Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway.
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.
Department of Surgery, The University of Hong Kong, Hong Kong, China.|Department of Transplantation and Hepatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Wei
W
Geng
Department of Surgery, The University of Hong Kong, Hong Kong, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
Chung-Mau
CM
Lo
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Kevin T P
KT
Ng
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Chang-Chun
CC
Ling
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Xiang
X
Qi
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Chang-Xian
CX
Li
Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
Yuan
Y
Zhai
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Xiao-Bing
XB
Liu
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Yuen-Yuen
YY
Ma
Department of Surgery, The University of Hong Kong, Hong Kong, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
Kwan
K
Man
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000601:surgery*; D054357:Chemokine CXCL10 / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D016133:Polymerase Chain Reaction; D051381:Rats; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D054357:Chemokine CXCL10; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D002945:Cisplatin
HCC; IP10; cisplatin resistance; graft injury; liver transplantation