Relevance of microRNA‐18a and microRNA‐199a‐5p to hepatocellular carcinoma recurrence after living donor liver transplantation

Abstract

There are few reports about recurrence-related microRNAs (miRNAs) after liver transplantation (LT) for hepatocellular carcinoma (HCC). The purpose of this study was to identify novel recurrence-related miRNAs after living donor liver transplantation (LDLT) for HCC. First, we performed microarray analyses of samples from a liver with primary HCC, a liver that was noncancerous, and a liver that had recurrence-metastasis from 3 patients with posttransplant recurrence. Then we selected miRNAs with consistently altered expression in both primary HCC and recurrence as potential candidates of recurrence-related miRNAs. Expression of the miRNAs in HCC and noncancerous livers was assessed in 70 HCC patients who underwent LDLT. The target genes regulated by the recurrence-related miRNAs were identified. MicroRNA-18a (miR-18a) expression was increased, and microRNA-199a-5p (miR-199a-5p) expression was decreased in both primary HCC and recurrence. Increased miR-18a expression correlated with high levels of tumor markers, large tumor size, and a high recurrence rate. Decreased miR-199a-5p expression correlated with high levels of tumor markers, portal venous invasion, and a high recurrence rate. In HCC cells, miR-18a regulated the expression of tumor necrosis factor alpha-induced protein 3 (TNFAIP3), and miR-199a-5p regulated the expression of hypoxia-inducible factor 1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), insulin-like growth factor 1 receptor, and insulin-like growth factor 2. In conclusion, increased miR-18a levels and decreased miR-199a-5p levels are relevant to HCC recurrence after LDLT. MiR-18a and miR-199a-5p could be novel therapeutic targets of recurrent HCC after LDLT.Liver Transplantation 22 665-676 2016 AASLD.Received August 31, 2015; accepted December 9, 2015.Hepatocellular carcinoma (HCC) is the most frequent cancer of the liver and the third most common cause of cancer deaths worldwide.(1) Curative treatment is limited to hepatic resection and liver transplantation (LT). However, the overall cumulative recurrence rate after hepatic resection is approximately 80% at 5 years.(2) Among various recurrent patterns of HCC, the prognosis of extrahepatic recurrence-metastasis (M) is much poorer than that of intrahepatic metastasis and multicentric recurrence. (3)(4)(5) LT can overcome the problems of intrahepatic metastasis and multicentric recurrence theoretically. However, the recurrence of HCC after LT is a critical problem to be solved because the outcomes of patients with HCC recurrence after LT are extremely poor. (6) Abbreviations: AFP, alpha-fetoprotein; DCP, des-gamma-carboxyprothrombin; DDLT, deceased donor liver transplantation; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIF1A, hypoxia-inducible factor 1 alpha; IGF1R, insulin-like growth factor 1 receptor; IGF2, insulin-like growth factor 2; LDLT, living donor liver transplantation; LT, liver transplantation; M, recurrence-metastasis; miR-18a, microRNA-18a; miR-199a-5p, microRNA-199a-5p;...

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