| First Author | Nabeshima T | Year | 2020 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 318 |
| Issue | 3 | Pages | G419-G427 |
| PubMed ID | 31961719 | Mgi Jnum | J:293394 |
| Mgi Id | MGI:6452695 | Doi | 10.1152/ajpgi.00296.2019 |
| Citation | Nabeshima T, et al. (2020) Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma. Am J Physiol Gastrointest Liver Physiol 318(3):G419-G427 |
| abstractText | 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 Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma.NEW & NOTEWORTHY 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 Keap1 deletion to mice harboring mutant K-ras and p53 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. |
