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Loss of Apc Cooperates with Activated Oncogenes to Induce Liver Tumor Formation in Mice.
- Source :
-
The American journal of pathology [Am J Pathol] 2021 May; Vol. 191 (5), pp. 930-946. Date of Electronic Publication: 2021 Feb 03. - Publication Year :
- 2021
-
Abstract
- Hepatocellular carcinoma (HCC) and hepatoblastoma are the major types of primary liver cancer in adulthood and childhood, respectively. Wnt/β-catenin signaling deregulation is one of the most frequent genetic events in hepatocarcinogenesis. APC regulator of WNT signaling pathway (APC) encodes an inhibitor of the Wnt cascade and acts as a tumor suppressor. Germline defects of the APC gene lead to familial adenomatous polyposis, and its somatic mutations occur in multiple tumor types. However, the contribution of APC in hepatocarcinogenesis remains unclear. Therefore, APC mutations and expression patterns were examined in human HCC and hepatoblastoma samples. Whether loss of Apc alone or in cooperation with other oncogenes triggers liver tumor development in vivo was also investigated. sgApc alone could not drive liver tumor formation, but synergized with activated oncogenes (YapS127A, TazS89A, and c-Met) to induce hepatocarcinogenesis. Mechanistically, Apc deletion induced the activation of β-catenin and its downstream targets in mouse liver tumors. Furthermore, Ctnnb1 ablation or TCF4-mediated transcription blockade completely prevented liver tumor formation, indicating the requirement of a functional β-catenin pathway for loss of Apc-driven hepatocarcinogenesis. This study shows that a subset of HCC patients with loss-of-function APC mutations might benefit from therapeutic strategies targeting the Wnt/β-catenin pathway.<br /> (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenomatous Polyposis Coli pathology
Adenomatous Polyposis Coli Protein genetics
Animals
Carcinogenesis
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Hepatoblastoma pathology
Humans
Liver pathology
Liver Neoplasms pathology
Loss of Function Mutation
Male
Mice
Mice, Inbred C57BL
Oncogenes
Adenomatous Polyposis Coli genetics
Adenomatous Polyposis Coli Protein metabolism
Carcinoma, Hepatocellular genetics
Hepatoblastoma genetics
Liver Neoplasms genetics
Wnt Signaling Pathway genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 191
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 33545120
- Full Text :
- https://doi.org/10.1016/j.ajpath.2021.01.010