ABSTRACT
Diagnosis and prediction of the severity of hepatitis C virus recurrence (HCVrec) after liver transplantation (LT) remain a challenge. MicroRNAs have been recently recognized as potential disease biomarkers. Archival liver biopsy samples from 43 HCV+ LT recipients were collected at clinical HCVrec time and at 3 years post-LT. Patients were classified as progressors (P = F0/F1) or nonprogressors (NP = F3/F4) according to the severity of fibrosis on the 3-year biopsy. Training (n = 27) and validation (n = 16) sets were defined. RNA was isolated from all biopsies at clinical HCVrec time, labeled and hybridized to miRNA-arrays. Progressors versus nonprogressors were compared using the two-sample t-test. A p-value ≤0.01 was considered significant. The ingenuity pathway analysis tool was used for microRNA and miRNA:mRNA ontology data integration. Nine microRNAs were differentially expressed between groups. A supervised cluster analysis separated samples in two well-defined groups (progressors vs. nonprogressors). Pathway analysis associated those microRNAs with hepatitis, steatosis, fibrosis, cirrhosis and T cell-related immune response. Data integration identified 17 genes from a previous genomic study as 9-microRNAs signature targets. Seven microRNAs were successfully validated in the validation set using QPCR. We have identified a 9-microRNA signature able to identify early post-LT patients at high risk of severe HCVrec during long-term follow-up.
Subject(s)
Hepatitis C/surgery , Liver Cirrhosis/diagnosis , Liver Cirrhosis/surgery , Liver Transplantation/adverse effects , MicroRNAs/genetics , Postoperative Complications , Adult , Aged , Biomarkers/analysis , Biomarkers/metabolism , Disease Progression , Female , Follow-Up Studies , Gene Expression Profiling , Graft Rejection , Graft Survival , Hepacivirus/pathogenicity , Hepatitis C/complications , Hepatitis C/virology , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/etiology , Liver Cirrhosis/virology , Longitudinal Studies , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Prognosis , Prospective Studies , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Recurrence , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Risk FactorsABSTRACT
Important progress has been made in improving short-term outcomes in solid organ transplantation. However, long-term outcomes have not improved during the last decades. There is a critical need for biomarkers of donor quality, early diagnosis of graft injury and treatment response. MicroRNAs (miRNAs) are a class of small single-stranded noncoding RNAs that function through translational repression of specific target mRNAs. MiRNA expression has been associated with different diseases and physiological conditions. Moreover, miRNAs have been detected in different biological fluids and these circulating miRNAs can distinguish diseased individuals from healthy controls. The noninvasive nature of circulating miRNA detection, their disease specificity and the availability of accurate techniques for detecting and monitoring these molecules has encouraged a pursuit of miRNA biomarker research and the evaluation of specific applications in the transplant field. miRNA expression might develop as excellent biomarkers of allograft injury and function. In this minireview, we summarize the main accomplishments of recently published reports focused on the identification of miRNAs as biomarkers in organ quality, ischemia-reperfusion injury, acute rejection, tolerance and chronic allograft dysfunction emphasizing their mechanistic and clinical potential applications and describing their methodological limitations.
