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Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma.
- Source :
-
American Journal of Physiology: Gastrointestinal & Liver Physiology . Mar2020, Vol. 318 Issue 3, pG419-G427. 9p. - Publication Year :
- 2020
-
Abstract
- The activation of the Kelchlike 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 cholangiocyterelated 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01931857
- Volume :
- 318
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- American Journal of Physiology: Gastrointestinal & Liver Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 142016751
- Full Text :
- https://doi.org/10.1152/ajpgi.00296.2019