Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis
Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis
复制标题
DOI：
10.1093/carcin/bgx043
复制
发表时间：
2017-06-01
期刊：
影响因子：
4.7
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Hamada, Shin;Taguchi, Keiko;Shimosegawa, Tooru
Keap 1-Nrf 2系统通过调节正常组织和器官中的氧化应激反应来维持体内平衡，并且在各种癌症中用于增殖、存活和获得治疗抗性。胰腺癌仍然是难治性癌症之一，尽管其他类型的癌症的临床结果有所改善，但由于其对治疗干预的侵袭性和难治性。当前的研究旨在使用胰腺特异性突变K-ras和p53（KPC）小鼠模型来阐明Nrf 2对胰腺癌发生的贡献。KPC小鼠（KPCN）中Nrf 2的缺失减少了癌前病变的形成以及侵袭性胰腺癌的发展。KPCN小鼠胰腺癌细胞株谷胱甘肽S-转移酶（GST）、UDP葡萄糖醛酸转移酶（UGT）和ABC转运蛋白表达降低。沿着这些生化变化，KPCN小鼠的细胞系显示对氧化应激和化疗剂的敏感性增加。目前的研究表明，Nrf 2在胰腺癌发生中的作用与肺和食管的化疗耐药性不同，Nrf 2可能成为胰腺癌的新治疗靶点。
The Keap1-Nrf2 system contributes to the maintenance of homeostasis by regulating oxidative stress responses in normal tissues and organs, and is exploited in various cancers for proliferation, survival and acquisition of therapy resistance. Pancreatic cancer remains one of the intractable cancers, despite the improved clinical outcomes of other types of cancer, due to its invasive and refractory nature to therapeutic intervention. The current study aimed to clarify the contribution of Nrf2 to pancreatic carcinogenesis using a pancreas-specific mutant K-ras and p53 (KPC) mouse model. Deletion of Nrf2 in KPC mice (KPCN) decreased the formation of precancerous lesions as well as the development of invasive pancreatic cancer. The pancreatic tumor-derived cancer cell lines from KPCN mouse showed decreased expression of glutathione S-transferases (GST), UDP glucuronosyltransferases (UGT) and ABC transporters. Along with these biochemical changes, cell lines from KPCN mice revealed increased sensitivity to oxidative stress and chemotherapeutic agent. The current study revealed that Nrf2 contributes to pancreatic carcinogenesis in a way distinct from the chemoresistance of lung and esophagus, and that Nrf2 could be a novel therapeutic target of pancreatic cancer.