High glucose promotes pancreatic cancer cells to escape from immune surveillance via AMPK-Bmi1-GATA2-MICA/B pathway
High glucose promotes pancreatic cancer cells to escape from immune surveillance via AMPK-Bmi1-GATA2-MICA/B pathway
复制标题
高糖通过AMPK-Bmi1-GATA2-MICA/B通路促进胰腺癌细胞逃避免疫监视
DOI：
10.1186/s13046-019-1209-9
复制
发表时间：
2019-05-14
影响因子：
11.3
通讯作者：
Yin, Tao
中科院分区：
文献类型：
--
作者：
Duan, Qingke;Li, Hehe;Yin, Tao
MHC-I类链相关蛋白A/B(MICA/B)是肿瘤细胞逃避NK细胞杀伤的机制之一。异常的代谢状态，如高血糖，可能会造成细胞应激环境，导致免疫功能障碍。高血糖常见于大多数胰腺癌患者，且与预后不良有关。本研究旨在通过降低MICA/B的表达来检测高糖对NK细胞介导的胰腺癌细胞杀伤作用的影响。方法采用乳酸脱氢酶释放法比较不同葡萄糖浓度下NK细胞对胰腺癌细胞的杀伤作用。采用定量聚合酶链式反应、Western Blot、流式细胞仪和免疫荧光等方法检测高糖对MICA/B、Bmi1、GATA2、磷酸化AMPK表达的影响，探讨其可能的作用机制。结果高糖通过抑制MICA/B的表达，保护胰腺癌免受NK细胞介导的杀伤作用。BMI1是一种多梳状蛋白，受高糖诱导表达上调，并通过促进GATA2抑制MICA/B在胰腺癌中的表达。此外，高糖抑制AMP激活的蛋白激酶信号转导，导致Bmi1高表达。结论高糖可促进高血糖肿瘤微环境下胰腺癌细胞的免疫逃逸。在此过程中，AMPK-Bmi1-GATA2轴的结构性激活可能介导MICA/B抑制，可能成为进一步干预胰腺癌免疫逃逸的治疗靶点。
BackgroundModulation 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.MethodsThe 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.ResultsIn 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.ConclusionOur 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.