Transcriptome Analysis of Acute Phase Liver Graft Injury in Liver Transplantation

Abstract

Background: Liver transplantation remains the treatment of choice for a selected group of hepatocellular carcinoma (HCC) patients. However, the long-term benefit is greatly hampered by post-transplant HCC recurrence. Our previous studies have identified liver graft injury as an acute phase event leading to post-transplant tumor recurrence. Methods: To re-examine this acute phase event at the molecular level and in an unbiased way, RNA sequencing (RNA-Seq) was performed on liver graft biopsies obtained from the transplant recipients two hours after portal vein reperfusion with an aim to capture frequently altered pathways that account for post-transplant tumor recurrence. Liver grafts from recurrent recipients (n = 6) were sequenced and compared with those from recipients without recurrence (n = 5). Results: RNA expression profiles comparison pointed to several frequently altered pathways, among which pathways related to cell adhesion molecules were the most involved. Subsequent validation using quantitative polymerase chain reaction confirmed the differential involvement of two cell adhesion molecules HFE (hemochromatosis) and CD274 and their related molecules in the acute phase event. Conclusion: This whole transcriptome strategy unravels the molecular landscape of liver graft gene expression alterations, which can identify key pathways and genes that are involved in acute phase liver graft injury that may lead to post-transplant tumor recurrence.

Glutathione S-transferase A2 (GSTA2) Promotes Hepatocellular Carcinoma Recurrence After Liver Transplantation Through Modulating Reactive Oxygen Species Metabolism

“…Multivariate Cox Regression analysis of the signi cant predictors of disease-free survival showed that there was no a signi cantly independent predictor de ned ( Table 3), suggesting that these predictors dependently in uenced the disease-free survival of HCC recipients. These above ndings agreed with our previous study that early phase injury-induced molecules play in uential roles in late phase HCC recurrence after liver transplantation (14). Altogether, our results indicated that EPC GSTA2…”

“…Identi cation of GSTA2 as a HCC-recurrence associated gene at early-phase after liver transplantation RNA sequencing was previously performed on liver biopsies collected from early phase after liver transplantation (2 hours after portal vein reperfusion) (14). To identify differentially expressed earlyphase genes associated with late-phase HCC recurrence, the transcription pro le of the liver biopsies from the recurrent recipients (N = 6) was compared to the non-recurrent recipients (N = 5) through a one-by-one comparison approach.…”

“…RNA-sequencing analysis (14) was previously performed to compare the transcription pro le of early phase liver biopsies from HCC recipients with (N = 6) and without (N = 5) post-transplantation HCC recurrence. Gene expression level between any given two samples was gauged by the number of sequencing data mapped to the gene, RPKM (reads per kilobase per million mapped reads).…”

“…In addition, a panel of circulating microRNAs have been identi ed to be signi cantly up-regulated at early phase of HCC recipients who developed with recurred HCC at late phase after liver transplantation (13). Recently, by transcriptome analysis of the early phase liver biopsies, several key pathways and genes have been identi ed such as adhesion molecules HFE and CD274 whose expression level at early phase shows signi cant correlation with late phase HCC recurrence after liver transplantation (14). Collectively, understanding on early phase hepatic injury after liver transplantation should provide important clues for future development of prognostic and therapeutic strategies to combat HCC recurrence after liver transplantation.…”

Special Issue: Cancer Biomarkers and Targets in Digestive Organs

“…While liver transplantation is a potentially curative treatment of hepatocellular carcinoma, liver graft injury has been identified as an acute phase event that leads to post-transplant tumor recurrence. Lee et al examined this acute phase event at the molecular level by transcriptomic analysis of liver grafts from recipients with or without tumor recurrence following liver transplantation [21]. This study reveals the altered genetic expression in liver grafts, and paves the way to identify key molecular pathways that may be involved in post-transplant tumor recurrence.…”