| First Author | Liang Y | Year | 2018 |
| Journal | Hepatology | Volume | 67 |
| Issue | 5 | Pages | 1807-1822 |
| PubMed ID | 29152756 | Mgi Jnum | J:320555 |
| Mgi Id | MGI:6873809 | Doi | 10.1002/hep.29661 |
| Citation | Liang Y, et al. (2018) beta-catenin deficiency in hepatocytes aggravates hepatocarcinogenesis driven by oncogenic beta-catenin and MET. Hepatology 67(5):1807-1822 |
| abstractText | Both activating and inactivating mutations in catenin beta1 (ctnnb1), which encodes beta-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 beta-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of beta-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 beta-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 beta1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in beta-catenin-deficient livers, featured by up-regulation of extracellular signal-regulated kinase (Erk), protein kinase B (Akt), and Wnt/beta-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 beta-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;67:1807-1822). |
