Dataset Information


?-catenin deficiency in hepatocytes aggravates hepatocarcinogenesis driven by oncogenic ?-catenin and MET.

ABSTRACT: Both activating and inactivating mutations in catenin ?1 (ctnnb1), which encodes ?-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 ?-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of ?-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 ?-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 ?1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in ?-catenin-deficient livers, featured by up-regulation of extracellular signal-regulated kinase (Erk), protein kinase B (Akt), and Wnt/?-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 ?-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).

PROVIDER: S-EPMC5906147 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

2015-01-01 | S-EPMC4280291 | BioStudies
| S-EPMC8435276 | BioStudies
2017-01-01 | S-EPMC5397318 | BioStudies
| S-EPMC6819211 | BioStudies
| S-EPMC4010419 | BioStudies
| S-EPMC5777711 | BioStudies
2017-01-01 | S-EPMC5809589 | BioStudies
| S-EPMC8656042 | BioStudies
| S-EPMC5073058 | BioStudies
| S-EPMC7206928 | BioStudies