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

Abstract

Both activating and inactivating mutations in catenin β1 (ctnnb1), which encodes 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 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 β-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 β1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in β-catenin-deficient livers, featured by up-regulation of extracellular signal-regulated kinase (Erk), protein kinase B (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.

CONCLUSION:

These data argue that while dominantly activating mutants of β-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).

• Authors: Yan Liang, Yun Feng, Min Zong, Xu-Fu Wei, Jin Lee, Yukuan Feng, Hairi Li, Guang-Shun Yang, Zhong-Jun Wu, Xiang-Dong Fu, Gen-Sheng Feng
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 67 Issue 5 Pg. 1807-1822 (05 2018) ISSN: 1527-3350 [Electronic] United States
• PMID: 29152756 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the American Association for the Study of Liver Diseases.

Chemical References

• CTNNB1 protein, human
• MAS1 protein, human
• Proto-Oncogene Mas
• beta Catenin
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Carcinogenesis (genetics)
• Carcinoma, Hepatocellular (genetics, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (genetics)
• Hepatocytes (metabolism)
• Humans
• Liver (pathology)
• Liver Neoplasms (genetics, metabolism)
• Mice
• Oncogenes
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• Signal Transduction
• beta Catenin (genetics, metabolism)