miR‑30a‑3p inhibits the proliferation of liver cancer cells by targeting DNMT3a through the PI3K/AKT signaling pathway

Chen,Qiong; Gao,Yuan; Yu,Qin; Tang,Feng; Zhao,Pei‑Wei; Luo,Su‑Kun; Lin,Ju‑Sheng; Mei,Hong

doi:10.3892/ol.2019.11179

miR‑30a‑3p inhibits the proliferation of liver cancer cells by targeting DNMT3a through the PI3K/AKT signaling pathway

Authors:
- Qiong Chen
- Yuan Gao
- Qin Yu
- Feng Tang
- Pei‑Wei Zhao
- Su‑Kun Luo
- Ju‑Sheng Lin
- Hong Mei
View Affiliations

Affiliations: Department of Gastroenterology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China, Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China, Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China, Clinical Research Center, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
Published online on: December 3, 2019 https://doi.org/10.3892/ol.2019.11179
Pages: 606-614
Copyright: © Chen 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

MicroRNAs (miRNAs or miRs) are crucial for normal development and maintenance of homeostasis. Dysregulated miRNA expression contributes to numerous pathological conditions, including cancer tumorigenesis. However, a limited number of studies have examined the regulatory effects of miR‑30a‑3p in tumorigenesis. Therefore, the present study investigated the mechanistic process of tumorigenesis in liver cancer. The results revealed a high expression of DNA methyltransferase 3a (DNMT3a) and a low expression of miR‑30a‑3p in HepG2 cells compared with that in the L02 cell line. A luciferase reporter assay demonstrated that DNMT3a is a direct target of miR‑30a‑3p. In addition, DNMT3a overexpression significantly enhanced cell proliferation, which was reversed by a miR‑30a‑3p mimic. Similarly, the miR‑30a‑3p mimic blocked DNMT3a‑triggered cell cycle processes and apoptosis by attenuating active p‑AKT and p‑PI3K in HepG2 cells. In summary, the results of the present study demonstrate that miR‑30a‑3p is essential for cell proliferation regulation via its association with AKT/PI3K signaling in liver cancer. These results provide insight into the molecular mechanism by which miR‑30a‑3p inhibits liver cancer cell proliferation and provides a foundation for its clinical development and application.

View Figures

View References

1	Liu Y, Wang Y, Sun X, Mei C, Wang L, Li Z and Zha X: miR-449a promotes liver cancer cell apoptosis by downregulation of Calpain 6 and POU2F1. Oncotarget. 7:13491–13501. 2016.PubMed/NCBI
2	Azlin AH, Looi LM and Cheah PL: Tissue microarray immunohistochemical profiles of p53 and pRB in hepatocellular carcinoma and hepatoblastoma. Asian Pac J Cancer Prev. 15:3959–3963. 2014. View Article : Google Scholar : PubMed/NCBI
3	López-Terrada D, Cheung SW, Finegold MJ and Knowles BB: Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol. 40:1512–1515. 2009. View Article : Google Scholar
4	Liu CY, Chen KF and Chen PJ: Treatment of liver cancer. Cold Spring Harb Perspect Med. 5:a0215352015. View Article : Google Scholar : PubMed/NCBI
5	Yang G, Song Y, Zhou X, Deng Y, Liu T, Weng G, Yu D and Pan S: DNA methyltransferase 3, a target of microRNA-29c, contributes to neuronal proliferation by regulating the expression of brain-derived neurotrophic factor. Mol Med Rep. 12:1435–1442. 2015. View Article : Google Scholar : PubMed/NCBI
6	Cocozza S, Akhtar MM, Miele G and Monticelli A: CpG islands undermethylation in human genomic regions under selective pressure. PLoS One. 6:e231562011. View Article : Google Scholar : PubMed/NCBI
7	Cui H, Wang L, Gong P, Zhao C, Zhang S, Zhang K, Zhou R, Zhao Z and Fan H: Deregulation between miR-29b/c and DNMT3A is associated with epigenetic silencing of the CDH1 gene, affecting cell migration and invasion in gastric cancer. PLoS One. 10:e01239262015. View Article : Google Scholar : PubMed/NCBI
8	Huang C, Liu H, Gong XL, Wu LY and Wen B: Effect of evodiamine and berberine on the interaction between DNMTs and target microRNAs during malignant transformation of the colon by TGF-β1. Oncol Rep. 37:1637–1645. 2017. View Article : Google Scholar : PubMed/NCBI
9	Huang C, Liu H, Gong XL, Wu L and Wen B: Expression of DNA methyltransferases and target microRNAs in human tissue samples related to sporadic colorectal cancer. Oncol Rep. 36:2705–2714. 2016. View Article : Google Scholar : PubMed/NCBI
10	Wang YC, Tang FY, Chen SY, Chen YM and Chiang EP: Glycine-N methyltransferase expression in HepG2 cells is involved in methyl group homeostasis by regulating transmethylation kinetics and DNA methylation. J Nutr. 141:777–782. 2011. View Article : Google Scholar : PubMed/NCBI
11	Kloosterman WP and Plasterk RH: The diverse functions of microRNAs in animal development and disease. Dev Cell. 11:441–450. 2006. View Article : Google Scholar : PubMed/NCBI
12	Zhou L, Liu F, Wang X and Ouyang G: The roles of microRNAs in the regulation of tumor metastasis. Cell Biosci. 5:322015. View Article : Google Scholar : PubMed/NCBI
13	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ding T, Xu JH, Sun MM, Zhu S and Gao J: Predicting microRNA biological functions based on genes discriminant analysis. Comput Biol Chem. 71:230–235. 2017. View Article : Google Scholar : PubMed/NCBI
15	Xu N, Zhang J, Shen C, Luo Y, Xia L, Xue F and Xia Q: Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. Biochem Biophys Res Commun. 423:826–831. 2012. View Article : Google Scholar : PubMed/NCBI
16	Carthew RW and Sontheimer EJ: Origins and mechanisms of miRNAs and siRNAs. Cell. 136:642–655. 2009. View Article : Google Scholar : PubMed/NCBI
17	Jia XQ, Cheng HQ, Qian X, Bian CX, Shi ZM, Zhang JP, Jiang BH and Feng ZQ: Lentivirus-mediated overexpression of microRNA-199a inhibits cell proliferation of human hepatocellular carcinoma. Cell Biochem Biophys. 62:237–244. 2012. View Article : Google Scholar : PubMed/NCBI
18	Wang Y, Chen FQ, Zhao M, Yang Z, Li J, Zhang S, Zhang W, Ye L and Zhang X: The long noncoding RNA HULC promotes liver cancer by increasing the expression of the HMGA2 oncogene via sequestration of the microRNA-186. J Biol Chem. 292:15395–15407. 2017. View Article : Google Scholar : PubMed/NCBI
19	Chen R, Liao JY, Huang J, Chen WL, Ma XJ and Luo XD: Downregulation of SRC kinase signaling inhibitor 1 (SRCIN1) expression by MicroRNA-32 promotes proliferation and epithelial-mesenchymal transition in human liver cancer cells. Oncol Res. 26:573–579. 2018. View Article : Google Scholar : PubMed/NCBI
20	Yin S, Fan Y, Zhang H, Zhao Z, Hao Y, Li J, Sun C, Yang J, Yang Z, Yang X, et al: Differential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis. Nat Commun. 7:110122016. View Article : Google Scholar : PubMed/NCBI
21	Chen KJ, Hou Y, Wang K, Li J, Xia Y, Yang XY, Lv G, Xing XL and Shen F: Reexpression of Let-7g microRNA inhibits the proliferation and migration via K-Ras/HMGA2/snail axis in hepatocellular carcinoma. Biomed Res Int. 2014:7424172014.PubMed/NCBI
22	Ma Y, She XG, Ming YZ and Wan QQ: miR-24 promotes the proliferation and invasion of HCC cells by targeting SOX7. Tumour Biol. 35:10731–10736. 2014. View Article : Google Scholar : PubMed/NCBI
23	Ke K and Lou T: MicroRNA-10a suppresses breast cancer progression via PI3K/Akt/mTOR pathway. Oncol Lett. 14:5994–6000. 2017.PubMed/NCBI
24	Li Y, Nie Y, Tu S, Wang H, Zhou Y, Du Y, Cao J and Ye M: Epigenetically deregulated miR-200c is involved in a negative feedback loop with DNMT3a in gastric cancer cells. Oncol Rep. 36:2108–2116. 2016. View Article : Google Scholar : PubMed/NCBI
25	Ingegnere T, Mariotti FR, Pelosi A, Quintarelli C, De Angelis B, Tumino N, Besi F, Cantoni C, Locatelli F, Vacca P and Moretta L: Human CAR NK cells: A new non-viral method allowing high efficient transfection and strong tumor cell killing. Front Immunol. 10:9572019. View Article : Google Scholar : PubMed/NCBI
26	Song H, Li D, Wu T, Xie D, Hua K, Hu J, Deng X, Ji C, Deng Y and Fang L: MicroRNA-301b promotes cell proliferation and apoptosis resistance in triple-negative breast cancer by targeting CYLD. BMB Rep. 51:602–607. 2018. View Article : Google Scholar : PubMed/NCBI
27	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
28	Zhang ZM, Lu R, Wang PC, Yu Y, Chen D, Gao L, Liu S, Ji D, Rothbart SB, Wang Y, et al: Structural basis for DNMT3A-mediated de novo DNA methylation. Nature. 554:387–391. 2018. View Article : Google Scholar : PubMed/NCBI
29	Zhou Y, Gu P, Shi W, Li J, Hao Q, Cao X, Lu Q and Zeng Y: MicroRNA-29a induces insulin resistance by targeting PPARδ in skeletal muscle cells. Int J Mol Med. 37:931–938. 2016. View Article : Google Scholar : PubMed/NCBI
30	Li XY, Feng XZ, Tang JZ, Dong K, Wang JF, Meng CC, Wang J, Mo YW and Sun ZW: MicroRNA-200b inhibits the proliferation of hepatocellular carcinoma by targeting DNA methyltransferase 3a. Mol Med Rep. 13:3929–3935. 2016. View Article : Google Scholar : PubMed/NCBI
31	Zhu Y, Zheng G, Wang H, Jia Y, Zhang Y, Tang Y, Li W, Fan Y, Zhang X, Liu Y and Liu S: Downregulated miR-29a/b/c during contact inhibition stage promote 3T3-L1 adipogenesis by targeting DNMT3A. PLoS One. 12:e01706362017. View Article : Google Scholar : PubMed/NCBI
32	Zhang Q, Feng Y, Liu P and Yang J: MiR-143 inhibits cell proliferation and invasion by targeting DNMT3A in gastric cancer. Tumour Biol. 39:10104283177113122017. View Article : Google Scholar : PubMed/NCBI
33	Wang L, Yao J, Sun H, He K, Tong D, Song T and Huang C: MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A. Oncol Lett. 13:329–338. 2017. View Article : Google Scholar : PubMed/NCBI
34	Wang W, Lin H, Zhou L, Zhu Q, Gao S, Xie H, Liu Z, Xu Z, Wei J, Huang X and Zheng S: MicroRNA-30a-3p inhibits tumor proliferation, invasiveness and metastasis and is downregulated in hepatocellular carcinoma. Eur J Surg Oncol. 40:1586–1594. 2014. View Article : Google Scholar : PubMed/NCBI
35	Liu X, Ji Q, Zhang C, Liu X, Liu Y, Liu N, Sui H, Zhou L, Wang S and Li Q: miR-30a acts as a tumor suppressor by double-targeting COX-2 and BCL9 in H. pylori gastric cancer models. Sci Rep. 7:71132017. View Article : Google Scholar : PubMed/NCBI
36	Lu W, Lu T and Wei X: Downregulation of DNMT3a expression increases miR-182-induced apoptosis of ovarian cancer through caspase-3 and caspase-9-mediated apoptosis and DNA damage response. Oncol Rep. 36:3597–3604. 2016. View Article : Google Scholar : PubMed/NCBI
37	Li H, Yang F, Gao B, Yu Z, Liu X, Xie F and Zhang J: Hepatitis B virus infection in hepatocellular carcinoma tissues upregulates expression of DNA methyltransferases. Int J Clin Exp Med. 8:4175–4185. 2015.PubMed/NCBI
38	Zhao Z, Wu Q, Cheng J, Qiu X, Zhang J and Fan H: Depletion of DNMT3A suppressed cell proliferation and restored PTEN in hepatocellular carcinoma cell. J Biomed Biotechnol. 2010:7375352010. View Article : Google Scholar : PubMed/NCBI
39	Zhou GQ, Han F, Shi ZL, Yu L, Li XF, Yu C, Shen CL, Wan DW, Zhu XG, Li R and He SB: DNMT3A-mediated down-regulation of microRNA-105 promotes gastric cancer cell proliferation. Eur Rev Med Pharmacol Sci. 21:3377–3383. 2017.PubMed/NCBI
40	Xia Z, Zhang N and Ding D: Proliferation and migration of hepatoblastoma cells are mediated by IRS-4 via PI3K/Akt pathways. Int J Clin Exp Med. 7:3763–3769. 2014.PubMed/NCBI
41	Esmaeili MA, Farimani MM and Kiaei M: Anticancer effect of calycopterin via PI3K/Akt and MAPK signaling pathways, ROS-mediated pathway and mitochondrial dysfunction in hepatoblastoma cancer (HepG2) cells. Mol Cell Biochem. 397:17–31. 2014. View Article : Google Scholar : PubMed/NCBI
42	Liu J, Chen W, Zhang H, Liu T and Zhao L: miR-214 targets the PTEN-mediated PI3K/Akt signaling pathway and regulates cell proliferation and apoptosis in ovarian cancer. Oncol Lett. 14:5711–5718. 2017.PubMed/NCBI
43	He W and Cheng Y: Inhibition of miR-20 promotes proliferation and autophagy in articular chondrocytes by PI3K/AKT/mTOR signaling pathway. Biomed Pharmacother. 97:607–615. 2018. View Article : Google Scholar : PubMed/NCBI