Abstract
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.
Highlights
Liver transplantation is a promising treatment for the patients with hepatocellular carcinoma (HCC), the 3 year survival rate of liver transplantation for HCC was up to 80% and the 5 year survival rate reached 75% [1,2,3]
IP10 plays a significant role in acute phase graft injury and has potential value to predict tumor recurrence after liver transplantation for liver cancer patients [17]
Overexpression of IP10 contributed to HCC recurrence after liver transplantation through promoting of tumor cell proliferation and invasion, together with inducing angiogenesis by mobilization of circulating endothelial progenitor cells [17, 18]
Summary
Liver transplantation is a promising treatment for the patients with hepatocellular carcinoma (HCC), the 3 year survival rate of liver transplantation for HCC was up to 80% and the 5 year survival rate reached 75% [1,2,3]. The tumor recurrence is still the most serious threat to HCC patients after liver transplantation. Chemotherapy, as an alternative treatment for HCC, had a remarkable response rate in primary liver cancer [7,8,9,10,11]. It had no benefit on recurrent HCC patients [12].
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