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Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA
BACKGROUND: Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepat...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635605/ https://www.ncbi.nlm.nih.gov/pubmed/37938099 http://dx.doi.org/10.1097/HC9.0000000000000313 |
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author | Funato, Kazuyoshi Miyake, Nozomi Sekiba, Kazuma Miyakawa, Yu Seimiya, Takahiro Shibata, Chikako Kishikawa, Takahiro Otsuka, Motoyuki |
author_facet | Funato, Kazuyoshi Miyake, Nozomi Sekiba, Kazuma Miyakawa, Yu Seimiya, Takahiro Shibata, Chikako Kishikawa, Takahiro Otsuka, Motoyuki |
author_sort | Funato, Kazuyoshi |
collection | PubMed |
description | BACKGROUND: Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. METHODS: Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. RESULTS: Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor–signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. CONCLUSIONS: Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV. |
format | Online Article Text |
id | pubmed-10635605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-106356052023-11-10 Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA Funato, Kazuyoshi Miyake, Nozomi Sekiba, Kazuma Miyakawa, Yu Seimiya, Takahiro Shibata, Chikako Kishikawa, Takahiro Otsuka, Motoyuki Hepatol Commun Original Article BACKGROUND: Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. METHODS: Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. RESULTS: Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor–signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. CONCLUSIONS: Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV. Lippincott Williams & Wilkins 2023-11-08 /pmc/articles/PMC10635605/ /pubmed/37938099 http://dx.doi.org/10.1097/HC9.0000000000000313 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Original Article Funato, Kazuyoshi Miyake, Nozomi Sekiba, Kazuma Miyakawa, Yu Seimiya, Takahiro Shibata, Chikako Kishikawa, Takahiro Otsuka, Motoyuki Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA |
title | Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA |
title_full | Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA |
title_fullStr | Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA |
title_full_unstemmed | Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA |
title_short | Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA |
title_sort | cabozantinib inhibits hbv-rna transcription by decreasing stat3 binding to the enhancer region of cccdna |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635605/ https://www.ncbi.nlm.nih.gov/pubmed/37938099 http://dx.doi.org/10.1097/HC9.0000000000000313 |
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