Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway.
Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway.
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DOI：
10.18632/oncotarget.4832
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Man K
中科院分区：
文献类型：
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作者：
Geng W;Lo CM;Ng KT;Ling CC;Qi X;Li CX;Zhai Y;Liu XB;Ma YY;Man K
肿瘤复发仍然是肝脏手术后的一个障碍，尤其是肝细胞癌（HCC）患者的活体肝移植（LDLT）中。急性期肝移植损伤可能会导致肝移植后复发性肝癌对化疗反应不佳。我们在这里打算探索其机制并确定克服这种化疗耐药性的治疗靶点。在大鼠肝移植模型中研究了移植物损伤、IP10过度表达和多重耐药基因之间的关联，并在临床队列中进一步验证。在体外和体内研究了化疗后 IP10 对 HCC 细胞增殖和肿瘤生长的作用。通过检测内质网（ER）应激信号通路的激活揭示了其潜在机制。此外，进一步探讨了IP10中和抗体敏化顺铂治疗的效果。在大鼠肝移植模型中，在小尺寸肝移植中发现与多重耐药基因相关的IP10显着上调。临床上，循环IP10的高表达与接受LDLT的HCC患者的肿瘤复发显着相关。在顺铂治疗下，IP10 的过表达通过激活 ATF6/Grp78 信号传导促进 HCC 细胞增殖和肿瘤生长。 IP10 中和抗体对裸鼠进行顺铂治疗致敏。肝移植损伤引起的IP10过度表达可能通过ATF6/Grp78 ER应激信号通路导致顺铂耐药。 IP10 中和抗体可能是一种潜在的辅助疗法，使顺铂治疗敏感。
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.