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 journalArticle

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

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Liver Neoplasms
Arachidonic Acid
Transgenic Mice
Hepatocellular Carcinoma
Chronic Hepatitis B
Hepatitis B
Phosphorylation
Inflammation
Beauty
Protein Deficiency
Metabolomics
Viral Genes
Leukotrienes
Protein-Serine-Threonine Kinases
Liver
Virus Diseases
Prostaglandins
Disease Progression
Fibrosis
Necrosis

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HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism. / Chiu, Amy P.; Tschida, Barbara R.; Sham, Tung Ting; Lo, Lilian H.; Moriarity, Branden S; Li, Xiao Xiao; Lo, Regina C.; Hinton, David E.; Rowlands, Dewi K.; Chan, Chi On; Mok, Daniel K.W.; Largaespada, David A; Warner, Nadia; Keng, Vincent W.

In: Molecular Cancer Research, Vol. 17, No. 7, 01.07.2019, p. 1582-1593.

Research output: Contribution to journalArticle

Chiu, AP, Tschida, BR, Sham, TT, Lo, LH, Moriarity, BS, Li, XX, Lo, RC, Hinton, DE, Rowlands, DK, Chan, CO, Mok, DKW, Largaespada, DA, Warner, N & Keng, VW 2019, 'HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism', Molecular Cancer Research, vol. 17, no. 7, pp. 1582-1593. https://doi.org/10.1158/1541-7786.MCR-18-1127
Chiu, Amy P. ; Tschida, Barbara R. ; Sham, Tung Ting ; Lo, Lilian H. ; Moriarity, Branden S ; Li, Xiao Xiao ; Lo, Regina C. ; Hinton, David E. ; Rowlands, Dewi K. ; Chan, Chi On ; Mok, Daniel K.W. ; Largaespada, David A ; Warner, Nadia ; Keng, Vincent W. / HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism. In: Molecular Cancer Research. 2019 ; Vol. 17, No. 7. pp. 1582-1593.
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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.",
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T1 - HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism

AU - Chiu, Amy P.

AU - Tschida, Barbara R.

AU - Sham, Tung Ting

AU - Lo, Lilian H.

AU - Moriarity, Branden S

AU - Li, Xiao Xiao

AU - Lo, Regina C.

AU - Hinton, David E.

AU - Rowlands, Dewi K.

AU - Chan, Chi On

AU - Mok, Daniel K.W.

AU - Largaespada, David A

AU - Warner, Nadia

AU - Keng, Vincent W.

PY - 2019/7/1

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N2 - 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.

AB - 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.

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