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.

中文翻译：

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无嘌呤/无嘧啶脱氧核糖核酸内切酶 1 和 MicroRNA 轴在肝细胞癌中的临床意义。

背景和目的 肝细胞癌 (HCC) 预后因素的识别为治疗开辟了新的前景。循环和细胞肿瘤-miRNA 是非编码RNA，可以通过转录后机制控制参与肿瘤发生的基因的表达。这些 microRNA (miRNA) 被认为是 HCC 的新预后和预测因素。无嘌呤/无嘧啶脱氧核糖核酸内切酶 1 (APE1) 有助于特定肿瘤 miRNA 的质量控制和加工，并且是多种肿瘤的负面预后因素。目前的工作目的是： a) 定义 APE1 在 HCC 中的预后价值；b) 识别受 APE1 调节的 miRNA 及其相关靶基因，c) 研究它们的预后价值。方法我们使用癌症基因组图谱（通常称为TCGA）数据分析来评估APE1在HCC中的表达。为了通过特定的小干扰 RNA 来鉴定 APE1 消耗后的差异表达 miRNA (DEmiRNA)，我们在 JHH-6 HCC 肿瘤细胞系中使用了 NGS 和纳米线方法。进行生物信息学分析以确定涉及 APE1 调节 miRNA 的信号通路。进行微阵列分析以确定与血清 APE1 表达相关的 miRNA。结果 根据 TCGA-肝脏 HCC（称为 LIHC）数据集，与正常肝脏相比，APE1 在 HCC 组织中显着过度表达。富集分析表明，APE1 调节的 miRNA 参与与细胞增殖、转化和血管生成相关的信号传导和代谢途径，将细胞周期蛋白依赖性激酶 6 和溶酶体相关膜蛋白 2 确定为靶标。miR-33a-5p、miR-769 和 miR-877 与 HCC 患者较低的总生存率相关。通过阵列分析，我们鉴定了八种与 APE1 过表达相关的循环 DE-miRNA。训练阶段发现 sAPE1 与 miR-3180-3p 和 miR-769 之间呈正相关。结论 APE1 调节在 HCC 中具有预后价值的特定 miRNA。