deletion accelerates mutant /-driven cholangiocarcinoma.

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of deletion in a cholangiocarcinoma mouse model using a mutant / mouse. Introduction of the deletion into liver-specific mutant / expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as and in the -deleted mutant / expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific deletion to mice harboring mutant and accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.