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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

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A Letter to the Editors to this article was published on 24 May 2017

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.

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Abbreviations

ChIP:

Chromatin immunoprecipitation

CI:

Confidence interval

Ct:

Threshold cycle

HWE:

Hardy–Weinberg equilibrium

MAF:

Minor allele frequency

OR:

Odds ratio

qPCR:

Quantitative PCR

SP1:

Sp1 transcription factor

STR:

Short tandem repeat

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81270031, 81272737, and 81372375), Science and Technology Special Project of Clinical Medicine in Jiangsu Province (BL2014046), Science and Technology Project in Suzhou (SYS201524), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    Authors and Affiliations

    1. Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Ren-ai Road 199, Suzhou, 215123, China

      Li-Hua Tao, Xin-Ru Zhou, Qi Chen, Fan-Yi Meng, Hong-Jian Zhang & Wei-Peng Wang

    2. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China

      Li-Hua Tao, Fu-Chao Li, Rui Li & Wei-Chang Chen

    3. Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Wuxi, 214062, China

      Yong Mao & Dong Hua

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    Li-Hua Tao and Xin-Ru Zhou have contributed equally to this work.

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    Tao, LH., Zhou, XR., Li, FC. et al. 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. Cancer Immunol Immunother 66, 309–318 (2017). https://doi.org/10.1007/s00262-016-1936-0

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