Complement components C3a promoted tumor recurrence after liver transplantation

Abstract

Introduction: Complement components are the keys regulators orchestrating many cellular responses including immunological responses. Increasing evidences showed complement components involved in many liver pathology. Despite its significance, its functions in transplantation as well as hepatocellular carcinoma (HCC) remain poorly understood. Our preliminary studies suggested that among the family members, C3a displayed the highest susceptibility to various liver injuries. The study aimed to investigate the clinical impacts and therapeutic potentials of C3a in liver transplantation. Materials and methods: A clinical cohort of 70 HCC patients who underwent liver transplantation was included. Expression levels of tissue and plasma C3a were examined followed by the association analyses with patients post-transplant outcomes. Rat transplantation model and in vitro studies were performed to investigate the pro-tumor functions of C3a. Results: Clinically, we first identified the significant elevation of both graft and plasma C3a after liver transplantation (2.4-fold increase)(Fig.1). Such increased was then found to be highly determined by cold ischemia duration during transplantation (P< 0.01)(Fig.2). We further confirmed that hypoxia conditions could directly induce the up-regulation of C3a in hepatocytes (Fig.2). After liver transplantation, high level of C3a were found to be significantly correlated with aspartate aminotransferase (SGOT)(R2=0.42) and alanine aminotransferase (SGPT)(R2=0.20)(P< 0.01)(Fig.3). Importantly, patients with tumor recurrence and shortened recurrence-free duration were found to express higher level of C3a (P< 0.05)(Fig.3). Functionally, HCC cell lines with metastatic potentials expressed higher C3a receptors and significantly up-regulated metastatic related genes in response to C3a treatment (Fig.4). Conclusion: Here we showed that ischemia injuries induced the up-regulation of post-transplant C3a. The novel roles of C3a in liver functions and promoting recurrence after transplantation were revealed. Targeting the complement component signaling represent a potential therapeutic strategy in improving the clinical outcomes of liver transplantation.