Early-phase circulating miRNAs predict tumor recurrence and survival of hepatocellular carcinoma patients after liver transplantation
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Kevin Tak-Pan NG1,2, Chung Mau Lo1,2, Nathalie Wong3, Chang Xian Li1,2, Xiang Qi1,2, Xiao Bing Liu1,2, Wei Geng1,2, Oscar Wai-Ho Yeung1,2, Yuen Yuen Ma1,2, See Ching Chan1, Kwan Man1,2
1Department of Surgery, The University of Hong Kong, Hong Kong
2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, China
3Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Kwan Man, e-mail: [email protected]
Keywords: miR-1246, early-phase, liver transplantation, HCC recurrence, macrophage activation
Received: October 27, 2015 Accepted: February 16, 2016 Published: February 23, 2016
Post-liver transplantation tumor recurrence is a major challenge for hepatocellular carcinoma (HCC) recipients. We aimed to identify early-phase circulating microRNAs after liver transplantation for predicting tumor recurrence and survival of HCC recipients. Circulating microRNA profiles at early-phase (2-hour after portal vein reperfusion) after liver transplantation were compared between HCC recipients with (n=4) and without tumor recurrence (n=8) by microarray analyses. Candidate microRNAs were validated in 62 HCC recipients by quantitative RT-PCR. The prognostic values of microRNAs for tumor recurrence and survival were examined. Simulated in vitro ischemia-reperfusion injury models were employed to characterize the possible mechanism of up-regulation of circulating microRNAs. Our results showed that up-regulation of circulating miR-148a, miR-1246 or miR-1290 at early-phase was significantly associated with HCC recurrence after liver transplantation. Among them, miR-148a (p=0.030) and miR-1246 (p=0.009) were significant predictors of HCC recurrence. MiR-1246 was an independent predictor of overall (p=0.023) and disease-free survival (p=0.020) of HCC recipients. The level of early-phase circulating miR-1246 was positively correlated with serum AST and ALT levels in HCC recipients after liver transplantation. The expression of hepatic miR-1246 was positively correlated with TNFα mRNA. In vitro experiments indicated that injury-induced activation and differentiation of macrophages significantly elevated the expression and secretion of miR-1246. In conclusion, early-phase circulating miR-1246 is an indicator of hepatic injury and a novel prognostic biomarker for tumor recurrence and survival of HCC recipients after liver transplantation.
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