Abstract
Acquired resistance is a common phenomenon for HCC patients who undergone sorafenib treatment, however the mechanism by which acquired resistance develops remains elusive. In this study, we found that GRP78 could be detected in the serum samples of HCC patients and the conditional medium of multiple HCC cell lines, suggesting that GRP78 is secreted by HCC cells. Further studies showed that secreted GRP78 facilitated the proliferation and inhibited the apoptosis induced by sorafenib both in HCC cell lines and in tumor xenografts. We further found that secreted GRP78 could interact physically with EGFR, therefore activates EGFR signaling pathway. knockdown of EGFR decreased secreted GRP78 induced phosphorylation of SRC and STAT3. By contrast, overexpression of EGFR further enhanced the phosphorylation of SRC and STAT3 induced by secreted GRP78, suggesting the critical role of EGFR in secreted GRP78 conferred resistance to sorafeinib. Moreover, inhibition of SRC by PP2 antagonized the resistance to sorafenib and inhibited the activation of STAT3 conferred by secreted GRP78. Taken together, our results showed that secreted GRP78 could interact with EGFR, activate EGFR-SRC-STAT3 signaling, conferring the resistance to sorafenib.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1]
We showed that glucose-regulated protein 78 (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 activates EGFR-SRC-STAT3 signaling
The results revealed that sorafenib treatment resulted in a significant increase in the secretion of GRP78 as compared with control cell treated with DMSO (Figure 1D)
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide [1]. Curative treatments such as surgical and locoregional therapies are the preferred treatment methods for HCC patients at early stages and improve the five-year survival rates up to 60–70% in well-selected patients [2]. The glucose-regulated protein 78 (GRP78) is one of the ER stress induced proteins [6] which is overexpressed in many human cancers [7,8,9] and plays critical roles in the regulation of tumor proliferation, invasion and metastasis [10,11] and acquired resistance to chemotherapies [12,13]. 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 activates EGFR-SRC-STAT3 signaling
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