The transforming growth factor-α and cyclin D1 genes are direct targets of β-catenin signaling in hepatocyte proliferation.

BACKGROUND & AIMS: β-Catenin is an oncogene frequently mutated in hepatocellular carcinoma. In this study, we investigated target genes of β-catenin signaling in hepatocyte proliferation.

METHODS

We studied transgenic mice displaying either inactivation or activation of the β-catenin pathway, focusing on analysis of liver proliferation due to aberrant β-catenin activation, and on the regeneration process during which β-catenin signaling is transiently activated. We localized in situ the various partners involved in proliferation or identified as targets of β-catenin in these transgenic and regenerating livers. We also performed comparative transcriptome analyses, using microarrays. Finally, we extracted, from deep-sequencing data, both the DNA regulatory elements bound to the β-catenin/Tcf nuclear complex and the expression levels of critical targets identified in microarrays.

RESULTS

β-Catenin activation during liver regeneration occurred during G1/S cell cycle progression and allowed zonal extension of the normal territory of active β-catenin and panlobular proliferation. We found that β-catenin controlled both cell-autonomous and non-cell-autonomous hepatocyte proliferation, through direct transcriptional and complex control of cyclin D1 gene expression and of the expression of a new target gene, Tgfα.

CONCLUSIONS

We propose that β-catenin controls panlobular hepatocyte proliferation partly by controlling, together with its Tcf4 nuclear partner, expression of the pro-proliferation cyclin D1 and Tgfα genes. This study constitutes a first step toward understanding the oncogenic properties of this prominent signaling pathway in the liver.