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. The gene discussed is EGFR; the disease is hepatocellular carcinoma.