Xu Lingxue, Wang Jingjing, Zhang Danhua, Song Lijie, Wu Han, Wang Jianyao, Miao Jinxin, Guo Haoran, Fang Sujuan, Si Lingling, Chen Jingfei, Wu Yifan, Wu Yangyang, Wang Lihong, Zhang Na, Chard Louisa, Wang Yaohe, Cheng Zhenguo
National Center for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, 450052, Zhengzhou, China.
Department of Surgical Oncology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
Cell Biosci. 2022 May 31;12(1):77. doi: 10.1186/s13578-022-00802-w.
Activating transcription factor-2 (ATF2) is a member of the basic leucine zipper family of DNA-binding proteins, which exhibits both oncogenic and tumor suppression activity in different tumors. However, the molecular mechanism of its dual function in cancer chemotherapy especially in gastric cancer has still not been elucidated.
The protein expression and location of ATF2 in gastric cancer tissues was detected with immunohistochemistry assay, and the clinical significance was analyzed using TCGA and GEO database. The activation and impact of ATF2 in cisplatin treated cells were evaluated with western blot, incucyte live cell analysis, clone formation and tumor xenografts assays. Interaction between ATF2 and p53 was confirmed with immunoprecipitation and GST-pull down. Potential molecular mechanism of ATF2 in different p53 status cells was analyzed with RNA sequencing and real-time quantitative PCR.
ATF2 mainly located in the nucleus of cancer cells, higher ATF2 level was associated with poor five-year survival of gastric patients, especially in those undergone chemotherapy treatment. Cisplatin treatment significantly activated ATF2 in p53 mutant cells. ATF2 could interact with the trans-activation domain of p53 and enhance cisplatin sensitivity in p53 wild type cell lines, while promoted cell survival in mutant p53 cancer cells by affecting ERK1/2 pathway.
This study confirmed the effect of ATF2 on cisplatin sensitivity was associated with the functional status of p53 in gastric cancer cells. Integrated analysis of ATF2 expression and P53 status could be used to evaluate the chemotherapy sensitivity and prognosis of gastric cancer patients.
激活转录因子2（ATF2）是DNA结合蛋白碱性亮氨酸拉链家族的成员，在不同肿瘤中兼具致癌和肿瘤抑制活性。然而，其在癌症化疗尤其是胃癌中的双重功能的分子机制仍未阐明。
采用免疫组织化学法检测ATF2在胃癌组织中的蛋白表达和定位，并利用TCGA和GEO数据库分析其临床意义。通过蛋白质免疫印迹法、Incucyte活细胞分析、克隆形成和肿瘤异种移植实验评估ATF2在顺铂处理细胞中的激活情况及其影响。通过免疫沉淀和谷胱甘肽-S-转移酶下拉实验证实ATF2与p53之间的相互作用。利用RNA测序和实时定量PCR分析ATF2在不同p53状态细胞中的潜在分子机制。
ATF2主要定位于癌细胞的细胞核，较高的ATF2水平与胃癌患者较差的五年生存率相关，尤其是在接受化疗的患者中。顺铂处理显著激活了p53突变细胞中的ATF2。ATF2可与p53的反式激活结构域相互作用，增强p53野生型细胞系对顺铂的敏感性，同时通过影响ERK1/2信号通路促进p53突变癌细胞的存活。
本研究证实ATF2对顺铂敏感性的影响与胃癌细胞中p53的功能状态有关。综合分析ATF2表达和P53状态可用于评估胃癌患者的化疗敏感性和预后。
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