摘要
Background and Aims:Identification of prognostic factors for hepatocellular carcinoma(HCC)opens new perspectives for therapy.Circulating and cellular onco-miRNAs are noncoding RNAs which can control the expression of genes involved in oncogenesis through post-transcriptional mechanisms.These microRNAs(miRNAs)are considered novel prognostic and predictive factors in HCC.The apurinic/apyrimidinic endodeoxyribonuclease 1(APE1)contributes to the quality control and processing of specific onco-miRNAs and is a negative prognostic factor in several tumors.The present work aims to:a)define APE1 prognostic value in HCC;b)identify miRNAs regulated by APE1 and their relative target genes and c)study their prognostic value.Methods:We used The Cancer Genome Atlas(commonly known as TCGA)data analysis to evaluate the expression of APE1 in HCC.To identify differentially-expressed miRNAs(DEmiRNAs)upon APE1 depletion through specific small interfering RNA,we used NGS and nanostring approaches in the JHH-6 HCC tumor cell line.Bioinformatics analyses were performed to identify signaling pathways involving APE1-regulated miRNAs.Microarray analysis was performed to identify miRNAs correlating with serum APE1 expression.Results:APE1 is considerably overexpressed in HCC tissues compared to normal liver,according to the TCGA-liver HCC(known as LIHC)dataset.Enrichment analyses showed that APE1-regulated miRNAs are implicated in signaling and metabolic pathways linked to cell proliferation,transformation,and angiogenesis,identifying Cyclin Dependent Kinase 6 and Lysosomal Associated Membrane Protein 2 as targets.miR-33a-5p,miR-769,and miR-877 are related to lower overall survival in HCC patients.Through array profiling,we identified eight circulating DE-miRNAs associated with APE1 overexpression.A training phase identified positive association between sAPE1 and miR-3180-3p and miR-769.Conclusions:APE1 regulates specific miRNAs having prognostic value in HCC.
基金
funded by a grant from Associazione Italiana per la Ricerca sul Cancro(AIRC)(Grant No.IG19862)to GT
partially funded by the region Friuli Venezia Giulia(D.NAMICA,PORFESR 2007-2013)
an intramural grant from the Italian Liver Foundation-ONLUS to CT.
