Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway
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Wei Geng1,3, Chung-Mau Lo1,2, Kevin T.P. Ng1, Chang-Chun Ling1, Xiang Qi1, Chang-Xian Li1, Yuan Zhai4, Xiao-Bing Liu1, Yuen-Yuen Ma1, Kwan Man1,2
1Department of Surgery, The University of Hong Kong, Hong Kong, China
2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
3Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
4Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
Kwan Man, e-mail: [email protected]
Keywords: IP10, HCC, liver transplantation, cisplatin resistance, graft injury
Received: May 20, 2015 Accepted: July 31, 2015 Published: August 12, 2015
Tumor recurrence remains an obstacle after liver surgery, especially in living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC). The acute-phase liver graft injury might potentially induce poor response to chemotherapy in recurrent HCC after liver transplantation. We here intended to explore the mechanism and to identify a therapeutic target to overcome such chemoresistance. The associations among graft injury, overexpression of IP10 and multidrug resistant genes were investigated in a rat liver transplantation model, and further validated in clinical cohort. The role of IP10 on HCC cell proliferation and tumor growth under chemotherapy was studied both in vitro and in vivo. The underlying mechanism was revealed by detecting the activation of endoplasmic reticulum (ER) stress signaling pathways. Moreover, the effect of IP10 neutralizing antibody sensitizing cisplatin treatment was further explored. In rat liver transplantation model, significant up-regulation of IP10 associated with multidrug resistant genes was found in small-for-size liver graft. Clinically, high expression of circulating IP10 was significant correlated with tumor recurrence in HCC patients underwent LDLT. Overexpression of IP10 promoted HCC cell proliferation and tumor growth under cisplatin treatment by activation of ATF6/Grp78 signaling. IP10 neutralizing antibody sensitized cisplatin treatment in nude mice. The overexpression of IP10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway. IP10 neutralizing antibody could be a potential adjuvant therapy to sensitize cisplatin treatment.
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