In this study, we showed that GRP78 secreted by HCC cells promotes the proliferation of HCC cells, and confers the resistance to sorafenib in an autocrine or paracrine manner by interacting physically with epidermal cell growth factor receptor (EGFR) and therefore activates EGFR-SRC-STAT3 signaling. This evidence concerns the gene HSPA5 and hepatocellular carcinoma.