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TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a deadly but poorly understood disease, and its treatment options are very limited. The aim of this study was to identify the molecular drivers of ICC and search for therapeutic targets. APPROACH AND RESULTS: We performed a Sleeping Beaut...
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/PMC9869956/ https://www.ncbi.nlm.nih.gov/pubmed/34995376 http://dx.doi.org/10.1002/hep.32317 |
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author | Shiode, Yuto Kodama, Takahiro Shigeno, Satoshi Murai, Kazuhiro Tanaka, Satoshi Newberg, Justin Y. Kondo, Jumpei Kobayashi, Shogo Yamada, Ryoko Hikita, Hayato Sakamori, Ryotaro Suemizu, Hiroshi Tatsumi, Tomohide Eguchi, Hidetoshi Jenkins, Nancy A. Copeland, Neal G. Takehara, Tetsuo |
author_facet | Shiode, Yuto Kodama, Takahiro Shigeno, Satoshi Murai, Kazuhiro Tanaka, Satoshi Newberg, Justin Y. Kondo, Jumpei Kobayashi, Shogo Yamada, Ryoko Hikita, Hayato Sakamori, Ryotaro Suemizu, Hiroshi Tatsumi, Tomohide Eguchi, Hidetoshi Jenkins, Nancy A. Copeland, Neal G. Takehara, Tetsuo |
author_sort | Shiode, Yuto |
collection | PubMed |
description | BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a deadly but poorly understood disease, and its treatment options are very limited. The aim of this study was to identify the molecular drivers of ICC and search for therapeutic targets. APPROACH AND RESULTS: We performed a Sleeping Beauty transposon‐based in vivo insertional mutagenesis screen in liver‐specific Pten‐deficient mice and identified TNF receptor–related factor 3 (Traf3) as the most significantly mutated gene in murine ICCs in a loss‐of‐function manner. Liver‐specific Traf3 deletion caused marked cholangiocyte overgrowth and spontaneous development of ICC in Pten knockout and Kras (G12D) mutant mice. Hepatocyte‐specific, but not cholangiocyte‐specific, Traf3‐deficient and Pten‐deficient mice recapitulated these phenotypes. Lineage tracing and single‐cell RNA sequencing suggested that these ICCs were derived from hepatocytes through transdifferentiation. TRAF3 and PTEN inhibition induced a transdifferentiation‐like phenotype of hepatocyte‐lineage cells into proliferative cholangiocytes through NF‐κB‐inducing kinase (NIK) up‐regulation in vitro. Intrahepatic NIK levels were elevated in liver‐specific Traf3‐deficient and Pten‐deficient mice, and NIK inhibition alleviated cholangiocyte overgrowth. In human ICCs, we identified an inverse correlation between TRAF3 and NIK expression, with low TRAF3 or high NIK expression associated with poor prognosis. Finally, we showed that NIK inhibition by a small molecule inhibitor or gene silencing suppressed the growth of multiple human ICC cells in vitro and ICC xenografts in vivo. CONCLUSIONS: TRAF3 inactivation promotes ICC development through NIK‐mediated hepatocyte transdifferentiation. The oncogenic TRAF3–NIK axis may be a potential therapeutic target for ICC. |
format | Online Article Text |
id | pubmed-9869956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-98699562023-01-27 TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation Shiode, Yuto Kodama, Takahiro Shigeno, Satoshi Murai, Kazuhiro Tanaka, Satoshi Newberg, Justin Y. Kondo, Jumpei Kobayashi, Shogo Yamada, Ryoko Hikita, Hayato Sakamori, Ryotaro Suemizu, Hiroshi Tatsumi, Tomohide Eguchi, Hidetoshi Jenkins, Nancy A. Copeland, Neal G. Takehara, Tetsuo Hepatology Original Articles: Liver Cancer BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a deadly but poorly understood disease, and its treatment options are very limited. The aim of this study was to identify the molecular drivers of ICC and search for therapeutic targets. APPROACH AND RESULTS: We performed a Sleeping Beauty transposon‐based in vivo insertional mutagenesis screen in liver‐specific Pten‐deficient mice and identified TNF receptor–related factor 3 (Traf3) as the most significantly mutated gene in murine ICCs in a loss‐of‐function manner. Liver‐specific Traf3 deletion caused marked cholangiocyte overgrowth and spontaneous development of ICC in Pten knockout and Kras (G12D) mutant mice. Hepatocyte‐specific, but not cholangiocyte‐specific, Traf3‐deficient and Pten‐deficient mice recapitulated these phenotypes. Lineage tracing and single‐cell RNA sequencing suggested that these ICCs were derived from hepatocytes through transdifferentiation. TRAF3 and PTEN inhibition induced a transdifferentiation‐like phenotype of hepatocyte‐lineage cells into proliferative cholangiocytes through NF‐κB‐inducing kinase (NIK) up‐regulation in vitro. Intrahepatic NIK levels were elevated in liver‐specific Traf3‐deficient and Pten‐deficient mice, and NIK inhibition alleviated cholangiocyte overgrowth. In human ICCs, we identified an inverse correlation between TRAF3 and NIK expression, with low TRAF3 or high NIK expression associated with poor prognosis. Finally, we showed that NIK inhibition by a small molecule inhibitor or gene silencing suppressed the growth of multiple human ICC cells in vitro and ICC xenografts in vivo. CONCLUSIONS: TRAF3 inactivation promotes ICC development through NIK‐mediated hepatocyte transdifferentiation. The oncogenic TRAF3–NIK axis may be a potential therapeutic target for ICC. Lippincott Williams & Wilkins 2023-02 2022-02-01 /pmc/articles/PMC9869956/ /pubmed/34995376 http://dx.doi.org/10.1002/hep.32317 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of 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 Articles: Liver Cancer Shiode, Yuto Kodama, Takahiro Shigeno, Satoshi Murai, Kazuhiro Tanaka, Satoshi Newberg, Justin Y. Kondo, Jumpei Kobayashi, Shogo Yamada, Ryoko Hikita, Hayato Sakamori, Ryotaro Suemizu, Hiroshi Tatsumi, Tomohide Eguchi, Hidetoshi Jenkins, Nancy A. Copeland, Neal G. Takehara, Tetsuo TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation |
title | TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation |
title_full | TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation |
title_fullStr | TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation |
title_full_unstemmed | TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation |
title_short | TNF receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through NF‐κB‐inducing kinase–mediated hepatocyte transdifferentiation |
title_sort | tnf receptor–related factor 3 inactivation promotes the development of intrahepatic cholangiocarcinoma through nf‐κb‐inducing kinase–mediated hepatocyte transdifferentiation |
topic | Original Articles: Liver Cancer |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9869956/ https://www.ncbi.nlm.nih.gov/pubmed/34995376 http://dx.doi.org/10.1002/hep.32317 |
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