HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism

Amy P. Chiu, Barbara R. Tschida, Tung Ting Sham, Lilian H. Lo, Branden S Moriarity, Xiao Xiao Li, Regina C. Lo, David E. Hinton, Dewi K. Rowlands, Chi On Chan, Daniel K.W. Mok, David A Largaespada, Nadia Warner, Vincent W. Keng

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Chronic 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.

Original languageEnglish (US)
Pages (from-to)1582-1593
Number of pages12
JournalMolecular Cancer Research
Issue number7
StatePublished - Jul 1 2019

Bibliographical note

Funding Information:
This project was supported by The Shenzhen Science and Technology Innovation Commission (JCYJ20170413154748190, to V.W. Keng; JCYJ20160229173844278, to D.K.-W. Mok; and JCYJ20160330171116798, to C.-O. Chan), Health Medical Research Fund (11122171), Food and Health Bureau, and the Hong Kong SAR Government, NSFC/RGC Joint Research Scheme (N-PolyU503/16; to V.W. Keng) and the NIH IMVTP grant no. T32 AI083196-04 (to B.R. Tschida), General Research Fund of the Research Grant Council of the Hong Kong Special Administrative Region (Project no. 15302718), Hong Kong Chinese Materia Medica Standards Project (to D.K.-W. Mok), the Large Equipment Funds and University Research Facility in Chemical and Environmental Analysis and Life Sciences of the Hong Kong Polytechnic University.

Publisher Copyright:
© 2019 American Association for Cancer Research.

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural


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