Clinical Significance of Apurinic/Apyrimidinic Endodeoxyribonuclease 1 and MicroRNA Axis in Hepatocellular Carcinoma

Background and Aims: Identification of prognostic factors for hepatocellular carcinoma (HCC) opens new perspectives for therapy. Circulating and cellular onco-miRNAs are noncod ing RNAs which can control the expression of genes involved in oncogenesis through post-transcriptional mechanisms. These microRNAs (miRNAs) are considered novel prognostic and pre-dictive factors in HCC. The apurinic/apyrimidinic endodeoxy-ribonuclease 1 (APE1) contributes to the quality control and processing of specific onco-miRNAs and is a negative prognos-tic factor in several tumors. The present work aims to: a) de -fine APE1 prognostic value in HCC; b) identify miRNAs regulat-ed by APE1 and their relative target genes and c) study their prognostic value. Methods: We used The Cancer Genome At-las (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 approach-es in the JHH-6 HCC tumor cell line. Bioinformatics analy-ses 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 Lyso-somal 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.

Automated summary

This study investigates the prognostic value of APE1 in HCC and identifies miRNAs regulated by APE1 that are associated with cell proliferation, transformation, and angiogenesis. The overexpression of APE1 in HCC tissues and the correlation between specific miRNAs and lower overall survival in HCC patients are discovered.