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

doi:10.1158/1541-7786.MCR-18-1127

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

Pediatric Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

17 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. 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 language	English (US)
Pages (from-to)	1582-1593
Number of pages	12
Journal	Molecular Cancer Research
Volume	17
Issue number	7
DOIs	https://doi.org/10.1158/1541-7786.MCR-18-1127
State	Published - 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.

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Journal Article
Research Support, N.I.H., Extramural

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10.1158/1541-7786.MCR-18-1127

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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

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

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

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. ",

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

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: {\textcopyright} 2019 American Association for Cancer Research.",

year = "2019",

month = jul,

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doi = "10.1158/1541-7786.MCR-18-1127",

language = "English (US)",

volume = "17",

pages = "1582--1593",

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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.

N1 - 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.

PY - 2019/7/1

Y1 - 2019/7/1

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. 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.

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

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