Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice

Autor: Masanori Goto, Bing Xin, Lingtong Meng, Takako Ooshio, Masahiro Yamamoto, Yuji Nishikawa, Hiroki Tanaka, Yusuke Mizukami, Yang Liu, Yuki Kamikokura, Yoko Okada
Rok vydání: 2021
Předmět:
0301 basic medicine
Heterozygote
Cancer Research
Carcinoma
Hepatocellular
Carcinogenesis
Cellular differentiation
Cre recombinase
Biology
Cholangiocarcinoma
Proto-Oncogene Proteins c-myc
Proto-Oncogene Proteins p21(ras)
Mice
03 medical and health sciences
0302 clinical medicine
medicine
Animals
HRAS
Progenitor cell
oncogenes and tumor‐suppressor genes
characteristics of cancer cells
Mice
Knockout
gene‐manipulated animal models
Calcium-Binding Proteins
Homozygote
Liver Neoplasms
Transdifferentiation
p53‐related genes
Original Articles
General Medicine
Cell Dedifferentiation
medicine.disease
Phenotype
experimental animal models and genetically engineered animals
Gene Expression Regulation
Neoplastic
cell differentiation
030104 developmental biology
Bile Duct Neoplasms
Oncology
animal model for carcinogenesis
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Cell Transdifferentiation
Knockout mouse
Cancer research
Original Article
Tumor Suppressor Protein p53
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
Popis: 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 HRASV12 (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.
The loss of p53 promotes ductular differentiation of hepatocyte‐derived tumor cells through either transdifferentiation or Myc‐mediated dedifferentiation. This figure shows a two‐dimensional perspective of the hepatocyte‐derived tumors with respect to transdifferentiation and dedifferentiation.
Databáze: OpenAIRE
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