miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3

Liang,Yiming; Li,Enliang; Min,Jiaqi; Gong,Chengwu; Gao,Jun; Ai,Jiyuan; Liao,Wenjun; Wu,Linquan

doi:10.3892/or.2018.6745

miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3

Authors:
- Yiming Liang
- Enliang Li
- Jiaqi Min
- Chengwu Gong
- Jun Gao
- Jiyuan Ai
- Wenjun Liao
- Linquan Wu
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of General Surgery, Children's Hospital of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China
Published online on: September 28, 2018 https://doi.org/10.3892/or.2018.6745
Pages: 3261-3272
Copyright: © Liang 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

The interferon-induced transmembrane protein 3 (IFITM3, also called 1‑8U) gene represents dysregulated expression in various tumors and is involved in tumorigenesis and progression. However, the role of IFITM3 and its underlying mechanism in hepatocellular carcinoma (HCC) are still far from elucidated. MicroRNAs (miRNAs), a class of endogenous (approximately 22 nucleotides) small noncoding RNAs, can post‑transcriptionally regulate gene expression by repressing protein translation or silencing the expression of target genes that play critical roles in various cancers. miR‑29a was identified as being aberrantly expressed in a significant proportion of HCC. However, the correlation between IFITM3 and miR‑29a has not been reported to date. In this study, we investigated the expression of IFITM3 in HCC and its effect on the biological behavior of HCC cells as well as the association between IFITM3 and miR‑29a. We determined that IFITM3 was upregulated and miR‑29a downregulated in HCC tissues and that they were associated with HCC tumor size, tumor multifocal, and venous invasion. The expression of IFITM3 in HCC tissues was negatively correlated with miR‑29a expression. Additionally, IFITM3 overexpression and miR‑29a nonoverexpression were related to poor prognosis of HCC patients. Knockdown of IFITM3 inhibited migration, invasion, proliferation and promoted apoptosis of HCC cells, which are consistent with the effects of upregulated miR‑29a. Additionally, after upregulation of IFITM3, the invasion, migration and proliferation abilities of HL‑7702 cells were increased, but the apoptosis rate was decreased. Furthermore, using a Dual‑Luciferase reporter gene assay, we identified IFITM3 as a new functional target gene of miR‑29a. In conclusion, our findings demonstrated that the migration, invasion, proliferation and apoptosis features of HCC cells could be regulated by miR‑29a via IFITM3. Thus, the present study indicated that miR‑29a and IFITM3 play critical roles in the development and progression of HCC, revealing that miR‑29a and IFITM3 may be novel potential therapeutic targets for patients with HCC.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
3	Ochiai T, Ikoma H, Okamoto K, Kokuba Y, Sonoyama T and Otsuji E: Clinicopathologic features and risk factors for extrahepatic recurrences of hepatocellular carcinoma after curative resection. World J Surg. 36:136–143. 2012. View Article : Google Scholar : PubMed/NCBI
4	Yang Y, Nagano H, Ota H, Morimoto O, Nakamura M, Wada H, Noda T, Damdinsuren B, Marubashi S, Miyamoto A, et al: Patterns and clinicopathologic features of extrahepatic recurrence of hepatocellular carcinoma after curative resection. Surgery. 141:196–202. 2007. View Article : Google Scholar : PubMed/NCBI
5	Gauthier A and Ho M: Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 43:147–154. 2013. View Article : Google Scholar : PubMed/NCBI
6	Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, et al: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 389:56–66. 2017. View Article : Google Scholar : PubMed/NCBI
7	Bailey CC, Zhong G, Huang IC and Farzan M: IFITM-family proteins: The cells first line of antiviral defense. Annu Rev Virol. 1:261–283. 2014. View Article : Google Scholar : PubMed/NCBI
8	Bailey CC, Kondur HR, Huang IC and Farzan M: Interferon-induced transmembrane protein 3 is a type II transmembrane protein. J Biol Chem. 288:32184–32193. 2013. View Article : Google Scholar : PubMed/NCBI
9	Feeley EM, Sims JS, John SP, Chin CR, Pertel T, Chen LM, Gaiha GD, Ryan BJ, Donis RO, Elledge SJ and Brass AL: IFITM3 inhibits influenza a virus infection by preventing cytosolic entry. PLoS Pathog. 7:e10023372011. View Article : Google Scholar : PubMed/NCBI
10	Li D, Peng Z, Tang H, Wei P, Kong X, Yan D, Huang F, Li Q, Le X, Li Q and Xie K: KLF4-mediated negative regulation of IFITM3 expression plays a critical role in colon cancer pathogenesis. Clin Cancer Res. 17:3558–3568. 2011. View Article : Google Scholar : PubMed/NCBI
11	Andreu P, Colnot S, Godard C, Laurent-Puig P, Lamarque D, Kahn A, Perret C and Romagnolo B: Identification of the IFITM family as a new molecular marker in human colorectal tumors. Cancer Res. 66:1949–1955. 2006. View Article : Google Scholar : PubMed/NCBI
12	Bing Z, Wang H, Gang Z and Ping L: The role of IFITM3 in the growth and migration of human glioma cells. BMC Neurol. 13:2102013. View Article : Google Scholar : PubMed/NCBI
13	Place RF, Li LC, Pookot D, Noonan EJ and Dahiya R: MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA. 105:1608–1613. 2008. View Article : Google Scholar : PubMed/NCBI
14	Filipowicz W, Bhattacharyya SN and Sonenberg N: Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet. 9:102–114. 2008. View Article : Google Scholar : PubMed/NCBI
15	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
16	Kota J, Chivukula RR, ODonnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, et al: Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 137:1005–1017. 2009. View Article : Google Scholar : PubMed/NCBI
17	Fang Y, Xue JL, Shen Q, Chen J and Tian L: MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology. 55:1852–1862. 2012. View Article : Google Scholar : PubMed/NCBI
18	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
19	Wong CC, Wong CM, Tung EK, Au SL, Lee JM, Poon RT, Man K and Ng IO: The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology. 140:322–331. 2011. View Article : Google Scholar : PubMed/NCBI
20	Zhu XC, Dong QZ, Zhang XF, Deng B, Jia HL, Ye QH, Qin LX and Wu XZ: microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med. 30:1321–1326. 2012. View Article : Google Scholar : PubMed/NCBI
21	Mahati S, Xiao L, Yang Y, Mao R and Bao Y: miR-29a suppresses growth and migration of hepatocellular carcinoma by regulating CLDN1. Biochem Biophys Res Commun. 486:732–737. 2017. View Article : Google Scholar : PubMed/NCBI
22	Kogure T, Kondo Y, Kakazu E, Ninomiya M, Kimura O and Shimosegawa T: Involvement of miRNA-29a in epigenetic regulation of transforming growth factor-beta-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Hepatol Res. 44:907–919. 2014. View Article : Google Scholar : PubMed/NCBI
23	Cho HJ, Kim SS, Nam JS, Kim JK, Lee JH, Kim B, Wang HJ, Kim BW, Lee JD, Kang DY, et al: Low levels of circulating microRNA-26a/29a as poor prognostic markers in patients with hepatocellular carcinoma who underwent curative treatment. Clin Res Hepatol Gastroenterol. 41:181–189. 2017. View Article : Google Scholar : PubMed/NCBI
24	Liu W, Liang B, Liu H, Huang Y, Yin X, Zhou F, Yu X, Feng Q, Li E, Zou Z and Wu L: Overexpression of nonSMC condensin I complex subunit G serves as a promising prognostic marker and therapeutic target for hepatocellular carcinoma. Int J Mol Med. 40:731–738. 2017. 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(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Li C, Miao R, Liu S, Wan Y, Zhang S, Deng Y, Bi J, Qu K, Zhang J and Liu C: Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis. Oncotarget. 8:28683–28695. 2017.PubMed/NCBI
27	Yuan R, Wang K, Hu J, Yan C, Li M, Yu X, Liu X, Lei J, Guo W, Wu L, et al: Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying beta-catenin degradation. Cancer Res. 74:5287–5300. 2014. View Article : Google Scholar : PubMed/NCBI
28	Fabbri M, Calore F, Paone A, Galli R and Calin GA: Epigenetic regulation of miRNAs in cancer. Adv Exp Med Biol. 754:137–148. 2013. View Article : Google Scholar : PubMed/NCBI
29	Yu G, Chen X, Chen S, Ye W, Hou K and Liang M: miR-19a, miR-122 and miR-223 are differentially regulated by hepatitis B virus X protein and involve in cell proliferation in hepatoma cells. J Transl Med. 14:1222016. View Article : Google Scholar : PubMed/NCBI
30	Lewin AR, Reid LE, McMahon M, Stark GR and Kerr IM: Molecular analysis of a human interferon-inducible gene family. Eur J Biochem. 199:417–423. 1991. View Article : Google Scholar : PubMed/NCBI
31	Hu J, Wang S, Zhao Y, Guo Q, Zhang D, Chen J, Li J, Fei Q and Sun Y: Mechanism and biological significance of the overexpression of IFITM3 in gastric cancer. Oncol Rep. 32:2648–2656. 2014. View Article : Google Scholar : PubMed/NCBI
32	Jia Y, Zhang M, Jiang W, Zhang Z, Huang S and Wang Z: Overexpression of IFITM3 predicts the high risk of lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma after Ivor-Lewis esophagectomy. PeerJ. 3:e13552015. View Article : Google Scholar : PubMed/NCBI
33	Yang M, Gao H, Chen P, Jia J and Wu S: Knockdown of interferon-induced transmembrane protein 3 expression suppresses breast cancer cell growth and colony formation and affects the cell cycle. Oncol Rep. 30:171–178. 2013. View Article : Google Scholar : PubMed/NCBI
34	Meister G: miRNAs get an early start on translational silencing. Cell. 131:25–28. 2007. View Article : Google Scholar : PubMed/NCBI
35	Chianchiano P, Pezhouh MK, Kim A, Luchini C, Cameron A, Weiss MJ, He J, Voltaggio L, Oshima K, Anders RA and Wood LD: Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations. Hum Pathol. 72:127–134. 2018. View Article : Google Scholar : PubMed/NCBI