title: A polymorphism in the promoter region of PD-L1 serves as a binding-site for SP1 and is associated with PD-L1 overexpression and increased occurrence of gastric cancer.
abstract: PD-L1 is a member of the B7 family co-inhibitory molecules and plays a critical role in tumor immune escape. In this study, we found a polymorphism rs10815225 in the PD-L1 promoter region was significantly associated with the occurrence of gastric cancer. The GG homozygous frequency was higher in the cancer patients than that in the precancerous lesions, which was higher than that in the health controls. This polymorphism locates in the binding-site of Sp1 transcription factor (SP1). The expression level of PD-L1 mRNA in the GG homozygous cancer patients was apparently higher than that in the GC heterozygotes. Luciferase reporter results showed that SP1 bonded to rs10815225 G-allelic PD-L1 promoter instead of C-allelic. Upregulation and knockdown of SP1 resulted in elevation and attenuation of PD-L1 in SGC-7901 cells, respectively. The chromatin immunoprecipitation results further confirmed the binding of SP1 to the promoter of PD-L1. Additionally, rs10815225 was found to be in disequilibrium with a functional polymorphism rs4143815 in the PD-L1 3'-UTR, and the haplotypes of these two polymorphisms were also markedly related to gastric cancer risk. These results revealed a novel mechanism underlying genetic polymorphisms influencing PD-L1 expression modify gastric cancer susceptibility.
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Ren-ai Road 199, Suzhou, 215123, China.|Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Tao
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Ren-ai Road 199, Suzhou, 215123, China.
authors.forename: Xin-Ru
authors.initials: XR
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
authors.forename: Fu-Chao
authors.initials: FC
authors.lastname: Li
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Ren-ai Road 199, Suzhou, 215123, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Ren-ai Road 199, Suzhou, 215123, China.
authors.forename: Fan-Yi
authors.initials: FY
authors.lastname: Meng
authors.affiliation: Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Wuxi, 214062, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Wuxi, 214062, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Hua
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Ren-ai Road 199, Suzhou, 215123, China.
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Ren-ai Road 199, Suzhou, 215123, China. wangweipeng@suda.edu.cn.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China. weichangchen@126.com.
authors.forename: Wei-Chang
authors.initials: WC
authors.lastname: Chen
mesh_terms: D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D006801:Humans; D011110:Polymorphism, Genetic; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D004273:DNA, Neoplasm; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human
keywords: Gastric cancer; PD-L1; Polymorphism; SP1