CD147 promotes DNA damage response and gemcitabine resistance via targeting ATM/ATR/p53 and affects prognosis in pancreatic cancer
CD147 promotes DNA damage response and gemcitabine resistance via targeting ATM/ATR/p53 and affects prognosis in pancreatic cancer
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CD147 通过靶向 ATM/ATR/p53 促进 DNA 损伤反应和吉西他滨耐药性，并影响胰腺癌的预后
DOI：
10.1016/j.bbrc.2020.05.005
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发表时间：
2020
影响因子：
3.1
通讯作者：
Chen Zhi-Nan
中科院分区：
文献类型：
--
作者：
Zhou Yinghui;Zheng Ming;Liu Zhenyu;Yang Haijiao;Zhu Ping;Jiang Jian-Li;Tang Juan;Chen Zhi-Nan
胰腺癌化疗耐药性的获得是胰腺癌治疗面临的主要临床挑战。化疗耐药性主要归因于异常的DNA损伤修复。然而，胰腺癌化疗耐药的潜在机制仍不清楚。在此，我们发现CD 147与胰腺导管腺癌（PDAC）患者的DNA损伤反应（DDR）指数和不良预后密切相关。CD 147敲除或单克隆抗体改善了吉西他滨在吉西他滨耐药细胞中的杀伤作用，表现出ATM/p53的活化降低。此外，我们发现CD 147与ATM，ATR和p53的相互作用，这在吉西他滨耐药细胞中增强。高CD 147/p-ATM/p-ATR/p-p53胞浆表达与PC患者生存率低相关。因此，我们的研究确定CD 147是影响胰腺癌患者吉西他滨治疗结果的DDR编程中的关键参与者。(C)2020由Elsevier Inc.出版。
The acquisition of chemoresistance is a major clinical challenge for pancreatic cancer (PC) treatment. Chemoresistance is largely attributed to aberrant DNA damage repair. However, the underlying mechanisms of chemoresistance in pancreatic cancer remain unclear. Here, we showed that CD147 was strongly correlated to DNA damage response (DDR) indices and poor prognosis in pancreatic ductal adenocarcinoma (PDAC) patients. CD147 knockdown or monoclonal antibodies improved the killing effects of gemcitabine in gemcitabine resistant cells, exhibiting reduced activation of ATM/p53. Moreover, we found the interaction of CD147 with ATM, ATR and p53, which was augmented in gemcitabine resistant cells. High CD147/p-ATM/p-ATR/p-p53 cytoplasmic expression associated with poor survival of PC patients. Our studies thus identify CD147 as a critical player in DDR programing that affects gemcitabine therapeutic outcomes of pancreatic cancer patients. (C) 2020 Published by Elsevier Inc.