MicroRNA‑133a and microRNA‑326 co‑contribute to hepatocellular carcinoma 5‑fluorouracil and cisplatin sensitivity by directly targeting B‑cell lymphoma‑extra large

Ma,Jin; Wang,Ting; Guo,Rui; Yang,Xiaoyan; Yin,Jie; Yu,Jia; Xiang,Qiong; Pan,Xia; Zu,Xuyu; Peng,Cuiying; Tang,Huifang; Lei,Xiaoyong

doi:10.3892/mmr.2015.4134

MicroRNA‑133a and microRNA‑326 co‑contribute to hepatocellular carcinoma 5‑fluorouracil and cisplatin sensitivity by directly targeting B‑cell lymphoma‑extra large

Authors:
- Jin Ma
- Ting Wang
- Rui Guo
- Xiaoyan Yang
- Jie Yin
- Jia Yu
- Qiong Xiang
- Xia Pan
- Xuyu Zu
- Cuiying Peng
- Huifang Tang
- Xiaoyong Lei
View Affiliations

Affiliations: Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, P.R. China, Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China, Cardiology Department, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
Published online on: July 29, 2015 https://doi.org/10.3892/mmr.2015.4134
Pages: 6235-6240

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

Chemotherapy is one of the most common treatments used for hepatocellular carcinoma (HCC), which effectively improves outcome and reduces tumor recurrence. However, the drug resistance mechanisms involved in chemotherapy, which is the predominant challenge in HCC treatment, remain to be fully elucidated. Therefore, there is an urgent requirement for the identification of novel therapeutic strategies or drugs. MicroRNAs (miRs) have become an area of interest, and in the present study, the effects of miR‑133a and miR‑326 on HepG2 cells, and their function on B‑cell lymphoma‑extra large (Bcl‑xl) in HepG2 cells were investigated. Using computational programs, Bcl‑xl was predicted as the common target gene of miR‑133a and miR‑326. A dual‑luciferase reporter assay was used to verify the target genes of miRs. The mRNA and protein levels of Bcl‑xl were observed to be downregulated following transfection with miR‑133a or miR‑326 mimics. Combining miR‑133a or miR‑326 with 5‑fluorouracil (5‑FU) or cisplatin (DDP) resulted in increased cell death. The results of the present study indicated that miR‑133a, miR‑326 and Bcl‑xl acted protectively against the apoptosis, induced by 5‑FU or DDP, in HepG2 cells. This suggested the potential use of miRs either as ancillary anti‑cancer drugs or as anti‑cancer drugs themselves.

View Figures

View References

1	Witko-Sarsat V: Apoptosis, cell death and inflammation. J Innate Immun. 2:201–203. 2010. View Article : Google Scholar : PubMed/NCBI
2	Ghatage DD, Gosavi SR, Ganvir SM and Hazarey VK: Apoptosis: Molecular mechanism. J Orofac Sci. 4:103–107. 2012. View Article : Google Scholar
3	Schultz DR and Harrington WJ Jr: Apoptosis: Programmed cell death at a molecular level. Semin Arthritis Rheum. 32:345–369. 2003. View Article : Google Scholar : PubMed/NCBI
4	Zinkel S, Gross A and Yang E: BCL2 family in DNA damage and cell cycle control. Cell Death Differ. 13:1351–1359. 2006. View Article : Google Scholar : PubMed/NCBI
5	Danial NN and Korsmeyer SJ: Cell death: critical control points. Cell. 116:205–219. 2004. View Article : Google Scholar : PubMed/NCBI
6	Petros AM, Olejniczak ET and Fesik SW: Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta. 1644:83–94. 2004. View Article : Google Scholar : PubMed/NCBI
7	Lynam-Lennon N, Maher SG and Reynolds JV: The roles of microRNA in cancer and apoptosis. Biol Rev Camb Philos Soc. 84:55–71. 2009. View Article : Google Scholar
8	Chen G, Umelo IA, Lv S, et al: miR-146a inhibits cell growth, cell migration and induces apoptosis in non-small cell lung cancer cells. PLoS One. 8:e603172013. View Article : Google Scholar : PubMed/NCBI
9	Di Leva G, Garofalo M and Croce CM: MicroRNAs in Cancer. Annu Rev Pathol. 9:287–314. 2014. View Article : Google Scholar :
10	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
11	Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013. View Article : Google Scholar : PubMed/NCBI
12	Xu J, Zhu X, Wu L, et al: MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/β-catenin pathway. Liver Int. 32:752–760. 2012. View Article : Google Scholar : PubMed/NCBI
13	Huang X, Huang F, Yang D, et al: Expression of microRNA-122 contributes to apoptosis in H9C2 myocytes. J Cell Mol Med. 16:2637–2646. 2012. View Article : Google Scholar : PubMed/NCBI
14	Tang Y, Zheng J, Sun Y, et al: MicroRNA-1 regulates cardiomyocyte apoptosis by targeting Bcl-2. Int Heart J. 50:377–387. 2009. View Article : Google Scholar : PubMed/NCBI
15	Xiong Y, Fang JH, Yun JP, et al: Effects of microRNA-29 on apoptosis, tumorigenicity and prognosis of hepatocellular carcinoma. Hepatology. 51:836–845. 2010.
16	Zhao A, Zeng Q, Xie X, et al: MicroRNA-125b induces cancer cell apoptosis through suppression of Bcl-2 expression. J Genet Genomics. 39:29–35. 2012. View Article : Google Scholar : PubMed/NCBI
17	Jia HY, Wang YX, Yan WT, et al: MicroRNA-125b Functions as a Tumor Suppressor in Hepatocellular Carcinoma Cells. Int J Mol Sci. 13:8762–8774. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lin CJ, Gong HY, Tseng HC, et al: miR-122 targets an anti-apoptotic gene, Bcl-w, in human hepatocellular carcinoma cell lines. Biochem Biophys Res Commun. 375:315–320. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kontos CK, Christodoulou MI and Scorilas A: Apoptosis-related BCL2-Family members: Key players in chemotherapy. Anticancer Agents Med Chem. 14:353–374. 2014. View Article : Google Scholar
20	Qiu T, Zhou L, Wang T, et al: miR-503 regulates the resistance of non-small cell lung cancer cells to cisplatin by targeting Bcl-2. Int J Mol Med. 32:593–598. 2013.PubMed/NCBI
21	Yang X, Yin J, Yu J, et al: miRNA-195 sensitizes human hepatocellular carcinoma cells to 5-FU by targeting BCL-w. Oncol Rep. 27:250–257. 2012.
22	Qin B, Xiao B, Liang D, et al: MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis. BMB Rep. 45:464–469. 2012. View Article : Google Scholar : PubMed/NCBI
23	Guo R, Wang Y, Shi WY, et al: MicroRNA miR-491–5p targeting both TP53 and Bcl-XL induces cell apoptosis in SW1990 pancreatic cancer cells through mitochondria-mediated pathway. Molecules. 17:14733–14747. 2012. View Article : Google Scholar : PubMed/NCBI
24	Ling HY, Ou HS, Feng SD, et al: CHANGES IN microRNA (miR) profile and effects of miR-320 in insulin-resistant 3T3-L1 adipocytes. Clin Exp Pharmacol Physiol. 36:e32–39. 2009. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2 (^−ΔΔC_T) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
26	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
27	Khatri R and Subramanian S: MicroRNA-135b and Its circuitry networks as potential therapeutic targets in colon cancer. Front Oncol. 3:2682013. View Article : Google Scholar : PubMed/NCBI
28	Nian W, Ao X, Wu Y, et al: miR-223 functions as a potent tumor suppressor of the Lewis lung carcinoma cell line by targeting insulin-like growth factor-1 receptor and cyclin-dependent kinase 2. Oncol Lett. 6:359–366. 2013.PubMed/NCBI
29	Georgantas RW, Streicher K, Zhu W, et al: MicroRNA oncogenes and tumor suppressors controlling malignant melanoma cell growth, apoptosis, migration, and invasion. J Clin Oncol. 29:85492011.
30	Wang XF, Shi ZM, Wang XR, et al: MiR-181d acts as a tumor suppressor in glioma by targeting K-ras and Bcl-2. J Cancer Res Clin Oncol. 138:573–584. 2012. View Article : Google Scholar
31	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
32	Ji F, Zhang H, Wang Y, et al: MicroRNA-133a, downregulated in osteosarcoma, suppresses proliferation and promotes apoptosis by targeting Bcl-xl and Mcl-1. Bone. 56:220–226. 2013. View Article : Google Scholar : PubMed/NCBI
33	Zhou J, Xu T, Yan Y, et al: MicroRNA-326 functions as a tumor suppressor in glioma by targeting the Nin one binding protein (NOB1). PLoS One. 8:e684692013. View Article : Google Scholar : PubMed/NCBI
34	Liang Z, Wu H, Xia J, et al: Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem Pharmacol. 79:817–824. 2010. View Article : Google Scholar :