Oncotarget

Research Papers:

Secreted GRP78 activates EGFR-SRC-STAT3 signaling and confers the resistance to sorafeinib in HCC cells

Rui Li, Gu Yanjiao, He Wubin, Wang Yue, Huang Jianhua, Zheng Huachuan, Su Rongjian and Luan Zhidong _

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Oncotarget. 2017; 8:19354-19364. https://doi.org/10.18632/oncotarget.15223

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Abstract

Rui Li1,*, Gu Yanjiao2,*, He Wubin3, Wang Yue4, Huang Jianhua5, Zheng Huachuan6, Su Rongjian7, Luan Zhidong8

1Department of Cell Biology, College of Basic Medicine, Jinzhou Medical University, Jinzhou, China

2Department of Pathology, College of Basic Medicine, Jinzhou Medical University, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China

3The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China

4Department of Cell Biology, College of Basic Medicine, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China

5The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China

6Life Science Institute of Jinzhou Medical University, Jinzhou, China

7Life Science Institute of Jinzhou Medical University, College of Basic Medicine of Jinzhou Medical University, Cell Biology and Genetic Department of Jinzhou Medical University, Key Lab of Molecular and Cellular Biology of the Education Department of Liaoning Province, Jinzhou, China

8Development Department of Jinzhou Medical University, Life Science Institute of Jinzhou Medical University, Jinzhou, China

*These authors have contributed equally to this work

Correspondence to:

Su Rongjian, email: [email protected]

Luan Zhidong, email: [email protected]

Keywords: Grp78, sorafenib, EGFR, STAT3, hepatocellular carcinoma

Received: September 13, 2016     Accepted: January 16, 2017     Published: February 09, 2017

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.


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