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

Abstract

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.

Oxidative Stress in Cancer

“…For example, the incidence of pancreatic cancer was markedly reduced in Nrf2-null mice relative to wildtype mice in a K-Ras G12D −driven cancer model (DeNicola et al, 2011), and the incidence of lung tumors in Nrf2null mice was also modestly reduced relative to wild-type mice in urethane-initiated cancer (Bauer et al, 2011;Satoh et al, 2013). Similarly, knockout of Keap1 in mice, leading to hyperactivation of Nrf2, accelerated cholangiocarcinoma driven by K-Ras G12D and Trp53 R172H (Nabeshima et al, 2020).…”

Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition

“…These results with the current observations suggest that excess Nrf2 activation might be associated with certain disadvantages in pancreatic lineage cells. In contrast to that in KPC::Keap1 CKO mice, Keap1 deletion in mice expressing liver-specific mutant K-ras and p53 resulted in accelerated cholangiocarcinoma development [19]. Therefore, the existence of mutant K-ras and activation of Nrf2 might suppress the unknown machinery that is indispensable for cell survival in pancreatic cancer.…”

Nrf2 expression in pancreatic stellate cells promotes progression of cancer

“…These models used small-molecule compounds in mouse models, which include both HSCs and hepatocytes that retain cell-to-cell interactions. In the mutant K-ras/p53-driven cholangiocarcinoma model mouse, Nrf2 activation by Keap1 deletion accelerated cancer progression (29).…”