MGP promotes CD8 + T cell exhaustion by activating the NF-κB pathway leading to liver metastasis of colorectal cancer

作者：Dawei Rong, Guangshun Sun, Zhiying Zheng, Li Liu, Xiaoyuan Chen, Fan Wu, Yichao Gu, Yongjiu Dai, Weizhe Zhong, Xiaopei Hao, Chuanyong Zhang, Xiongxiong Pan, Jinhai Tang, Weiwei Tang, Xuehao Wang · 发表于：International Journal of Biological Sciences · 年份：2022 · DOI：10.7150/ijbs.70137 · 被引用次数：126 · 研究领域：Galectins and Cancer Biology、Genetic factors in colorectal cancer、Cancer Immunotherapy and Biomarkers

Matrix Gla protein (MGP) was originally reported as a physiological suppressor of ectopia calcification and has also been reported to be associated with cancer. However, the relation between the biological functions of MGP and the immune response in colorectal cancer (CRC) remains unclear. Here, we investigated the regulatory role of MGP in the immune microenvironment of CRC. MGP expression in CRC samples was assessed by single-cell RNA sequencing and the Gene Expression Omnibus (GEO) database, and confirmed by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry analysis of human CRC samples. The effect of MGP on proliferation and invasion of CRC cells was evaluated by in vitro assays involving MGP knockdown and overexpression. Luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay were performed to identify transcriptional regulatory sites of the nuclear factor kappa-B (NF-B) and programmed cell death ligand 1 (PD-L1). In vivo experiments were performed in mouse model of CRC liver metastasis established via spleen injection. The results revealed that MGP was significantly upregulated in cancer cell clusters from the primary CRC or liver metastases, compared with that in the corresponding paracancerous tissues via single-cell RNA sequencing. MGP enriched intracellular free Ca 2+ levels and promoted NF-B phosphorylation, thereby activated PD-L1 expression to promote CD8 + T cell exhaustion in CRC. The luciferase reporter a...