MicroRNA‑875‑5p inhibits tumor growth and metastasis of hepatocellular carcinoma by targeting eukaryotic translation initiation factor 3 subunit a

Chen,Tianxiang; Sun,Liankang; Yao,Bowen; Wang,Liang; Wang,Yufeng; Niu,Yongshen; Liu,Runkun; Mo,Huanye; Liu,Zhikui; Tu,Kangsheng; Liu,Qingguang

doi:10.3892/or.2020.7743

MicroRNA‑875‑5p inhibits tumor growth and metastasis of hepatocellular carcinoma by targeting eukaryotic translation initiation factor 3 subunit a

Authors:
- Tianxiang Chen
- Liankang Sun
- Bowen Yao
- Liang Wang
- Yufeng Wang
- Yongshen Niu
- Runkun Liu
- Huanye Mo
- Zhikui Liu
- Kangsheng Tu
- Qingguang Liu
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Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: August 19, 2020 https://doi.org/10.3892/or.2020.7743
Pages: 2067-2079
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Accumulating evidence has demonstrated that aberrant microRNA (miRNA) expression is involved in hepatocellular carcinoma (HCC) progression. Previous findings suggested that miRNA (miR)‑875‑5p participates in the development of various types of cancer. However, the expression and function of miR‑875‑5p in HCC remains largely unclear. The analysis of clinical samples in the present study demonstrated that miR‑875‑5p expression was downregulated in HCC tissues compared to adjacent non‑tumor tissues, which was associated with a large tumor size, venous infiltration, advanced tumor‑node‑metastasis stage and unfavorable overall survival. In vitro experiments revealed that ectopic expression of miR‑875‑5p suppressed, whereas inhibition of miR‑875‑5p promoted HCC cell proliferation, migration, invasion and epithelial‑to‑mesenchymal transition (EMT) progression. Overexpression of miR‑875‑5p restrained HCC tumor growth and metastasis in vivo. Mechanistically, eukaryotic translation initiation factor 3 subunit a (eIF3a) was identified as the downstream target of miR‑875‑5p in HCC. Further experiments demonstrated that the expression of eIF3a was upregulated and negatively correlated with that of miR‑875‑5p in HCC tissues. In addition, miR‑875‑5p negatively regulated the luciferase activity of wild‑type, but not mutant 3'‑untranslated region (3'UTR) of eIF3a mRNA. miR‑875‑5p suppressed eIF3a expression at the mRNA and protein level in HCC cells. Additionally, eIF3a exerted an oncogenic role, and knockdown of eIF3a inhibited the proliferation, motility and EMT of HCC cells. In addition, eIF3a overexpression abolished the inhibitory effects of miR‑875‑5p on the proliferation, motility and EMT in HCC cells. In conclusion, miR‑875‑5p, which was downregulated in HCC, may inhibit tumor growth and metastasis by eIF3a downregulation via targeting its 3'UTR and may be a promising prognostic and therapeutic strategy in HCC.

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1	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
2	Forner A, Reig M and Bruix J: Hepatocellular carcinoma. Lancet. 391:1301–1314. 2018. View Article : Google Scholar : PubMed/NCBI
3	Chan AWH, Zhong J, Berhane S, Toyoda H, Cucchetti A, Shi K, Tada T, Chong CCN, Xiang BD, Li LQ, et al: Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection. J Hepatol. 69:1284–1293. 2018. View Article : Google Scholar : PubMed/NCBI
4	Di Leva G, Garofalo M and Croce CM: MicroRNAs in cancer. Annu Rev Pathol. 9:287–314. 2014. View Article : Google Scholar : PubMed/NCBI
5	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
6	Lin S and Gregory RI: MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 15:321–333. 2015. View Article : Google Scholar : PubMed/NCBI
7	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
8	Wang L, Mo H, Jiang Y, Wang Y, Sun L, Yao B, Chen T, Liu R, Li Q, Liu Q and Yin G: MicroRNA-519c-3p promotes tumor growth and metastasis of hepatocellular carcinoma by targeting BTG3. Biomed Pharmacother. 118:1092672019. View Article : Google Scholar : PubMed/NCBI
9	Xu Q, Zhu Q, Zhou Z, Wang Y, Liu X, Yin G, Tong X and Tu K: MicroRNA-876-5p inhibits epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by targeting BCL6 corepressor like 1. Biomed Pharmacother. 103:645–652. 2018. View Article : Google Scholar : PubMed/NCBI
10	Wang Y, Yang Z, Wang L, Sun L, Liu Z, Li Q, Yao B, Chen T, Wang C, Yang W, et al: MiR-532-3p promotes hepatocellular carcinoma progression by targeting PTPRT. Biomed Pharmacother. 109:991–999. 2019. View Article : Google Scholar : PubMed/NCBI
11	Liu Z, Wang Y, Dou C, Sun L, Li Q, Wang L, Xu Q, Yang W, Liu Q and Tu K: MicroRNA-1468 promotes tumor progression by activating PPAR-ү-mediated AKT signaling in human hepatocellular carcinoma. J Exp Clin Cancer Res. 37:492018. View Article : Google Scholar : PubMed/NCBI
12	Yao B, Li Y, Wang L, Chen T, Niu Y, Liu Q and Liu Z: MicroRNA-3194-3p inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by decreasing Wnt/β-catenin signaling through targeting BCL9. Artif Cells Nanomed Biotechnol. 47:3885–3895. 2019. View Article : Google Scholar : PubMed/NCBI
13	Zhang T, Cai X, Li Q, Xue P, Chen Z, Dong X and Xue Y: Hsa-miR-875-5p exerts tumor suppressor function through down-regulation of EGFR in colorectal carcinoma (CRC). Oncotarget. 7:42225–42240. 2016. View Article : Google Scholar : PubMed/NCBI
14	El Bezawy R, Cominetti D, Fenderico N, Zuco V, Beretta GL, Dugo M, Arrighetti N, Stucchi C, Rancati T, Valdagni R, et al: MiR-875-5p counteracts epithelial-to-mesenchymal transition and enhances radiation response in prostate cancer through repression of the EGFR-ZEB1 axis. Cancer Lett. 395:53–62. 2017. View Article : Google Scholar : PubMed/NCBI
15	Wang J, Lu Y, Ding H, Gu T, Gong C, Sun J, Zhang Z, Zhao Y and Ma C: The miR-875-5p inhibits SATB2 to promote the invasion of lung cancer cells. Gene. 644:13–19. 2018. View Article : Google Scholar : PubMed/NCBI
16	Yin JY, Shen J, Dong ZZ, Huang Q, Zhong MZ, Feng DY, Zhou HH, Zhang JT and Liu ZQ: Effect of eIF3a on response of lung cancer patients to platinum-based chemotherapy by regulating DNA repair. Clin Cancer Res. 17:4600–4609. 2011. View Article : Google Scholar : PubMed/NCBI
17	Dong Z and Zhang JT: Initiation factor eIF3 and regulation of mRNA translation, cell growth, and cancer. Crit Rev Oncol Hematol. 59:169–180. 2006. View Article : Google Scholar : PubMed/NCBI
18	Yin JY, Zhang JT, Zhang W, Zhou HH and Liu ZQ: eIF3a: A new anticancer drug target in the eIF family. Cancer Lett. 412:81–87. 2018. View Article : Google Scholar : PubMed/NCBI
19	Fang C, Chen YX, Wu NY, Yin JY, Li XP, Huang HS, Zhang W, Zhou HH and Liu ZQ: MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway. Sci Rep. 7:403842017. View Article : Google Scholar : PubMed/NCBI
20	Wang SQ, Liu Y, Yao MY and Jin J: Eukaryotic translation initiation factor 3a (eIF3a) promotes cell proliferation and motility in pancreatic cancer. J Korean Med Sci. 31:1586–1594. 2016. View Article : Google Scholar : PubMed/NCBI
21	Ding Z, Liu J, Wang J, Huang B and Zhong M: Upregulation of eukaryotic translation initiation factor 3 subunit a promotes cell survival in ameloblastoma. Oral Surg Oral Med Oral Pathol Oral Radiol. 128:146–153. 2019. View Article : Google Scholar : PubMed/NCBI
22	Miao B, Wei C, Qiao Z, Han W, Chai X, Lu J, Gao C, Dong R, Gao D, Huang C, et al: eIF3a mediates HIF1α-dependent glycolytic metabolism in hepatocellular carcinoma cells through translational regulation. Am J Cancer Res. 9:1079–1090. 2019.PubMed/NCBI
23	Liu Z, Dou C, Jia Y, Li Q, Zheng X, Yao Y, Liu Q and Song T: RIG-I suppresses the migration and invasion of hepatocellular carcinoma cells by regulating MMP9. Int J Oncol. 46:1710–1720. 2015. View Article : Google Scholar : PubMed/NCBI
24	Jansson MD and Lund AH: MicroRNA and cancer. Mol Oncol. 6:590–610. 2012. View Article : Google Scholar : PubMed/NCBI
25	Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013. View Article : Google Scholar : PubMed/NCBI
26	Dou C, Zhou Z, Xu Q, Liu Z, Zeng Y, Wang Y, Li Q, Wang L, Yang W, Liu Q and Tu K: Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca²+/PI3K/AKT pathway. Oncogene. 38:1239–1255. 2019. View Article : Google Scholar : PubMed/NCBI
27	Liu Z, Wang Y, Dou C, Xu M, Sun L, Wang L, Yao B, Li Q, Yang W, Tu K and Liu Q: Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma. Theranostics. 8:4649–4663. 2018. View Article : Google Scholar : PubMed/NCBI
28	Xu Q, Liu X, Liu Z, Zhou Z, Wang Y, Tu J, Li L, Bao H, Yang L and Tu K: MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway. Mol Cancer. 16:1032017. View Article : Google Scholar : PubMed/NCBI
29	Dou C, Liu Z, Xu M, Jia Y, Wang Y, Li Q, Yang W, Zheng X, Tu K and Liu Q: MiR-187-3p inhibits the metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting S100A4. Cancer Lett. 381:380–390. 2016. View Article : Google Scholar : PubMed/NCBI
30	Liu Z, Wang Y, Wang L, Yao B, Sun L, Liu R, Chen T, Niu Y, Tu K and Liu Q: Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res. 38:1942019. View Article : Google Scholar : PubMed/NCBI
31	Dong Z and Zhang JT: EIF3 p170, a mediator of mimosine effect on protein synthesis and cell cycle progression. Mol Biol Cell. 14:3942–3951. 2003. View Article : Google Scholar : PubMed/NCBI
32	Xu TR, Lu RF, Romano D, Pitt A, Houslay MD, Milligan G and Kolch W: Eukaryotic translation initiation factor 3, subunit a, regulates the extracellular signal-regulated kinase pathway. Mol Cell Biol. 32:88–95. 2012. View Article : Google Scholar : PubMed/NCBI
33	Dong Z, Liu LH, Han B, Pincheira R and Zhang JT: Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth. Oncogene. 23:3790–3801. 2004. View Article : Google Scholar : PubMed/NCBI
34	Liu RY, Dong Z, Liu J, Yin JY, Zhou L, Wu X, Yang Y, Mo W, Huang W, Khoo SK, et al: Role of eIF3a in regulating cisplatin sensitivity and in translational control of nucleotide excision repair of nasopharyngeal carcinoma. Oncogene. 30:4814–4823. 2011. View Article : Google Scholar : PubMed/NCBI
35	Zhang Y, Yu JJ, Tian Y, Li ZZ, Zhang CY, Zhang SF, Cao LQ, Zhang Y, Qian CY, Zhang W, et al: eIF3a improve cisplatin sensitivity in ovarian cancer by regulating XPC and p27Kip1 translation. Oncotarget. 6:25441–25451. 2015. View Article : Google Scholar : PubMed/NCBI
36	Spilka R, Ernst C, Bergler H, Rainer J, Flechsig S, Vogetseder A, Lederer E, Benesch M, Brunner A, Geley S, et al: eIF3a is over-expressed in urinary bladder cancer and influences its phenotype independent of translation initiation. Cell Oncol (Dordr). 37:253–267. 2014. View Article : Google Scholar : PubMed/NCBI
37	Heo CK, Hwang HM, Lee HJ, Kwak SS, Yoo JS, Yu DY, Lim KJ, Lee S and Cho EW: Serum anti-EIF3A autoantibody as a potential diagnostic marker for hepatocellular carcinoma. Sci Rep. 9:110592019. View Article : Google Scholar : PubMed/NCBI
38	Fattovich G, Stroffolini T, Zagni I and Donato F: Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology. 127 (5 Suppl 1):S35–S50. 2004. View Article : Google Scholar : PubMed/NCBI
39	He P, Yu ZJ, Sun CY, Jiao SJ and Jiang HQ: Knockdown of eIF3a attenuates the pro-fibrogenic response of hepatic stellate cells induced by TGF-β1. Cell Mol Biol (Noisy-le-grand). 62:107–111. 2016.PubMed/NCBI
40	Zhang YF, Wang Q, Luo J, Yang S, Wang JL and Li HY: Knockdown of elF3a inhibits collagen synthesis in renal fibroblasts via Inhibition of transforming growth factor-β1/Smad signaling pathway. Int J Clin Exp Pathol. 8:8983–8989. 2015.PubMed/NCBI
41	Li T and Zhao J: Knockdown of elF3a inhibits TGF-β1-induced extracellular matrix protein expression in keloid fibroblasts. Mol Med Rep. 17:4057–4061. 2018.PubMed/NCBI
42	Li XW, Wu YH, Li XH, Li D, Du J, Hu CP and Li YJ: Role of eukaryotic translation initiation factor 3a in bleomycin-induced pulmonary fibrosis. Eur J Pharmacol. 749:89–97. 2015. View Article : Google Scholar : PubMed/NCBI
43	Li WQ, Li XH, Wu YH, Du J, Wang AP, Li D and Li YJ: Role of eukaryotic translation initiation factors 3a in hypoxia-induced right ventricular remodeling of rats. Life Sci. 144:61–68. 2016. View Article : Google Scholar : PubMed/NCBI