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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

RETRACTED ARTICLE: miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3

Authors: Qiaoge Zhang, Ge Song, Lili Yao, Yankun Liu, Min Liu, Shengping Li, Hua Tang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Hepatitis B virus (HBV) plays a critical role in the tumorigenic behavior of human hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have been reported to participate in HCC development via the regulation of their target genes. However, HBV-modulated miRNAs involved in tumorigenesis remain to be identified. Here, we found that a novel highly expressed miRNA, TLRC-m0008_3p (miR-3928v), may be an important factor that promotes the malignancy of HBV-related HCC.

Methods

Solexa sequencing was applied to profile miRNAs, and RT-qPCR was used to identify and quantitate miRNAs. We studied miR-3928v function in HCC cell lines by MTT, colony formation, migration/invasion, and vascular mimicry (VM) assays in vitro and by a xenograft tumor model in vivo. Finally, we predicted and verified the target gene of miR-3928v by a reporter assay, studied the function of this target gene, and cloned the promoter of miR-3928v and the transcription factor for use in dual-luciferase reporter assays and EMSAs.

Results

A variant of miR-3928 (miR-3928v) was identified and found to be highly expressed in HBV (+) HCC tissues. Voltage-dependent anion channel 3 (VDAC3) was validated as a target of miR-3928v and found to mediate the effects of miR-3928v in promoting HCC growth and migration/invasion. Furthermore, HBx protein increased early growth response 1 (EGR1) expression and facilitated its translocation into the nucleus to enhance miR-3928v promoter activity in an NF-κB signaling-dependent manner.

Conclusions

miR-3928v is induced by HBx through the NF-κB/EGR1 signaling pathway and down-regulates the tumor suppressor gene VDAC3 to accelerate the progression of HCC.
Appendix
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Literature
1.
Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends--an update. Cancer Epidemiol Biomark Prev. 2016;25:16–27.CrossRef
2.
Iida-Ueno A, Enomoto M, Tamori A, Kawada N. Hepatitis B virus infection and alcohol consumption. World J Gastroenterol. 2017;23:2651–9.CrossRef
3.
Fu S, Zhou RR, Li N, Huang Y, Fan XG. Hepatitis B virus X protein in liver tumor microenvironment. Tumour Biol. 2016;37:15371–81.CrossRef
4.
Zhang XD, Wang Y, Ye LH. Hepatitis B virus X protein accelerates the development of hepatoma. Cancer Biol Med. 2014;11:182–90.
5.
Liu H, Yuan Y, Guo H, Mitchelson K, Zhang K, Xie L, Qin W, Lu Y, Wang J, Guo Y, et al. Hepatitis B virus encoded X protein suppresses apoptosis by inhibition of the caspase-independent pathway. J Proteome Res. 2012;11:4803–13.CrossRef
6.
Cho HK, Kim SY, Kyaw YY, Win AA, Koo SH, Kim HH, Cheong J. HBx induces the proliferation of hepatocellular carcinoma cells via AP1 over-expressed as a result of ER stress. Biochem J. 2015;466:115–21.CrossRef
7.
Saxena N, Kumar V. The HBx oncoprotein of hepatitis B virus deregulates the cell cycle by promoting the intracellular accumulation and re-compartmentalization of the cellular deubiquitinase USP37. PLoS One. 2014;9:e111256.CrossRef
8.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.CrossRef
9.
Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World J Biol Chem. 2017;8:45–56.CrossRef
10.
Song G, Wang R, Guo J, Liu X, Wang F, Qi Y, Wan H, Liu M, Li X, Tang H. miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively. Sci Rep. 2015;5:15793.CrossRef
11.
Yin D, Wang Y, Sai W, Zhang L, Miao Y, Cao L, Zhai X, Feng X, Yang L. HBx-induced miR-21 suppresses cell apoptosis in hepatocellular carcinoma by targeting interleukin-12. Oncol Rep. 2016;36:2305–12.CrossRef
12.
Kong XX, Lv YR, Shao LP, Nong XY, Zhang GL, Zhang Y, Fan HX, Liu M, Li X, Tang H. HBx-induced MiR-1269b in NF-kappaB dependent manner upregulates cell division cycle 40 homolog (CDC40) to promote proliferation and migration in hepatoma cells. J Transl Med. 2016;14:189.CrossRef
13.
Kim HJ, Hong JM, Yoon KA, Kim N, Cho DW, Choi JY, Lee IK, Kim SY. Early growth response 2 negatively modulates osteoclast differentiation through upregulation of Id helix-loop-helix proteins. Bone. 2012;51:643–50.CrossRef
14.
Wang L, Sun H, Wang X, Hou N, Zhao L, Tong D, He K, Yang Y, Song T, Yang J, Huang C. EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway. Oncotarget. 2016;7:45302–16.CrossRef
15.
Tian H, Ge C, Li H, Zhao F, Hou H, Chen T, Jiang G, Xie H, Cui Y, Yao M, Li J. Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma. Hepatology. 2014;59:1459–70.CrossRef
16.
Grotegut S, von Schweinitz D, Christofori G, Lehembre F. Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of snail. EMBO J. 2006;25:3534–45.CrossRef
17.
Peng WX, Xiong EM, Ge L, Wan YY, Zhang CL, Du FY, Xu M, Bhat RA, Jin J, Gong AH. Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells. Exp Cell Res. 2016;340:62–70.CrossRef
18.
19.
Reina S, Checchetto V, Saletti R, Gupta A, Chaturvedi D, Guardiani C, Guarino F, Scorciapino MA, Magri A, Foti S, et al. VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications. Oncotarget. 2016;7:2249–68.CrossRef
20.
Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L. Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy. J Biol Chem. 2012;287:40652–60.CrossRef
21.
Caterino M, Ruoppolo M, Mandola A, Costanzo M, Orru S, Imperlini E. Protein-protein interaction networks as a new perspective to evaluate distinct functional roles of voltage-dependent anion channel isoforms. Mol BioSyst. 2017;13:2466–76.CrossRef
22.
De Pinto V, Guarino F, Guarnera A, Messina A, Reina S, Tomasello FM, Palermo V, Mazzoni C. Characterization of human VDAC isoforms: a peculiar function for VDAC3? Biochim Biophys Acta. 2010;1797:1268–75.CrossRef
23.
Rahmani Z, Huh KW, Lasher R, Siddiqui A. Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential. J Virol. 2000;74:2840–6.CrossRef
24.
Waris G, Huh KW, Siddiqui A. Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress. Mol Cell Biol. 2001;21:7721–30.CrossRef
25.
Yan Y, Luo YC, Wan HY, Wang J, Zhang PP, Liu M, Li X, Li S, Tang H. MicroRNA-10a is involved in the metastatic process by regulating Eph tyrosine kinase receptor A4-mediated epithelial-mesenchymal transition and adhesion in hepatoma cells. Hepatology. 2013;57:667–77.CrossRef
26.
Ren ZJ, Nong XY, Lv YR, Sun HH, An PP, Wang F, Li X, Liu M, Tang H. Mir-509-5p joins the Mdm2/p53 feedback loop and regulates cancer cell growth. Cell Death Dis. 2014;5:e1387.CrossRef
27.
Shimizu S, Narita M, Tsujimoto Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature. 1999;399:483–7.CrossRef
28.
Liu Y, Lou G, Wu W, Zheng M, Shi Y, Zhao D, Chen Z. Involvement of the NF-kappaB pathway in multidrug resistance induced by HBx in a hepatoma cell line. J Viral Hepat. 2011;18:e439–46.CrossRef
29.
Lim KH, Choi HS, Park YK, Park ES, Shin GC, Kim DH, Ahn SH, Kim KH. HBx-induced NF-kappaB signaling in liver cells is potentially mediated by the ternary complex of HBx with p22-FLIP and NEMO. PLoS One. 2013;8:e57331.CrossRef
30.
Deckmann K, Rorsch F, Geisslinger G, Grosch S. Dimethylcelecoxib induces an inhibitory complex consisting of HDAC1/NF-kappaB(p65)RelA leading to transcriptional downregulation of mPGES-1 and EGR1. Cell Signal. 2012;24:460–7.CrossRef
31.
Zheng C, Ren Z, Wang H, Zhang W, Kalvakolanu DV, Tian Z, Xiao W. E2F1 induces tumor cell survival via nuclear factor-kappaB-dependent induction of EGR1 transcription in prostate cancer cells. Cancer Res. 2009;69:2324–31.CrossRef
32.
De Pinto V, Reina S, Gupta A, Messina A, Mahalakshmi R. Role of cysteines in mammalian VDAC isoforms’ function. Biochim Biophys Acta. 2016;1857:1219–27.CrossRef
33.
Reina S, Guarino F, Magri A, De Pinto V. VDAC3 as a potential marker of mitochondrial status is involved in cancer and pathology. Front Oncol. 2016;6:264.CrossRef
34.
He P, Zhang B, Liu D, Bian X, Li D, Wang Y, Sun G, Zhou G. Hepatitis B virus X protein modulates apoptosis in NRK-52E cells and activates Fas/FasL through the MLK3-MKK7-JNK3 signaling pathway. Cell Physiol Biochem. 2016;39:1433–43.CrossRef
35.
Song K, Han C, Zhang J, Lu D, Dash S, Feitelson M, Lim K, Wu T. Epigenetic regulation of MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X protein in hepatocellular carcinoma cells. Hepatology. 2013;58:1681–92.CrossRef
36.
Liu X, Zhang Y, Wang P, Wang H, Su H, Zhou X, Zhang L. HBX protein-induced downregulation of microRNA-18a is responsible for upregulation of connective tissue growth factor in HBV infection-associated Hepatocarcinoma. Med Sci Monit. 2016;22:2492–500.CrossRef
37.
Liu C, Chen S, Wang X, Chen Y, Tang N. 15d-PGJ(2) decreases PGE(2) synthesis in HBx-positive liver cells by interfering EGR1 binding to mPGES-1 promoter. Biochem Pharmacol. 2014;91:337–47.CrossRef
Metadata
Title
RETRACTED ARTICLE: miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3
Authors
Qiaoge Zhang
Ge Song
Lili Yao
Yankun Liu
Min Liu
Shengping Li
Hua Tang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0681-y

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