MicroRNA‑130a inhibits the proliferation, migration and invasive ability of hepatocellular carcinoma cells by downregulating Rho‑kinase 2

Zheng,Yansong; Xiang,Liangguang; Chen,Mingliu; Xiang,Chunhui

doi:10.3892/mmr.2018.9283

MicroRNA‑130a inhibits the proliferation, migration and invasive ability of hepatocellular carcinoma cells by downregulating Rho‑kinase 2

Authors:
- Yansong Zheng
- Liangguang Xiang
- Mingliu Chen
- Chunhui Xiang
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China, Department of General Surgery, Fuqing City Hospital, Fuqing, Fujian 350300, P.R. China, Department of Neurosurgery, The Central Hospital of Enshi Autonomy State, Enshi, Hubei 445000, P.R. China
Published online on: July 16, 2018 https://doi.org/10.3892/mmr.2018.9283
Pages: 3077-3084

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

MicroRNA‑130a (miR‑130a) has been reported to be downregulated in hepatocellular carcinoma (HCC). However, the roles and underlying tumor‑suppressive mechanisms of miR‑130a in the pathogenesis of HCC remain unclear. In the current study, reduced expression of miR‑130a was observed in tumor tissues of patients with HCC in addition to in four HCC cell lines, BEL‑7402, MHCC97H, HepG2 and Huh7. Results of methyl thiazolyl tetrazolium (MTT) assays identified decreased growth rates of MHCC97H and HepG2 cells transfected with miR‑130a mimics. The in vitro colony formation assays demonstrated that the number of colonies formed by cells transfected with miR‑130a mimics and cells transfected with miR‑130a inhibitors was lower and higher, respectively, than that formed by the cells transfected with miR‑negative control. In addition, it was identified that overexpression of miR‑130a reduced the migration and invasiveness of MHCC97H and HepG2 cells. Luciferase reporter assays demonstrated that miR‑130a directly targeted the 3'‑untranslated region of Rho‑kinase 2 (ROCK2) mRNA. Northern and western blot analyses indicated that miR‑130a could modulate the mRNA and protein expression of ROCK2. Additionally, small‑interfering RNA‑mediated knockdown of ROCK2 decreased the proliferation, migration and invasiveness of MHCC97H and HepG2 cells. Overall, these observation suggest that miR‑130a is a regulator of ROCK2 and can inhibit proliferation, migration and invasive ability of HCC cells, at least in part, by suppressing the expression of ROCK2. The current study provides further insight into the molecular mechanisms of HCC pathogenesis and suggests a new potential biotarget for HCC treatment.

View Figures

View References

1	Arzumanyan A, Reis HM and Feitelson MA: Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 13:123–135. 2013. View Article : Google Scholar : PubMed/NCBI
2	Zhang Y, Takahashi S, Tasaka A, Yoshima T, Ochi H and Chayama K: Involvement of microRNA-224 in cell proliferation, migration, invasion, and anti-apoptosis in hepatocellular carcinoma. J Gastroenterol Hepatol. 28:565–575. 2013. View Article : Google Scholar : PubMed/NCBI
3	Zhao C, Li Y, Zhang M, Yang Y and Chang L: miR-126 inhibits cell proliferation and induces cell apoptosis of hepatocellular carcinoma cells partially by targeting Sox2. Hum Cell. 28:91–99. 2015. View Article : Google Scholar : PubMed/NCBI
4	He C, Dong X, Zhai B, Jiang X, Dong D, Li B, Jiang H, Xu S and Sun X: MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget. 6:28867–28881. 2015. View Article : Google Scholar : PubMed/NCBI
5	Shi J, Wu X, Surma M, Vemula S, Zhang L, Yang Y, Kapur R and Wei L: Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment. Cell Death Dis. 4:e4832013. View Article : Google Scholar : PubMed/NCBI
6	Kümper S, Mardakheh FK, McCarthy A, Yeo M, Stamp GW, Paul A, Worboys J, Sadok A, Jørgensen C, Guichard S and Marshall CJ: Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis. Elife. 5:e129942016. View Article : Google Scholar :
7	Julian L and Olson MF: Rho-associated coiled-coil containing kinases (ROCK): Structure, regulation, and functions. Small GTPases. 5:e298462014. View Article : Google Scholar : PubMed/NCBI
8	Schofield AV, Steel R and Bernard O: Rho-associated coiled-coil kinase (ROCK) protein controls microtubule dynamics in a novel signaling pathway that regulates cell migration. J Biol Chem. 287:43620–43629. 2012. View Article : Google Scholar : PubMed/NCBI
9	Wong CC, Wong CM, Tung EK, Man K and Ng IO: Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion. Hepatology. 49:1583–1594. 2009. View Article : Google Scholar : PubMed/NCBI
10	Molnár A, Schwach F, Studholme DJ, Thuenemann EC and Baulcombe DC: miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii. Nature. 447:1126–1129. 2007. View Article : Google Scholar : PubMed/NCBI
11	Lin L, Gan H, Zhang H, Tang W, Sun Y, Tang X, Kong D, Zhou J, Wang Y and Zhu Y: MicroRNA-21 inhibits SMAD7 expression through a target sequence in the 3′ untranslated region and inhibits proliferation of renal tubular epithelial cells. Mol Med Rep. 10:707–712. 2014. View Article : Google Scholar : PubMed/NCBI
12	Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, Chow A, O'Connor ST, Li S, Chin AR, et al: Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 17:183–194. 2015. View Article : Google Scholar : PubMed/NCBI
13	Mendell JT and Olson EN: MicroRNAs in stress signaling and human disease. Cell. 148:1172–1187. 2012. View Article : Google Scholar : PubMed/NCBI
14	Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y and Zheng X: miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer lett. 275:44–53. 2009. View Article : Google Scholar : PubMed/NCBI
15	Li B, Huang P, Qiu J, Liao Y, Hong J and Yuan Y: MicroRNA-130a is down-regulated in hepatocellular carcinoma and associates with poor prognosis. Med Oncol. 31:2302014. View Article : Google Scholar : PubMed/NCBI
16	Sun T, Fu J, Shen T, Lin X, Liao L, Feng XH and Xu J: The small C-terminal domain phosphatase 1 inhibits cancer cell migration and invasion by dephosphorylating Ser(P)68-twist1 to accelerate twist1 protein degradation. J Biol Chem. 291:11518–11528. 2016. View Article : Google Scholar : PubMed/NCBI
17	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
18	Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B and Perrier A: OLT for HCC Consensus Group: Recommendations for liver transplantation for hepatocellular carcinoma: An international consensus conference report. Lancet Oncol. 13:e11–e22. 2012. View Article : Google Scholar : PubMed/NCBI
19	Giordano S and Columbano A: MicroRNAs: New tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma? Hepatology. 57:840–847. 2013. View Article : Google Scholar : PubMed/NCBI
20	Acunzo M, Visone R, Romano G, Veronese A, Lovat F, Palmieri D, Bottoni A, Garofalo M, Gasparini P, Condorelli G, et al: miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222. Oncogene. 31:634–642. 2012. View Article : Google Scholar : PubMed/NCBI
21	Shen S, Guo X, Yan H, Lu Y, Ji X, Li L, Liang T, Zhou D, Feng XH, Zhao JC, et al: A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis. Cell Res. 25:997–1012. 2015. View Article : Google Scholar : PubMed/NCBI
22	Matsuoka T and Yashiro M: Rho/ROCK signaling in motility and metastasis of gastric cancer. World J Gastroenterol. 20:13756–13766. 2014. View Article : Google Scholar : PubMed/NCBI
23	Vigil D, Kim TY, Plachco A, Garton AJ, Castaldo L, Pachter JA, Dong H, Chen X, Tokar B, Campbell SL and Der CJ: ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. Cancer Res. 72:5338–5347. 2012. View Article : Google Scholar : PubMed/NCBI
24	Liu T, Yu X, Li G, Yuan R, Wang Q, Tang P, Wu L, Liu X, Peng X and Shao J: Rock2 regulates Cdc25A through ubiquitin proteasome system in hepatocellular carcinoma cells. Exp Cell Res. 318:1994–2003. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wang W, Zhou X and Wei M: MicroRNA-144 suppresses osteosarcoma growth and metastasis by targeting ROCK1 and ROCK2. Oncotarget. 6:10297–10308. 2015.PubMed/NCBI
26	Huang D, Du X, Yuan R, Chen L, Liu T, Wen C, Huang M, Li M, Hao L and Shao J: Rock2 promotes the invasion and metastasis of hepatocellular carcinoma by modifying MMP2 ubiquitination and degradation. Biochem Biophys Res Commun. 453:49–56. 2014. View Article : Google Scholar : PubMed/NCBI
27	Lin S and Gregory RI: MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 15:321–333. 2015. View Article : Google Scholar : PubMed/NCBI
28	Kroiss A, Vincent S, Decaussin-Petrucci M, Meugnier E, Viallet J, Ruffion A, Chalmel F, Samarut J and Allioli N: Androgen-regulated microRNA-135a decreases prostate cancer cell migration and invasion through downregulating ROCK1 and ROCK2. Oncogene. 34:2846–2855. 2015. View Article : Google Scholar : PubMed/NCBI
29	Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, Bian XW, Guan XY, Lin MC, Zeng YX, et al: The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 61:278–289. 2012. View Article : Google Scholar : PubMed/NCBI
30	Boll K, Reiche K, Kasack K, Mörbt N, Kretzschmar AK, Tomm JM, Verhaegh G, Schalken J, Von Bergen M, Horn F and Hackermüller J: MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene. 32:277–285. 2013. View Article : Google Scholar : PubMed/NCBI