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Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice
The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for t...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353893/ https://www.ncbi.nlm.nih.gov/pubmed/34051011 http://dx.doi.org/10.1111/cas.14996 |
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author | Liu, Yang Xin, Bing Yamamoto, Masahiro Goto, Masanori Ooshio, Takako Kamikokura, Yuki Tanaka, Hiroki Meng, Lingtong Okada, Yoko Mizukami, Yusuke Nishikawa, Yuji |
author_facet | Liu, Yang Xin, Bing Yamamoto, Masahiro Goto, Masanori Ooshio, Takako Kamikokura, Yuki Tanaka, Hiroki Meng, Lingtong Okada, Yoko Mizukami, Yusuke Nishikawa, Yuji |
author_sort | Liu, Yang |
collection | PubMed |
description | The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC‐CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRAS(V12) (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS‐ or HRAS/Myc‐induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte‐derived liver tumors were induced in heterozygous and homozygous p53‐knockout (KO) mice by hydrodynamic tail vein injection of HRAS‐ or Myc‐containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase‐expressing plasmid. The HRAS‐induced and HRAS/Myc‐induced tumors in the wild‐type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53‐KO mice was consistent with cHCC‐CCA. The expression of fetal/neonatal liver proteins, including delta‐like 1, was detected in the HRAS/Myc‐induced but not in the HRAS‐induced cHCC‐CCA tissues. The dedifferentiation in the HRAS/Myc‐induced tumors was more marked in the homozygous p53‐KO mice than in the heterozygous p53‐KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte‐derived tumor cells through either transdifferentiation or Myc‐mediated dedifferentiation. |
format | Online Article Text |
id | pubmed-8353893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83538932021-08-15 Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice Liu, Yang Xin, Bing Yamamoto, Masahiro Goto, Masanori Ooshio, Takako Kamikokura, Yuki Tanaka, Hiroki Meng, Lingtong Okada, Yoko Mizukami, Yusuke Nishikawa, Yuji Cancer Sci Original Articles The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC‐CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRAS(V12) (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS‐ or HRAS/Myc‐induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte‐derived liver tumors were induced in heterozygous and homozygous p53‐knockout (KO) mice by hydrodynamic tail vein injection of HRAS‐ or Myc‐containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase‐expressing plasmid. The HRAS‐induced and HRAS/Myc‐induced tumors in the wild‐type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53‐KO mice was consistent with cHCC‐CCA. The expression of fetal/neonatal liver proteins, including delta‐like 1, was detected in the HRAS/Myc‐induced but not in the HRAS‐induced cHCC‐CCA tissues. The dedifferentiation in the HRAS/Myc‐induced tumors was more marked in the homozygous p53‐KO mice than in the heterozygous p53‐KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte‐derived tumor cells through either transdifferentiation or Myc‐mediated dedifferentiation. John Wiley and Sons Inc. 2021-06-27 2021-08 /pmc/articles/PMC8353893/ /pubmed/34051011 http://dx.doi.org/10.1111/cas.14996 Text en © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Liu, Yang Xin, Bing Yamamoto, Masahiro Goto, Masanori Ooshio, Takako Kamikokura, Yuki Tanaka, Hiroki Meng, Lingtong Okada, Yoko Mizukami, Yusuke Nishikawa, Yuji Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice |
title | Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice |
title_full | Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice |
title_fullStr | Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice |
title_full_unstemmed | Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice |
title_short | Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice |
title_sort | generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353893/ https://www.ncbi.nlm.nih.gov/pubmed/34051011 http://dx.doi.org/10.1111/cas.14996 |
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