circ Res. 121:970–980. 2017. View Article : Google Scholar : PubMed/NCBI
27	Wen Y, Han J, Chen J, Dong J, Xia Y, Liu J, Jiang Y, Dai J, Lu J, Jin G, et al: Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int J Cancer. 137:1679–1690. 2015. View Article : Google Scholar : PubMed/NCBI