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Clinical significance of apurinic/apyrimidinic endodeoxyribonuclease 1 and microRNAs axis in hepatocellular carcinoma [NanoString]

ABSTRACT: Hepatocellular carcinoma is the most frequent species of liver cancer and the identification of new prognostic factors opens new perspectives for therapy. Circulating and cellular onco-miRNAs are non coding RNAs which can control oncogenesis-related gene expression through post-transcriptional mechanisms and are considered novel prognostic and predictive factors in cancer biology. The apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) contributes in the quality control and processing of specific onco-miRNAs, and is a negative prognostic factor in many tumors. The present work aims: a) to define APE1 prognostic value in HCC; b) to identify miRNAs regulated by APE1 and their relative target genes, and c) to study their prognostic value.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222851 | GEO | 2023/09/21

REPOSITORIES: GEO

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Project description:The presence of oxidized DNA lesions, such as 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic sites (AP sites), has been described as epigenetic signals that are involved in gene expression control. In mammals, Apurinic-apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is the main AP endonuclease of the base excision repair (BER) pathway and is involved in active demethylation processes. In addition, APE1/Ref-1, through its redox function, regulates several transcriptional factors. However, the transcriptional control targets of each APE1 function are not completely known. In this study, a transcriptomic approach was used to investigate the effects of chemical inhibition of APE1/Ref-1 redox or DNA repair functions by E3330 or methoxyamine (MX) in an inflammatory cellular model. Under lipopolysaccharide (LPS) stimulation, both E3330 and MX reduced the expression of some cytokines and chemokines. Interestingly, E3330 treatment reduced cell viability after 48 h of the treatment. Genes related to inflammatory response and mitochondrial processes were downregulated in both treatments. In the E3330 treatment, RNA processing and ribosome biogenesis genes were downregulated, while they were upregulated in the MX treatment. Furthermore, in the E3330 treatment, the cellular stress response was the main upregulated process, while the cellular macromolecule metabolic process was observed in MX-upregulated genes. Nuclear respiratory factor 1 (NRF1) was predicted to be a master regulator of the downregulated genes in both treatments, while the ETS transcription factor ELK1 (ELK1) was predicted to be a master regulator only for E3330 treatment. Decreased expression of ELK1 and its target genes and a reduced 28S/18S ratio were observed, suggesting impaired rRNA processing. In addition, both redox and repair functions can affect the expression of NRF1 and GABPA target genes. The master regulators predicted for upregulated genes were YY1 and FLI1 for the E3330 and MX treatments, respectively. In summary, the chemical inhibition of APE1/Ref-1 affects gene expression regulated mainly by transcriptional factors of the ETS family, showing partial overlap of APE1 redox and DNA repair functions, suggesting that these activities are not entirely independent. This work provides a new perspective on the interaction between APE1 redox and DNA repair activity in inflammatory response modulation and transcription.

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Clinical significance of apurinic/apyrimidinic endodeoxyribonuclease 1 and microRNAs axis in hepatocellular carcinoma [NanoString]

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