Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

Tatsuhide Nabeshima, Shin Hamada, Keiko Taguchi, Yu Tanaka, Ryotaro Matsumoto, Masayuki Yamamoto, Atsushi Masamune

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)G419-G427
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume318
Issue number3
DOIs
Publication statusPublished - 2020

Keywords

  • Bile duct formation
  • Cholangiocarcinoma
  • Kelch-like ECH-associated protein 1
  • NF-E2-related factor 2
  • Sox9

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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