Secreted GRP78 Confers The Resistance To Sorafenib By Activating EGFR-Src-STAT3 Signaling In Hepatocellular Carcinoma

ObjectiveTo explore the interaction between EGFR on cell surface and exocrine GRP78,to explain the role and mechanism of exocrine GRP78 and EGFR in the resistance of hepatocarcinoma cells to sorafenib.GRP78 was used as a marker for clinical diagnosis and treatment target for hepatoma.Methods1.To culture hepatocarcinoma cells and were analysed by western blot to detect the content of exocrine GRP78 and expression of EGFR on cell surface,then appropriate cell lines were chosed.2.Serum were collected from patients with hepatocarcinoma and normal human,then the difference of serum GRP78 was analyzed by ELISA.3.rh GRP78 effects on the sensitivity of hepatoma cells to sorafenib and its mechanism were detected at cellular line.MTT,Western blot,pull down and colony formation assay were used to analyze.4.The tumor model was established at the animal level,and then divided into three groups: rh GRP78 group,sorafenib group and rh GRP78 / sorafenib group.The treatment was performed by gavage.The tumor tissue was taken out and weighed after a period of time,then immunohistochemistry were used to compare the differences between the three groups.Results1.GRP78 could be secreted by HCC cells.2.Secreted GRP78 facilitates the proliferation and inhibits cell apoptosis induced by sorafenib.3.Secreted GRP78 interacted physically with EGFR and induced its activation.4.EGFR dictates the responsiveness of HCC cells to secreted GRP78.ConclusionGRP78 secreted by tumor cells could confer the resistance to sorafenib in an autocrine or paracrine manner,activating EGFR-Src-STAT3 signaling and EGFR dictates the responsiveness of HCC cells to secreted GRP78.