MicroRNA signatures associated with acute phase small-for-size liver graft injury and tumor invasiveness

Abstract

BACKGROUND: Higher incidence of tumor recurrence is a major obstacle of living donor liver transplanatation (LDLT) for the patients with hepatocellular carcinoma (HCC). The occurrence of acute phase small-for-size graft injury is an important factor contributing to late phase tumor invasion and recurrence. Understanding the molecular mechanism of acute phase injury due to small-for-size graft transplantation is thus indispensible for development of therapeutic strategy to reduce the likelihood of tumor recurrence after LDLT. OBJECTIVE: We aim to study the microRNA profiles associated with acute phase graft injury causing later tumor invasiveness after liver transplantation using small-for-size graft. MATERIALS AND METHODS: A rat othotopic liver transplantation model was set up using whole (100%) graft (Group W) and small-for-size (50%) graft (Group S) as donors. The recipients were injected with a rat hepatoma cell line (MH7777, 2x105) via the portal vein after reperfusion. The rats were sacrificed at days 1, 3, 14 and 21 after transplantation for histological and molecular analyses. MicroRNA profile of acute phase (day 1) between Group W and Group S was characterized by applying Low Density Array (LDA) analysis. The differential microRNAs were confirmed by real-time RT-PCR. RESULTS: Severe acute graft injury was found in Group S at day 1 compared to Group W. Moreover, early development and more progressive as well as invasive patterns of liver tumors were detected in Group S compared to group W. LDA microRNA array analysis showed that there were 63 differential microRNAs found in Group S compared to Group W at day 1 after liver transplantation including 37 up-regulated and 26 down-regulated microRNAs. Among them, many differential microRNAs were predicted to target genes involved in important physiological processes including angiogenesis (mir- 205, mir-429, mir-369-3p, mir-741), growth factor receptors (mir-196b, mir-216b, mir-494, mir-302a, mir-694, mir-337-3p, mir-449a, mir-449c, mir-495, mir-694, mir-699, mir-704), MAPK signaling (mir-1, mir-207, mir-217, mir-411, mir-455 and mir-743b) and cytokine regulation (mir-494, mir-878, mir-878-3p and mir-489). CONCLUSION: MicroRNA manipulation could be an important mechanism resulting from acute phase injury in small-for-size liver transplantation. The roles of microRNAs in small-for-size acute phase injury are needed to characterize.