High glucose promotes pancreatic cancer cells to escape from immune surveillance via AMPK-Bmi1-GATA2-MICA/B pathway

Journal of Experimental & Clinical Cancer Research

Qiang Shen¹  Hehe Li²  Tao Yin²  Chunyou Wang²  Qingke Duan²  Hengqiang Zhao²  Heshui Wu²  Chenggang Gao²  Shihong Wu² 

[1] Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center;Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology;

关键词: Pancreatic cancer;    NK cells;    High glucose;    MICA/B;    Immune surveillance;   

DOI  :  10.1186/s13046-019-1209-9

来源: DOAJ

【 摘 要 】

Abstract Background Modulation of cell surface expression of MHC class I chain-related protein A/B (MICA/B) has been proven to be one of the mechanisms by which tumor cells escape from NK cell-mediated killing. Abnormal metabolic condition, such as high glucose, may create a cellular stress milieu to induce immune dysfunction. Hyperglycemia is frequently presented in the majority of pancreatic cancer patients and is associated with poor prognosis. In this study, we aimed to detect the effects of high glucose on NK cell-mediated killing on pancreatic cancer cells through reduction of MICA/B expression. Methods The lysis of NK cells on pancreatic cancer cells were compared at different glucose concentrations through lactate dehydrogenase release assay. Then, qPCR, Western Blot, Flow cytometry and Immunofluorescence were used to identify the effect of high glucose on expression of MICA/B, Bmi1, GATA2, phosphorylated AMPK to explore the underlying mechanisms in the process. Moreover, an animal model with diabetes mellitus was established to explore the role of high glucose on NK cell-mediated cytotoxicity on pancreatic cancer in vivo. Results In our study, high glucose protects pancreatic cancer from NK cell-mediated killing through suppressing MICA/B expression. Bmi1, a polycomb group (PcG) protein, was found to be up-regulated by high glucose, and mediated the inhibition of MICA/B expression through promoting GATA2 in pancreatic cancer. Moreover, high glucose inhibited AMP-activated protein kinase signaling, leading to high expression of Bmi1. Conclusion Our findings identify that high glucose may promote the immune escape of pancreatic cancer cells under hyperglycemic tumor microenvironment. In this process, constitutive activation of AMPK-Bmi1-GATA2 axis could mediate MICA/B inhibition, which may serve as a therapeutic target for further intervention of pancreatic cancer immune evasion.

【 授权许可】

Unknown