miR‑642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38&nbsp;MAPK signaling pathway

Yu,Zaijun; Du,Yuehe; Li,Hongying; Huang,Jichao; Jiang,Deqing; Fan,Jilong; Shen,Yuelan; Zhang,Lingling; Yu,Xiujuan; Xu,Na; Ke,Qungang

doi:10.3892/ol.2020.11935

miR‑642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38 MAPK signaling pathway

Authors:
- Zaijun Yu
- Yuehe Du
- Hongying Li
- Jichao Huang
- Deqing Jiang
- Jilong Fan
- Yuelan Shen
- Lingling Zhang
- Xiujuan Yu
- Na Xu
- Qungang Ke
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The Second People's Hospital of Lianyungang, Lianyungang, Jiangsu 222006, P.R. China, Department of Emergency Office, Center for Disease Control and Prevention of Lianyungang, Lianyungang, Jiangsu 222003, P.R. China
Published online on: July 30, 2020 https://doi.org/10.3892/ol.2020.11935
Article Number: 74
Copyright: © Yu 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

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and high risk. Study of the role and mechanism of miRNAs are a hot spot of research providing new treatment ideas in malignant tumors. The effect of miR‑642a on HCC progression and the underlying molecular mechanism were investigated. Expression of miR‑642a and SEMA4C was measured by western blot analysis and RT‑PCR. miR‑642a expression was elevated while SEMA4C expression was attenuated in HCC tissues and cells. Results of luciferase reporter and western blot analyses show that miR‑642a modulated SEMA4C expression by binding to its 3'UTR. Moreover, miR‑642a negatively regulated SEMA4C expression. HCC cell migration and invasion was tested by Transwell assays. The findings revealed that the number of migrated and invaded cells were reduced by miR‑642a mimic and raised by miR‑642a inhibitor, indicating that miR‑642a showed a suppression effect on HCC cell migration and invasion. Additionally, the migration and invasion of HCC cells were inhibited by SEMA4C siRNA, and SEMA4C reversed miR‑642a effect on HCC migration and invasion. Furthermore, p38 MAPK signaling pathway was proven to be inhibited by miR‑642a mimic, whereas facilitated by miR‑642a inhibitor and SEMA4C siRNA could overturn the promotion effect of miR‑642a inhibitor. Briefly, miR‑642a targeted SEMA4C to repress HCC cell migration and invasion through p38 MAPK signaling pathway providing a new strategy for treatment of HCC patients.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Fornari F, Ferracin M, Trerè D, Milazzo M, Marinelli S, Galassi M, Venerandi L, Pollutri D, Patrizi C, Borghi A, et al: Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, identify cirrhotic patients with HCC. PLoS One. 10:e01414482015. View Article : Google Scholar : PubMed/NCBI
3	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
4	Kassahun WT, Fangmann J, Harms J, Hauss J and Bartels M: Liver resection and transplantation in the management of hepatocellular carcinoma: A review. Exp Clin Transplant. 4:549–558. 2006.PubMed/NCBI
5	Dilou N, Patouillard B and Audigier JC: Staging systems in hepatocellular carcinoma. Gastroenterol Clin Biol. 28:359–366. 2004.(In French). View Article : Google Scholar : PubMed/NCBI
6	Ono K, Kuwabara Y and Han J: MicroRNAs and cardiovascular diseases. FEBS J. 278:1619–1633. 2011. View Article : Google Scholar : PubMed/NCBI
7	Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS and Johnson JM: Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 433:769–773. 2005. View Article : Google Scholar : PubMed/NCBI
8	Zhao S, Li J, Zhang G, Wang Q, Wu C, Zhang Q, Wang H, Sun P, Xiang R and Yang S: Exosomal miR-451a functions as a tumor suppressor in hepatocellular carcinoma by targeting LPIN1. Cell Physiol Biochem. 53:19–35. 2019. View Article : Google Scholar : PubMed/NCBI
9	Wu J, Huang WJ, Xi HL, Liu LY, Wang ST, Fan WZ and Peng BG: Tumor-suppressive miR-3650 inhibits tumor metastasis by directly targeting NFASC in hepatocellular carcinoma. Aging (Albany NY). 11:3432–3434. 2019. View Article : Google Scholar : PubMed/NCBI
10	Chen S, Wang L, Yao B, Liu Q and Guo C: miR-1307-3p promotes tumor growth and metastasis of hepatocellular carcinoma by repressing DAB2 interacting protein. Biomed Pharmacother. 117:1090552019. View Article : Google Scholar : PubMed/NCBI
11	Zhang J, Zhu Y, Hu L, Yan F and Chen J: miR-494 induces EndMT and promotes the development of HCC (hepatocellular carcinoma) by targeting SIRT3/TGF-β/SMAD signaling pathway. Sci Rep. 9:72132019. View Article : Google Scholar : PubMed/NCBI
12	Tang J, Zhuo H, Zhang X, Jiang R, Ji J, Deng L, Qian X, Zhang F and Sun B: A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma. Cell Death Dis. 5:e15492014. View Article : Google Scholar : PubMed/NCBI
13	Gurrapu S, Pupo E, Franzolin G, Lanzetti L and Tamagnone L: Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential. Cell Death Differ. 25:1259–1275. 2018. View Article : Google Scholar : PubMed/NCBI
14	Wei JC, Yang J, Liu D, Wu MF, Qiao L, Wang JN, Ma QF, Zeng Z, Ye SM, Guo ES, et al: Tumor-associated lymphatic endothelial cells promote lymphatic metastasis by highly expressing and secreting SEMA4C. Clin Cancer Res. 23:214–224. 2017. View Article : Google Scholar : PubMed/NCBI
15	Le AP, Huang Y, Pingle SC, Kesari S, Wang H, Yong RL, Zou H and Friedel RH: Plexin-B2 promotes invasive growth of malignant glioma. Oncotarget. 6:7293–7304. 2015. View Article : Google Scholar : PubMed/NCBI
16	Lu J, Lin Y, Li F, Ye H, Zhou R, Jin Y, Li B, Xiong X and Cheng N: miR-205 suppresses tumor growth, invasion, and epithelial-mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma. FASEB J. 32:fj201800113R2018. View Article : Google Scholar
17	Wu H, Wang X, Liu S, Wu Y, Zhao T, Chen X, Zhu L, Wu Y, Ding X, Peng X, et al: Sema4C participates in myogenic differentiation in vivo and in vitro through the p38 MAPK pathway. Eur J Cell Biol. 86:331–344. 2007. View Article : Google Scholar : PubMed/NCBI
18	Wang ZF, Liao F, Wu H and Dai J: Glioma stem cell-derived exosomal miR-26a promotes angiogenesis of microvessel endothelial cells in glioma. J Exp Clin Cancer Res. 38:2012019. View Article : Google Scholar : PubMed/NCBI
19	Zhang J, Hou L, Liang R, Chen X, Zhang R, Chen W and Zhu J: CircDLST promotes the tumorigenesis and metastasis of gastric cancer by sponging miR-502-5p and activating the NRAS/MEK1/ERK1/2 signaling. Mol Cancer. 18:802019. View Article : Google Scholar : PubMed/NCBI
20	Ma M, Dai J, Tang H, Xu T, Yu S, Si L, Cui C, Sheng X, Chi Z, Mao L, et al: MicroRNA-23a-3p inhibits mucosal melanoma growth and progression through targeting adenylate cyclase 1 and attenuating cAMP and MAPK pathways. Theranostics. 9:945–960. 2019. View Article : Google Scholar : PubMed/NCBI
21	Thorns C, Schurmann C, Gebauer N, Wallaschofski H, Kümpers C, Bernard V, Feller AC, Keck T, Habermann JK, Begum N, et al: Global microRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer Res. 34:2249–2254. 2014.PubMed/NCBI
22	Nordentoft I, Birkenkamp-Demtroder K, Agerbæk M, Theodorescu D, Ostenfeld MS, Hartmann A, Borre M, Ørntoft TF and Dyrskjøt L: miRNAs associated with chemo-sensitivity in cell lines and in advanced bladder cancer. BMC Med Genomics. 5:402012. View Article : Google Scholar : PubMed/NCBI
23	Epis MR, Giles KM, Kalinowski FC, Barker A, Cohen RJ and Leedman PJ: Regulation of expression of deoxyhypusine hydroxylase (DOHH), the enzyme that catalyzes the activation of eIF5A, by miR-331-3p and miR-642-5p in prostate cancer cells. J Biol Chem. 287:35251–35259. 2012. View Article : Google Scholar : PubMed/NCBI
24	Ye SM, Han M, Kan CY, Yang LL, Yang J, Ma QF and Wang SX: Expression and clinical significance of Sema4C in esophageal cancer, gastric cancer and rectal cancer. Zhonghua Yi Xue Za Zhi. 92:1954–1958. 2012.(In Chinese). PubMed/NCBI
25	Song J and Li Y: miR-25-3p reverses epithelial-mesenchymal transition via targeting Sema4C in cisplatin-resistance cervical cancer cells. Cancer Sci. 108:23–31. 2017. View Article : Google Scholar : PubMed/NCBI
26	Zhang Y and Huang S: Up-regulation of miR-125b reverses epithelial-mesenchymal transition in paclitaxel-resistant lung cancer cells. Biol Chem. Aug 20–2015.(Epub ahead of print). doi: 10.1515/hsz-2015-0153. View Article : Google Scholar
27	Li J, Wang Q, Wen R, Liang J, Zhong X, Yang W, Su D and Tang J: miR-138 inhibits cell proliferation and reverses epithelial-mesenchymal transition in non-small cell lung cancer cells by targeting GIT1 and SEMA4C. J Cell Mol Med. 19:2793–2805. 2015. View Article : Google Scholar : PubMed/NCBI
28	Chen J, Ji T, Wu D, Jiang S, Zhao J, Lin H and Cai X: Human mesenchymal stem cells promote tumor growth via MAPK pathway and metastasis by epithelial mesenchymal transition and integrin α5 in hepatocellular carcinoma. Cell Death Dis. 10:4252019. View Article : Google Scholar : PubMed/NCBI
29	Chatterjee S, Patra D, Chakraborti U, Sengupta D, Ghosh P, Basu A, Sadhukhan GC and Chowdhury KD: Association of p38 MAPK-p53-Fas aggregation in S-allyl cysteine mediated regulation of hepatocarcinoma. Environ Toxicol. 34:928–940. 2019. View Article : Google Scholar : PubMed/NCBI
30	Zhang GP, Yue X and Li SQ: Cathepsin C interacts with TNF-alpha/p38 MAPK signaling pathway to promote proliferation and metastasis in hepatocellular carcinoma. Cancer Res Treat. 52:10–23. 2020. View Article : Google Scholar : PubMed/NCBI