Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma
Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma
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DOI：
10.1152/ajpgi.00296.2019
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发表时间：
2020-03-01
影响因子：
4.5
通讯作者：
Masamune, Atsushi
中科院分区：
文献类型：
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作者：
Nabeshima, Tatsuhide;Hamada, Shin;Masamune, Atsushi
Kelch样ECH相关蛋白1（Keap 1）-NF-E2相关因子2（Nrf 2）通路的激活除了氧化应激反应外还有助于癌症进展。据报道，功能丧失的Keap 1突变会激活Nrf 2，导致癌症进展。我们使用突变K-ras/p53小鼠研究了Keap 1缺失对胆管癌小鼠模型的影响。将Keap 1缺失引入肝脏特异性突变K-ras/p53表达导致浸润性胆管癌的形成。基因表达谱的综合分析确定了广泛的上调Nrf 2靶基因，如Nqo 1和Gstm 1在Keap 1缺失突变K-ras/p53表达肝脏，伴随着上调胆管细胞相关基因。在这些基因中，转录因子Sox 9在发育不良的胆管中高表达。Keap-Nrf 2-Sox 9轴可能作为胆管癌的新的治疗靶点。新&值得注意的是Keap 1-Nrf 2系统除了在癌细胞中的氧化应激反应外，还具有多种作用。在携带突变K-ras和p53的小鼠中加入肝脏特异性Keap 1缺失，加速了胆管癌的形成，同时标志着Nrf 2的激活。这个过程涉及Sox 9阳性细胞的扩增，表明向胆管细胞表型的分化增加。
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 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.