Program

PO1-8-27

PID1 promotes hepatocarcinogenesis by interacting with ARG1 and EGFR

[Speaker] Ming Xiang:1
[Co-author] Qianqian Xu:1, Senlin Li:1
1:Huazhong University of Science and Technology, China

BACKGROUND: The obesity related gene PID1, phosphotyrosine interaction domain containing 1, was reported to be a potential target for insulin resistance. However, no studies have covered its function on hepatocarcinoma. Here we investigate what role does PID1 play in the formation of liver cancer.
METHODS: Tumor-bearing mice were prepared by subcutaneously inoculating C57BL/6 mice with hepatocarcinoma cell line H22. Hydrodynamics-based transfection was applied to induce the liver specific overexpression of PID1. Flow cytometry was exerted to detect the proportion and function of immune cells. Real-time qPCR and western blot were used to detect the relevant mRNA and protein expression. Chromatography-mass spectrometry and immunoprecipitation were conducted to identify proteins interacted with PID1. Chromatin immunoprecipitation was operated to measure the modification of H3K4me3 of PID1 promoter.
RESULTS: PID1 overexpression specially in liver developed an immunosuppressive environment, with the reduction of CD3+, CD4+, CD8+T cells, retarded maturation of dendritic cells (DCs), pronounced differentiation of regulatory T cells (Tregs), and recruitment of myeloid-derived suppressor cells (MDSCs), which promoted liver cancer progression. In addition, proliferation related genes and anti-inflammatory genes were activated when PID1 overexpressed, which also suppressed pro-inflammatory genes, induced glycolysis and lipid metabolism genes with the induction of liver cancer. Hepatic knockdown of PID1 attenuated liver xenografted tumor growth and induced anti-tumor immunity. Importantly, experiments identified that PID1 could bind with epidermal growth factor receptor (EGFR) to activate downstream KRAS/ERK pathway, and interact with ARG1 to activate and enhance the T cell inhibition of MDSCs. Furthermore, EGFR expression interruption blocked the tumor-promotion effect of PID1, while the immunosuppression indications still remain. Ulteriorly , PID1 gene existed tri-methylation of histone H3 at lysine 4 (H3K4me3) modification, and experiments on hepatocarcinoma cell demonstrated PID1 overexpression partly by activating the H3K4me3 modification.
CONCLUSION: PID1 promoted hepatocarcinogenesis by synergetic induction of EGFR-mediated tumorigenesis and MDSCs-mediated immunosuppression.
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