Mechanism of miR‑107‑targeting of regulator of G‑protein signaling 4 in hepatocellular carcinoma

Xiao,Di; Gao,Hai‑Xia

doi:10.3892/ol.2019.10857

Mechanism of miR‑107‑targeting of regulator of G‑protein signaling 4 in hepatocellular carcinoma

Authors:
- Di Xiao
- Hai‑Xia Gao
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Affiliations: Department of Liver Disease, Jinan Infectious Disease Hospital, Jinan, Shandong 250021, P.R. China, Department of ICU, Jinan Infectious Disease Hospital, Jinan, Shandong 250021, P.R. China
Published online on: September 12, 2019 https://doi.org/10.3892/ol.2019.10857
Pages: 5145-5154
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the mechanism of microRNA (miR)‑107 in targeting regulator of G‑protein signaling 4 (RGS4) in hepatic carcinoma. SK‑HEP‑1 cells were transfected with miR‑107 mimics and control mimics. Reverse transcription‑quantitative PCR was performed to determine the miR‑107 expression levels, and following miR‑107 upregulation, MTT, colony formation, transwell and wound‑healing assays were performed to assess cell proliferation, colony‑forming ability, invasion and migration, respectively. In addition, the effect of miR‑107 upregulation on the cell cycle and apoptosis in SK‑HEP‑1 cells was evaluated using flow cytometry. Western blot analysis was performed to measure the protein expression levels of RGS4, epidermal growth factor receptor (EGFR), CXC chemokine receptor type 4 (CXCR4) and matrix metalloproteinase (MMP)‑2 and ‑9. Expression level changes and the association between miR‑107 and RGS4 in HCC cells were assessed using dual luciferase analysis. The results indicated that the overexpression of miR‑107 in HCC cells suppressed cellular proliferation, invasion, migration and colony‑forming ability, but promoted apoptosis and G1 phase arrest. Furthermore, miR‑107 mimics notably increased the protein expression level of RGS4, but significantly downregulated that of EGFR, CXCR4 and MMP‑2 and ‑9. Together, these findings suggest that targeting this potential mechanism of miR‑107 may be beneficial in the treatment of patients with HCC.

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1	Diaz-Gonzalez A, Forner A, Rodriguez de Lope C and Varela M: New challenges in clinical research on hepatocellular carcinoma. Rev Esp Enferm Dig. 108:485–493. 2016.PubMed/NCBI
2	Singal AG, Pillai A and Tiro J: Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: A metaanalysis. PLoS Med. 11:e10016242014. View Article : Google Scholar : PubMed/NCBI
3	Mittal S, Kanwal F, Ying J, Chung R, Sada YH, Temple S, Davila JA and El-Serag HB: Effectiveness of surveillance for hepatocellular carcinoma in clinical practice: A United States cohort. J Hepatol. 65:1148–1154. 2016. View Article : Google Scholar : PubMed/NCBI
4	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
5	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
6	Garzon R, Calin GA and Croce CM: MicroRNAs in cancer. Annu Rev Med. 60:167–179. 2009. View Article : Google Scholar : PubMed/NCBI
7	Iorio MV and Croce CM: microRNA involvement in human cancer. Carcinogenesis. 33:1126–1133. 2012. View Article : Google Scholar : PubMed/NCBI
8	Ryan BM, Robles AI and Harris CC: Genetic variation in microRNA networks: The implications for cancer research. Nat Rev Cancer. 10:389–402. 2010. View Article : Google Scholar : PubMed/NCBI
9	Esquela-Kerscher A and Slack FJ: Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
10	Chen CZ: MicroRNAs as oncogenes and tumor suppressors. N Engl J Med. 353:1768–1771. 2005. View Article : Google Scholar : PubMed/NCBI
11	Zhang Y, Li T, Qiu Y, Zhang T, Guo P, Ma X, Wei Q and Han L: Serum microRNA panel for early diagnosis of the onset of hepatocellular carcinoma. Medicine (Baltimore). 96:e56422017. View Article : Google Scholar : PubMed/NCBI
12	El-Serag HB, Marrero JA, Rudolph L and Reddy R: Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 134:1752–1763. 2008. View Article : Google Scholar : PubMed/NCBI
13	Ayremlou N, Mozdarani H, Mowla SJ and Delavari A: Increased levels of serum and tissue miR-107 in human gastric cancer: Correlation with tumor hypoxia. Cancer Biomark. 15:851–860. 2015. View Article : Google Scholar : PubMed/NCBI
14	Takahashi Y, Forrest AR, Maeno E, Hashimoto T, Daub CO and Yasuda J: MiR-107 and MiR-185 can induce cell cycle arrest in human non-small cell lung cancer cell lines. PLoS One. 4:e66772009. View Article : Google Scholar : PubMed/NCBI
15	Lee KH, Lotterman C, Karikari C, Omura N, Feldmann G, Habbe N, Goggins MG, Mendell JT and Maitra A: Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology. 9:293–301. 2009. View Article : Google Scholar : PubMed/NCBI
16	Wang S, Ma G, Zhu H, Lv C, Chu H, Tong N, Wu D, Qiang F, Gong W, Zhao Q, et al: miR-107 regulates tumor progression by targeting NF1 in gastric cancer. Sci Rep. 6:365312016. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Chen F, Zhao M, Yang Z, Zhang S, Ye L, Gao H and Zhang X: MiR-107 suppresses proliferation of hepatoma cells through targeting HMGA2 mRNA 3′UTR. Biochem Biophys Res Commun. 480:455–460. 2016. View Article : Google Scholar : PubMed/NCBI
18	Jiang R, Zhang C, Liu G, Gu R and Wu H: MicroRNA-107 promotes proliferation, migration, and invasion of osteosarcoma cells by targeting tropomyosin 1. Oncol Res. 25:1409–1419. 2017. View Article : Google Scholar : PubMed/NCBI
19	He J, Zhang W, Zhou Q, Zhao T, Song Y, Chai L and Li Y: Low-expression of microRNA-107 inhibits cell apoptosis in glioma by upregulation of SALL4. Int J Biochem Cell Biol. 45:1962–1973. 2013. View Article : Google Scholar : PubMed/NCBI
20	Yamakuchi M, Lotterman CD, Bao C, Hruban RH, Karim B, Mendell JT, Huso D and Lowenstein CJ: P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proc Natl Acad Sci USA. 107:6334–6339. 2010. View Article : Google Scholar : PubMed/NCBI
21	Hollinger S and Hepler JR: Cellular regulation of RGS proteins: Modulators and integrators of G protein signaling. Pharmacol Rev. 54:527–559. 2002. View Article : Google Scholar : PubMed/NCBI
22	Gerber KJ, Squires KE and Hepler JR: Roles for regulator of G protein signaling proteins in synaptic signaling and plasticity. Mol Pharmacol. 89:273–286. 2016. View Article : Google Scholar : PubMed/NCBI
23	Xie Y, Wolff DW, Wei T, Wang B, Deng C, Kirui JK, Jiang H, Qin J, Abel PW and Tu Y: Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4. Cancer Res. 69:5743–5751. 2009. View Article : Google Scholar : PubMed/NCBI
24	Louwette S, Van Geet C and Freson K: Regulators of G protein signaling: role in hematopoiesis, megakaryopoiesis and platelet function. J Thromb Haemost. 10:2215–2222. 2012. View Article : Google Scholar : PubMed/NCBI
25	Xie Z, Chan EC and Druey KM: R4 regulator of G protein signaling (RGS) proteins in inflammation and immunity. AAPS J. 18:294–304. 2016. View Article : Google Scholar : PubMed/NCBI
26	Siderovski DP and Willard FS: The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. Int J Biol Sci. 1:51–66. 2005. View Article : Google Scholar : PubMed/NCBI
27	Ross EM and Wilkie TM: GTPase-activating proteins for heterotrimeric G proteins: Regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem. 69:795–827. 2000. View Article : Google Scholar : PubMed/NCBI
28	Park HJ, Kim SH and Moon DO: Growth inhibition of human breast carcinoma cells by overexpression of regulator of G-protein signaling 4. Oncol Lett. 13:4357–4363. 2017. View Article : Google Scholar : PubMed/NCBI
29	Bansal G, Druey KM and Xie Z: R4RGS proteins: Regulation of G-protein signaling and beyond. Pharmacol Ther. 116:473–495. 2007. View Article : Google Scholar : PubMed/NCBI
30	Cheng C, Yue W, Li L, Li S, Gao C, Si L and Tian H: Regulator of G-protein signaling 4: A novel tumor suppressor with prognostic significance in non-small cell lung cancer. Biochem Biophys Res Commun. 469:384–391. 2016. View Article : Google Scholar : PubMed/NCBI
31	Falzone L, Salemi R, Travali S, Scalisi A, McCubrey JA, Candido S and Libra M: MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma. Aging (Albany NY). 8:933–944. 2016. View Article : Google Scholar : PubMed/NCBI
32	Marusak C, Bayles I, Ma J, Gooyit M, Gao M, Chang M and Bedogni B: The thiirane-based selective MT1-MMP/ MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination. Pharmacol Res. 113:515–520. 2016. View Article : Google Scholar : PubMed/NCBI
33	Sooro MA, Zhang N and Zhang P: Targeting EGFR-mediated autophagy as a potential strategy for cancer therapy. Int J Cancer. 143:2116–2125. 2018. View Article : Google Scholar : PubMed/NCBI
34	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
35	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
36	Cai L and Cai X: Up-regulation of miR-9 expression predicate advanced clinicopathological features and poor prognosis in patients with hepatocellular carcinoma. Diagn Pathol. 9:10002014. View Article : Google Scholar : PubMed/NCBI
37	Ram Kumar RM, Boro A and Fuchs B: Involvement and clinical aspects of microRNA in osteosarcoma. Int J Mol Sci. 17:E8772016. View Article : Google Scholar : PubMed/NCBI
38	Gao B, Hao S, Tian W, Jiang Y, Zhang S, Guo L, Zhao J, Zhang G, Yan J and Luo D: MicroRNA-107 is downregulated and having tumor suppressive effect in breast cancer by negatively regulating BDNF. J Gene Med. Dec 19–2017.(Epub ahead of print). doi: 10.1002/jgm.2932. View Article : Google Scholar
39	Imamura T, Komatsu S, Ichikawa D, Miyamae M, Okajima W, Ohashi T, Kiuchi J, Nishibeppu K, Konishi H, Shiozaki A, et al: Depleted tumor suppressor miR-107 in plasma relates to tumor progression and is a novel therapeutic target in pancreatic cancer. Sci Rep. 7:57082017. View Article : Google Scholar : PubMed/NCBI
40	Zhang L, Ma P, Sun LM, Han YC, Li BL, Mi XY, Wang EH and Song M: MiR-107 down-regulates SIAH1 expression in human breast cancer cells and silencing of miR-107 inhibits tumor growth in a nude mouse model of triple-negative breast cancer. Mol Carcinog. 55:768–777. 2016. View Article : Google Scholar : PubMed/NCBI
41	Xia H, Li Y and Lv X: MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human nonsmall lung cancer. Int J Oncol. 49:1325–1333. 2016. View Article : Google Scholar : PubMed/NCBI
42	Datta J, Smith A, Lang JC, Islam M, Dutt D, Teknos TN and Pan Q: microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase cvarepsilon. Oncogene. 31:4045–4053. 2012. View Article : Google Scholar : PubMed/NCBI
43	Hao J, Michalek C, Zhang W, Zhu M, Xu X and Mende U: Reguation of cardiomyocyte signaling by RGS proteins: Differential selectivity towards G proteins and susceptibility to regulation. J Mol Cell Cardiol. 41:51–61. 2006. View Article : Google Scholar : PubMed/NCBI
44	Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M, Lin MF and Tu Y: Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene. 25:3719–3734. 2006. View Article : Google Scholar : PubMed/NCBI
45	Xu Z, Zuo Y, Wang J, Yu Z, Peng F, Chen Y, Dong Y, Hu X, Zhou Q, Ma H, et al: Overexpression of the regulator of G-protein signaling 5 reduces the survival rate and enhances the radiation response of human lung cancer cells. Oncol Rep. 33:2899–2907. 2015. View Article : Google Scholar : PubMed/NCBI
46	Liang G, Bansal G, Xie Z and Druey KM: RGS16 inhibits breast cancer cell growth by mitigating phosphatidylinositol 3-kinase signaling. J Biol Chem. 284:21719–21727. 2009. View Article : Google Scholar : PubMed/NCBI
47	James MA, Lu Y, Liu Y, Vikis HG and You M: RGS17, an overexpressed gene in human lung and prostate cancer, induces tumor cell proliferation through the cyclic AMP-PKA-CREB pathway. Cancer Res. 69:2108–2116. 2009. View Article : Google Scholar : PubMed/NCBI
48	Kelly P, Moeller BJ, Juneja J, Booden MA, Der CJ, Daaka Y, Dewhirst MW, Fields TA and Casey PJ: The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci USA. 103:8173–8178. 2006. View Article : Google Scholar : PubMed/NCBI
49	Hu Y, Xing J, Chen L, Zheng Y and Zhou Z: RGS22 inhibits pancreatic adenocarcinoma cell migration through the G12/13 α subunit/F-actin pathway. Oncol Rep. 34:2507–2514. 2015. View Article : Google Scholar : PubMed/NCBI
50	Tan X, Thapa N, Sun Y and Anderson RA: A kinase-independent role for EGF receptor in autophagy initiation. Cell. 160:145–160. 2015. View Article : Google Scholar : PubMed/NCBI