The Function Of Androgen Receptor For Immune Surveillance Mediated By NK Cells During Hepatocellular Carcinoma Progression And Chemotherapy

Gender disparity has long been considered as a key to fully understand hepatocellular carcinoma(HCC)development.At the same time,immune surveillance mediated by NK cells during HCC development and progression still need more investigation before applied in clinical settings.Purpose:We studied the role of androgen receptor(AR)during NK cells mediated tumor surveillance in HCC in this project.By such dissection,we aim to provide novel information for better application of NK cell based immunotherapy against HCC.Methods:We performed LDH cytotoxicity assay in various expression level of AR HCC tumor cells and observed an influenced function of NK cells.During mechanism dissection we used luciferase reporter assay and chromatin immunoprecipitation assay to prove AR could bind to certain gene's promoter region then functioning.Furthermore,we applied microRNA related method and protein degradation studies to investigate cisplatin induced AR down-regulation.Finally,these in vitro data have all been verified with clinical samples and animal models.Results:Our data indicated AR could transcriptionally inhibit IL-12A expression,which served as a subunit for IL-12.The down-regulation of IL-12 caused by such scenario could help HCC tumor cell evade from NK cell mediated immune surveillance.Furthermore,sorafenib,one of the drugs for advanced HCC therapy,could up-regulate the IL-12A via suppressing AR then enhance NK cells' cytotoxicity.On the other hand,classical chemotherapy drug cisplatin was observed to accelerate degradation of AR in HCC,which induced increasing of ULBP2.This phenotype also made HCC tumor cells become more vulnerable to NK cells killing.Meanwhile,data collected from clinical samples and animal models also supported our claims.