Gemcitabine treatment promotes pancreatic cancer sternness through the Nox/ROS/NF-κB/STAT3 signaling cascade
Gemcitabine treatment promotes pancreatic cancer sternness through the Nox/ROS/NF-κB/STAT3 signaling cascade
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吉西他滨治疗通过 Nox/ROS/NF-kappa B/STAT3 信号级联促进胰腺癌的严重程度
DOI：
10.1016/j.canlet.2016.08.023
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发表时间：
2016-11-01
期刊：
影响因子：
9.7
通讯作者：
Yin, Tao
中科院分区：
文献类型：
--
作者：
Zhang, Zhengle;Duan, Qingke;Yin, Tao
吉西他滨是治疗晚期胰腺癌的标准化疗药物，但由于存在严重的耐药性，其疗效有限。然而，所涉及的机制仍不清楚。肿瘤干细胞具有很强的致瘤性，与肿瘤的耐药性和复发密切相关。在这项研究中，我们证明了一定剂量的吉西他滨增加了CD 24（+）和CD 133（+）细胞的比例以及干细胞相关基因（如Bmi 1，Nanog和Sox 2）的表达。吉西他滨治疗后干性增强伴随着细胞迁移、化疗耐药性和肿瘤发生的增加。此外，我们发现吉西他滨促进磷酸化STAT 3与Bmi 1、Nanog和Sox 2基因启动子的结合。此外，STAT 3的抑制部分逆转吉西他滨诱导的球体形成、迁移、化疗耐药性和肿瘤复发。我们还证明了STAT 3的激活和吉西他滨增强的干性是NADPH氧化酶（Nox）产生的，ROS依赖的，NF-κ B B部分介导的过程。总之，我们的研究结果表明胰腺癌干细胞通过Nox/ROS/NF-κ B/STAT 3信号通路在对吉西他滨治疗产生耐药性中起关键作用。这些发现将为确定可用于使胰腺癌细胞对化疗敏感的潜在靶点提供新的见解。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Gemcitabine, the standard chemotherapy drug for advanced pancreatic cancer, has shown limited benefits because of profound chemoresistance. However, the mechanism involved remains unclear. Cancer stem cells exhibit great tumorigenicity and are closely correlated with drug resistance and tumor relapse. In this study, we demonstrated that certain doses of gemcitabine increased the ratios of CD24(+) and CD133(+) cells and the expression of sternness-associated genes such as Bmi1, Nanog, and Sox2. The enhancement of stemness after gemcitabine treatment was accompanied by increased cell migration, chemoresistance, and tumorigenesis. Moreover, we found that gemcitabine promoted the binding of phosphorylated STAT3 to the promoter of Bmi1, Nanog, and Sox2 genes. Furthermore, inhibition of STAT3 partially reversed gemcitabine-induced sphere formation, migration, chemoresistance, and tumor relapse. We also demonstrated that the activation of STAT3 and gemcitabine-enhanced sternness was NADPH oxidase (Nox)-generated, ROS-dependent, and NF-kappa B partially mediated the process. Together, our results suggest a pivotal role of pancreatic cancer stem cells in developing chemoresistance toward gemcitabine treatment through the Nox/ROS/NF-kappa B/STAT3 signaling pathway. These findings will provide new insight for identifying potential targets that can be used to sensitize pancreatic cancer cells to chemotherapy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.