ß-catenin deficiency in hepatocytes aggravates hepatocarcinogenesis driven by oncogenic ß-catenin and MET.
Hepatology
; 67(5): 1807-1822, 2018 05.
Article
en En
| MEDLINE
| ID: mdl-29152756
ABSTRACT
Both activating and inactivating mutations in catenin ß1 (ctnnb1), which encodes ß-catenin, have been implicated in liver tumorigenesis in humans and mice, although the underlying mechanisms are not fully understood. Herein, we show that deletion of endogenous ß-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of ß-catenin (CAT) in combination with the hepatocyte growth factor receptor MET proto-oncogene receptor tyrosine kinase (MET). Although the mitogenic signaling and cell cycle progression was modestly impaired after CAT/MET transfection, the ß-catenin-deficient livers displayed changes in transcriptomes, increased DNA damage response, expanded Sox9+ cells, and up-regulation of protumorigenic cytokines, including interleukin-6 and transforming growth factor ß1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in ß-catenin-deficient livers, featured by up-regulation of extracellular signal-regulated kinase (Erk), protein kinase B (Akt), and Wnt/ß-catenin signaling and cyclin D1 expression. The resultant mouse tumors showed similar transcriptomes to human HCC samples with concomitant CTNNB1 mutations and MET overexpression. CONCLUSION:
These data argue that while dominantly activating mutants of ß-catenin are oncogenic, inhibiting the oncogenic signaling pathway generates a pro-oncogenic microenvironment that may facilitate HCC recurrence following a targeted therapy of the primary tumor. An effective therapeutic strategy must require disruption of the oncogenic signaling in tumor cells and suppression of the secondary tumor-promoting stromal effects in the liver microenvironment. (Hepatology 2018;671807-1822).
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Carcinoma Hepatocelular
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Proteínas Proto-Oncogénicas c-met
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Hepatocitos
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Beta Catenina
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Neoplasias Hepáticas
Límite:
Animals
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Humans
Idioma:
En
Revista:
Hepatology
Año:
2018
Tipo del documento:
Article
País de afiliación:
Canadá