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

TitleC-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism
Authors
Issue Date2021
PublisherSpringer Nature [academic journals on nature.com]. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2021, v. 40, p. 1147-1161 How to Cite?
AbstractChronic 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.
DescriptionHybrid open access
Persistent Identifierhttp://hdl.handle.net/10722/300865
ISSN
2020 Impact Factor: 9.867
2015 SCImago Journal Rankings: 4.047
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorZHANG, Y-
dc.contributor.authorYan, Q-
dc.contributor.authorGONG, L-
dc.contributor.authorXu, H-
dc.contributor.authorLiu, B-
dc.contributor.authorFANG, X-
dc.contributor.authorYU, D-
dc.contributor.authorLi, L-
dc.contributor.authorWei, T-
dc.contributor.authorWANG, Y-
dc.contributor.authorWONG, CN-
dc.contributor.authorLYU, Z-
dc.contributor.authorTANG, Y-
dc.contributor.authorSham, PC-
dc.contributor.authorGuan, X-
dc.date.accessioned2021-07-06T03:11:17Z-
dc.date.available2021-07-06T03:11:17Z-
dc.date.issued2021-
dc.identifier.citationOncogene, 2021, v. 40, p. 1147-1161-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/300865-
dc.descriptionHybrid open access-
dc.description.abstractChronic 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.-
dc.languageeng-
dc.publisherSpringer Nature [academic journals on nature.com]. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleC-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism-
dc.typeArticle-
dc.identifier.emailLi, L: lilei728@HKUCC-COM.hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.emailGuan, X: xyguan@hku.hk-
dc.identifier.authoritySham, PC=rp00459-
dc.identifier.authorityGuan, X=rp00454-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41388-020-01593-5-
dc.identifier.pmid33323975-
dc.identifier.pmcidPMC7878188-
dc.identifier.scopuseid_2-s2.0-85097529675-
dc.identifier.hkuros323266-
dc.identifier.volume40-
dc.identifier.spage1147-
dc.identifier.epage1161-
dc.publisher.placeUnited Kingdom-

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