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C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism

Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integr...

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Autores principales: Zhang, Yu, Yan, Qian, Gong, Lanqi, Xu, Hang, Liu, Beilei, Fang, Xiaona, Yu, Dandan, Li, Lei, Wei, Ting, Wang, Ying, Wong, Ching Ngar, Lyu, Zhaojie, Tang, Ying, Sham, Pak Chung, Guan, Xin-Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878188/
https://www.ncbi.nlm.nih.gov/pubmed/33323975
http://dx.doi.org/10.1038/s41388-020-01593-5
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author Zhang, Yu
Yan, Qian
Gong, Lanqi
Xu, Hang
Liu, Beilei
Fang, Xiaona
Yu, Dandan
Li, Lei
Wei, Ting
Wang, Ying
Wong, Ching Ngar
Lyu, Zhaojie
Tang, Ying
Sham, Pak Chung
Guan, Xin-Yuan
author_facet Zhang, Yu
Yan, Qian
Gong, Lanqi
Xu, Hang
Liu, Beilei
Fang, Xiaona
Yu, Dandan
Li, Lei
Wei, Ting
Wang, Ying
Wong, Ching Ngar
Lyu, Zhaojie
Tang, Ying
Sham, Pak Chung
Guan, Xin-Yuan
author_sort Zhang, Yu
collection PubMed
description Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3′-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment.
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spelling pubmed-78781882021-02-22 C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism Zhang, Yu Yan, Qian Gong, Lanqi Xu, Hang Liu, Beilei Fang, Xiaona Yu, Dandan Li, Lei Wei, Ting Wang, Ying Wong, Ching Ngar Lyu, Zhaojie Tang, Ying Sham, Pak Chung Guan, Xin-Yuan Oncogene Article Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3′-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment. Nature Publishing Group UK 2020-12-15 2021 /pmc/articles/PMC7878188/ /pubmed/33323975 http://dx.doi.org/10.1038/s41388-020-01593-5 Text en © The Author(s) 2020, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Yu
Yan, Qian
Gong, Lanqi
Xu, Hang
Liu, Beilei
Fang, Xiaona
Yu, Dandan
Li, Lei
Wei, Ting
Wang, Ying
Wong, Ching Ngar
Lyu, Zhaojie
Tang, Ying
Sham, Pak Chung
Guan, Xin-Yuan
C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism
title C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism
title_full C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism
title_fullStr C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism
title_full_unstemmed C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism
title_short C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism
title_sort c-terminal truncated hbx initiates hepatocarcinogenesis by downregulating txnip and reprogramming glucose metabolism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878188/
https://www.ncbi.nlm.nih.gov/pubmed/33323975
http://dx.doi.org/10.1038/s41388-020-01593-5
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