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Article: HBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism

TitleHBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism
Authors
KeywordsHEPATITIS-B-VIRUS
HEPATOCELLULAR-CARCINOMA
DRUG-RESISTANCE
X PROTEIN
MUTATIONS
Issue Date2019
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mcr.aacrjournals.org/
Citation
Molecular Cancer Research, 2019, v. 17 n. 7, p. 1582-1593 How to Cite?
AbstractChronic hepatitis B viral (HBV) infection remains a high underlying cause for hepatocellular carcinoma (HCC) worldwide, while the genetic mechanisms behind this remain unclear. This study elucidated the mechanisms contributing to tumor development induced by the HBV X (HBx) gene of predominantly Asian genotype B HBV and its common HBx variants. To compare the potential tumorigenic effects of K130M/V131I (Mut) and wild-type (WT) HBx on HCC, the Sleeping Beauty (SB) transposon system was used to deliver HBx Mut and WT into the livers of fumarylacetoacetate hydrolase (Fah)-deficient mice and in the context of transformation related protein 53 (Trp53) deficiency. From our results, HBx Mut had a stronger tumorigenic effect than its WT variant. Also, inflammation, necrosis, and fibrosis were evident in HBx experimental animals. Reduction of forkhead box O1 (FOXO1) with increased phosphorylation of upstream serine/threonine kinase (AKT) was detected under HBx Mut overexpression. Thus, it is proposed that HBx Mut enhances disease progression by reducing FOXO1 via phosphorylation of AKT. At the metabolomic level, HBx altered the expression of genes that participated in arachidonic acid (AA) metabolism, as a result of inflammation via accumulation of proinflammatory factors such as prostaglandins and leukotriene in liver. Taken together, the increased rate of HCC observed in chronic hepatitis B patients with K130M/V131I-mutated X protein, may be due to changes in AA metabolism and AKT/FOXO1 signaling. Implications: Our findings suggested that HBx-K130M/V131I–mutant variant promoted HCC progression by activating AKT/FOXO1 pathway and inducing stronger inflammation in liver via AA metabolism.
Persistent Identifierhttp://hdl.handle.net/10722/279209
ISSN
2017 Impact Factor: 4.597
2015 SCImago Journal Rankings: 2.534
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChiu, AP-
dc.contributor.authorTschida, BR-
dc.contributor.authorSham, TT-
dc.contributor.authorLO, LH-
dc.contributor.authorMoriarity, BS-
dc.contributor.authorLi, XX-
dc.contributor.authorLo, RC-
dc.contributor.authorHinton, DE-
dc.contributor.authorRowlands, DK-
dc.contributor.authorChan, CO-
dc.contributor.authorMok, DKW-
dc.contributor.authorLargaespada, DA-
dc.contributor.authorWarner, N-
dc.contributor.authorKeng, VW-
dc.date.accessioned2019-10-21T02:21:37Z-
dc.date.available2019-10-21T02:21:37Z-
dc.date.issued2019-
dc.identifier.citationMolecular Cancer Research, 2019, v. 17 n. 7, p. 1582-1593-
dc.identifier.issn1541-7786-
dc.identifier.urihttp://hdl.handle.net/10722/279209-
dc.description.abstractChronic hepatitis B viral (HBV) infection remains a high underlying cause for hepatocellular carcinoma (HCC) worldwide, while the genetic mechanisms behind this remain unclear. This study elucidated the mechanisms contributing to tumor development induced by the HBV X (HBx) gene of predominantly Asian genotype B HBV and its common HBx variants. To compare the potential tumorigenic effects of K130M/V131I (Mut) and wild-type (WT) HBx on HCC, the Sleeping Beauty (SB) transposon system was used to deliver HBx Mut and WT into the livers of fumarylacetoacetate hydrolase (Fah)-deficient mice and in the context of transformation related protein 53 (Trp53) deficiency. From our results, HBx Mut had a stronger tumorigenic effect than its WT variant. Also, inflammation, necrosis, and fibrosis were evident in HBx experimental animals. Reduction of forkhead box O1 (FOXO1) with increased phosphorylation of upstream serine/threonine kinase (AKT) was detected under HBx Mut overexpression. Thus, it is proposed that HBx Mut enhances disease progression by reducing FOXO1 via phosphorylation of AKT. At the metabolomic level, HBx altered the expression of genes that participated in arachidonic acid (AA) metabolism, as a result of inflammation via accumulation of proinflammatory factors such as prostaglandins and leukotriene in liver. Taken together, the increased rate of HCC observed in chronic hepatitis B patients with K130M/V131I-mutated X protein, may be due to changes in AA metabolism and AKT/FOXO1 signaling. Implications: Our findings suggested that HBx-K130M/V131I–mutant variant promoted HCC progression by activating AKT/FOXO1 pathway and inducing stronger inflammation in liver via AA metabolism.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mcr.aacrjournals.org/-
dc.relation.ispartofMolecular Cancer Research-
dc.subjectHEPATITIS-B-VIRUS-
dc.subjectHEPATOCELLULAR-CARCINOMA-
dc.subjectDRUG-RESISTANCE-
dc.subjectX PROTEIN-
dc.subjectMUTATIONS-
dc.titleHBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism-
dc.typeArticle-
dc.identifier.emailLo, RC: loregina@hku.hk-
dc.identifier.authorityLo, RC=rp01359-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/1541-7786.MCR-18-1127-
dc.identifier.pmid30975706-
dc.identifier.pmcidPMC6610579-
dc.identifier.hkuros308141-
dc.identifier.volume17-
dc.identifier.issue7-
dc.identifier.spage1582-
dc.identifier.epage1593-
dc.identifier.isiWOS:000473534700015-
dc.publisher.placeUnited States-

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