Cross-talk between EPAS-1/HIF-2α and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell
Cross-talk between EPAS-1/HIF-2α and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell
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EPAS-1/HIF-2α与PXR信号通路的串扰调控胃癌细胞多药耐药
DOI：
10.1016/j.biocel.2016.01.006
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发表时间：
2016-03-01
影响因子：
4
通讯作者：
Xu, Binghe
中科院分区：
文献类型：
--
作者：
Zhao, Jiuda;Bai, Zhenzhong;Xu, Binghe
EPAS-1/HIF-2 α（含有内皮PAS结构域的蛋白1/低氧诱导转录因子2 α）是在包括胃癌在内的多种人类癌症中表达的转录因子。虽然EPAS-1已被研究多年，但其在致癌转化过程中的功能需要进一步研究。本研究发现EPAS-1对胃癌细胞株BGC-823的生长有促进作用。我们的研究结果表明，EPAS-1与孕烷X受体（PXR）相互作用，PXR是一种调节多个基因转录的核受体，参与多药耐药（MDR）过程。通过免疫共沉淀和GST-pull down分析鉴定EPAS-1和PXR之间的蛋白质-蛋白质相互作用。通过这种相互作用，EPAS-1将PXR募集到PXR靶基因CYP 3A 4的启动子/增强子区域的反应元件中。EPAS-1的过表达增加了PXR应答基因的表达，促进了BGC-823细胞的增殖，并增强了BGC-823细胞对化疗药物如丝裂霉素C和紫杉醇的细胞毒性的抵抗力。通过siRNA降低EPAS-1的表达水平，可抑制BGC-823细胞的增殖，并增强其对化疗药物的敏感性。提示EPAS-1和PXR可能协同参与胃癌的发生发展，尤其是多药耐药过程。这些发现可能有助于发现更有效的胃癌治疗靶向药物。(C)2016爱思唯尔有限公司版权所有。
EPAS-1/HIF-2 alpha (Endothelial PAS domain-containing protein 1/hypoxia-inducible transcription factors 2 alpha) is a transcription factor expressed in a wide range of human cancers, including stomach cancer. Although EPAS-1 has been studied for years, its function in oncogenic transformation processes needs to be further investigated. In this study, we found that EPAS-1 would promote the growth of stomach cancer cell line BGC-823. Our results revealed that EPAS-1 interacts with Pregnane X Receptor (PXR), a nuclear receptor that regulates multiple genes' transcription involved in multi-drugs resistance (MDR) process. Protein-protein interaction between EPAS-1 and PXR was identified by co-immunoprecipitation and GST-pull down assays. By this interaction, EPAS-1 recruited PXR to its response elements in promoter/enhancer regions of CYP3A4, a PXR target gene. Over-expression of EPAS-1 increased the expression of PXR responsive genes, enhanced the proliferation of BGC-823 cells and boosted the resistance of BGC-823 cells against the cytotoxicity of chemotherapeutic drugs, e.g. Mitomycin C and Paclitaxel. Reduction of EPAS-1 level via its siRNA disrupted the proliferation, and enhanced the susceptibility of BGC-823 cells to those chemotherapeutic drugs. Our findings suggested that EPAS-1 and PXR may cooperatively participate in development and especially MDR process of stomach cancer. These findings may contribute to more effective targeted drugs discovery for the stomach cancer therapy. (C) 2016 Elsevier Ltd. All rights reserved.