β-Catenin Deficiency in Hepatocytes Aggravates Hepatocarcinogenesis Driven by Oncogenic β-Catenin and MET

ABSTRACT

Both activating and inactivating mutations in ctnnb1, encoding β-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 β-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of β-catenin (CAT) in combination with HGF receptor MET. Although the mitogenic signaling and cell cycle progression was modestly impaired after CAT/MET transfection, the β-catenin-deficient livers displayed changes in transcriptomes, increased DNA damage response, expanded Sox9⁺ cells, and upregulation of pro-tumorigenic cytokines including IL-6 and TGF-β1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in β-catenin-deficient livers, featured by upregulation of Erk, Akt and Wnt/β-catenin signaling and cyclin D1 expression. The resultant mouse tumors showed similar transcriptomes to human HCC samples with concomitant CTNNB1 mutations and MET overexpression. These data argue that while dominantly activating mutants of β-catenin are oncogenic, inhibiting the oncogenic signaling pathway generates a pro-oncogenic microenvironment, which may facilitate HCC recurrence following a targeted therapy of the primary tumor. Therefore, an effective therapeutic strategy must require disruption of the oncogenic signaling in tumor cells and also suppression of the secondary tumor-promoting stromal effects in the liver microenvironment. This article is protected by copyright. All rights reserved.

http://ift.tt/2hGvlqX