PMID- 29981339 OWN - NLM STAT- MEDLINE DCOM- 20190930 LR - 20201209 IS - 1090-2422 (Electronic) IS - 0014-4827 (Linking) VI - 370 IP - 2 DP - 2018 Sep 15 TI - Hepatitis B virus suppresses the secretion of insulin-like growth factor binding protein 1 to facilitate anti-apoptotic IGF-1 effects in HepG2 cells. PG - 399-408 LID - S0014-4827(18)30392-6 [pii] LID - 10.1016/j.yexcr.2018.07.002 [doi] AB - Hepatitis B virus (HBV) infection is a major global health burden as chronic hepatitis B (CHB) is associated with the development of liver diseases including hepatocellular carcinoma (HCC). To gain insight into the mechanisms causing HBV-related HCC, we investigated the effects of HBV replication on global host cell gene expression using human HepG2 liver cells. By microarray analysis, we identified 54 differentially expressed genes in HBV-replicating HepG2 cells. One of the differentially-expressed genes was insulin-like growth factor binding protein 1 (IGFBP1) which was downregulated in HBV-replicating cells. Consistent with the gene expression data, IGFBP1 was suppressed at both the cellular and secreted protein levels in the presence of HBV replication. Transient transfection experiments with an inducible plasmid encoding the HBV X protein (HBx) revealed that HBx alone was sufficient to modulate IGFBP1 expression. Small interference RNA (siRNA)-mediated loss of function studies revealed that knockdown of IGFBP1 reduced apoptosis induced by either thapsigargin (TG) or staurosporine (STS). Treatment of cells with recombinant insulin-like growth factor 1 (IGF-1) decreased both TG- or STS-induced apoptosis. Interestingly, addition of recombinant IGFBP1 reversed the anti-apoptotic effect of IGF-1 on TG-induced, but not STS-induced, apoptosis. In conclusion, our results suggest an anti-apoptotic autocrine function of HBV-mediated downregulation of IGFBP1 in HepG2 cells. Such an effect may contribute to the development of HBV-mediated HCC by increasing pro-survival and anti-apoptotic IGF-1 effects. CI - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Nielsen, Kirstine Overgaard AU - Nielsen KO AD - Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics and Center for Non-Coding RNA in Technology and Health, Herlev and Gentofte Hospital, Herlev, Denmark. Electronic address: kirstineon@gmail.com. FAU - Mirza, Aashiq Hussain AU - Mirza AH AD - Department of Pediatrics and Center for Non-Coding RNA in Technology and Health, Herlev and Gentofte Hospital, Herlev, Denmark. Electronic address: aah2003@med.cornell.edu. FAU - Kaur, Simranjeet AU - Kaur S AD - Steno Diabetes Center Copenhagen, Department of T1D Biology, Gentofte, Denmark. Electronic address: Simranjeet.kaur@regionh.dk. FAU - Jacobsen, Kari Stougaard AU - Jacobsen KS AD - Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics and Center for Non-Coding RNA in Technology and Health, Herlev and Gentofte Hospital, Herlev, Denmark. Electronic address: karisj@gmail.com. FAU - Winther, Thilde Nordmann AU - Winther TN AD - Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: thildewinther@gmail.com. FAU - Glebe, Dieter AU - Glebe D AD - Institute of Medical Virology, National Reference Center for Hepatitis B and D Viruses, German Center for Infection Research, Biomedical Research Center Seltersberg, Justus-Liebig University Giessen, Giessen, Germany. Electronic address: dieter.glebe@viro.med.uni-giessen.de. FAU - Pociot, Flemming AU - Pociot F AD - Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics and Center for Non-Coding RNA in Technology and Health, Herlev and Gentofte Hospital, Herlev, Denmark; Steno Diabetes Center Copenhagen, Department of T1D Biology, Gentofte, Denmark. Electronic address: flemming.pociot@regionh.dk. FAU - Hogh, Birthe AU - Hogh B AD - Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bhogh@sund.ku.dk. FAU - Storling, Joachim AU - Storling J AD - Steno Diabetes Center Copenhagen, Department of T1D Biology, Gentofte, Denmark. Electronic address: joachim.stoerling@regionh.dk. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180704 PL - United States TA - Exp Cell Res JT - Experimental cell research JID - 0373226 RN - 0 (Insulin-Like Growth Factor Binding Protein 1) RN - 0 (Trans-Activators) RN - 0 (Viral Regulatory and Accessory Proteins) RN - 0 (hepatitis B virus X protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Apoptosis/*physiology MH - Carcinoma, Hepatocellular/pathology/*virology MH - Cell Line, Tumor MH - Cell Proliferation/physiology MH - Down-Regulation MH - Hep G2 Cells/*virology MH - Hepatitis B/virology MH - Hepatitis B virus/*pathogenicity MH - Humans MH - Insulin-Like Growth Factor Binding Protein 1/*metabolism MH - Insulin-Like Growth Factor I/metabolism MH - Liver Neoplasms/metabolism/pathology MH - Trans-Activators/metabolism MH - Viral Regulatory and Accessory Proteins OTO - NOTNLM OT - Apoptosis OT - HBx OT - HepG2 OT - Hepatitis B virus OT - IGF-1 OT - IGFBP1 EDAT- 2018/07/08 06:00 MHDA- 2019/10/01 06:00 CRDT- 2018/07/08 06:00 PHST- 2017/12/14 00:00 [received] PHST- 2018/06/30 00:00 [revised] PHST- 2018/07/03 00:00 [accepted] PHST- 2018/07/08 06:00 [pubmed] PHST- 2019/10/01 06:00 [medline] PHST- 2018/07/08 06:00 [entrez] AID - S0014-4827(18)30392-6 [pii] AID - 10.1016/j.yexcr.2018.07.002 [doi] PST - ppublish SO - Exp Cell Res. 2018 Sep 15;370(2):399-408. doi: 10.1016/j.yexcr.2018.07.002. Epub 2018 Jul 4.