2. Academic Validation
  3. HBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism

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

  • Mol Cancer Res. 2019 Jul;17(7):1582-1593. doi: 10.1158/1541-7786.MCR-18-1127.
Amy P Chiu 1 2,  Barbara R Tschida 3,  Tung-Ting Sham 1 2,  Lilian H Lo 1 2,  Branden S Moriarity 3,  Xiao-Xiao Li 1 2,  Regina C Lo 4,  David E Hinton 5,  Dewi K Rowlands 6,  Chi-On Chan 1 2,  Daniel K W Mok 1 2,  David A Largaespada 3,  Nadia Warner 7,  Vincent W Keng 8 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
  • 2 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
  • 3 Center for Genome Engineering, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
  • 4 Department of Pathology, The University of Hong Kong, Hong Kong, China.
  • 5 Nicholas School of the Environment, Duke University, Durham, North Carolina.
  • 6 Laboratory Animal Services Centre, The Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong, China.
  • 7 Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Victoria, Australia.
  • 8 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China. vincent.keng@polyu.edu.hk.
PMID: 30975706 DOI: 10.1158/1541-7786.MCR-18-1127
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. 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.

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