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

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2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1582-1593
Number of pages12
JournalMolecular Cancer Research
Volume17
Issue number7
DOIs
StatePublished - Jul 1 2019

PubMed: MeSH publication types

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

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    Chiu, A. P., Tschida, B. R., Sham, T. T., Lo, L. H., Moriarity, B. S., Li, X. X., Lo, R. C., Hinton, D. E., Rowlands, D. K., Chan, C. O., Mok, D. K. W., Largaespada, D. A., Warner, N., & Keng, V. W. (2019). HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism. Molecular Cancer Research, 17(7), 1582-1593. https://doi.org/10.1158/1541-7786.MCR-18-1127