title: Cross-talk between EPAS-1/HIF-2α and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell.
abstract: EPAS-1/HIF-2α (Endothelial PAS domain-containing protein 1/hypoxia-inducible transcription factors 2α) 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.
authors.affiliation: Department of medical oncology, Cancer Institute & Hospital, Peking Union Medical College/Chinese Academy of Medical Science, Beijing 100021, PR China; Department of Internal medicine-oncology, Affiliated Hospital of Qinghai University, Xining 810000, PR China.
authors.forename: Jiuda
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Qinghai University, Xining 810000, PR China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Bai
authors.affiliation: Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang 110016, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Feng
authors.affiliation: Department of Urology, General Hospital of Chinese PLA, Beijing 100853, PR China; Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin 150081, PR China.
authors.forename: Erlin
authors.initials: E
authors.lastname: Song
authors.affiliation: Department of medical oncology, Cancer Institute & Hospital, Peking Union Medical College/Chinese Academy of Medical Science, Beijing 100021, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Internal medicine-oncology, Affiliated Hospital of Qinghai University, Xining 810000, PR China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Internal medicine-oncology, Affiliated Hospital of Qinghai University, Xining 810000, PR China.
authors.forename: Guoshuang
authors.initials: G
authors.lastname: Shen
authors.affiliation: Department of Internal medicine-oncology, Affiliated Hospital of Qinghai University, Xining 810000, PR China.
authors.forename: Faxiang
authors.initials: F
authors.lastname: Ji
authors.affiliation: Department of Internal medicine-oncology, Affiliated Hospital of Qinghai University, Xining 810000, PR China.
authors.forename: Guoyuan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Internal medicine-oncology, Affiliated Hospital of Qinghai University, Xining 810000, PR China.
authors.forename: Xinfu
authors.initials: X
authors.lastname: Ma
authors.affiliation: National Scientific Data Sharing Platform of Population and Health, Beijing 100730, PR China.
authors.forename: Xingyi
authors.initials: X
authors.lastname: Hang
authors.affiliation: Department of medical oncology, Cancer Institute & Hospital, Peking Union Medical College/Chinese Academy of Medical Science, Beijing 100021, PR China. Electronic address: xubinghe2002@126.com.
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004742:Enhancer Elements, Genetic / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051544:Cytochrome P-450 CYP3A; D016685:Mitomycin; D017239:Paclitaxel; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: EPAS-1; HIF-2α; MDR; Mitomycin C and Paclitaxel; PXR; Stomach Cancer