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

Giovanna Mangiapane; Devis Pascut; Emiliano Dalla; Giulia Antoniali; Monica Degrassi; Lory Saveria Crocè; Veronica De Sanctis; Silvano Piazza; Giulia Canarutto; Claudio Tiribelli; Gianluca Tell

doi:10.14218/JCTH.2022.00179

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

J Clin Transl Hepatol. 2023 Nov 28;11(6):1291-1307. doi: 10.14218/JCTH.2022.00179. Epub 2023 Jul 17.

Authors

Affiliations

¹ Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Udine, Italy.
² Fondazione Italiana Fegato - ONLUS, Liver Cancer Unit, Trieste, Italy.
³ Department of Medical Sciences, University of Trieste, Trieste, Italy.
⁴ Clinica Patologie Fegato, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.
⁵ NGS Core Facility, Department CIBIO, University of Trento, Trento, Italy.
⁶ Computational Biology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy.

Abstract

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.

Keywords: APE1; Hepatocellular carcinoma; Prognostic factors; miRNAs.