Deciphering the Molecular Complexity of Hepatocellular Carcinoma: Unveiling Novel Biomarkers and Therapeutic Targets Through Advanced Bioinformatics Analysis

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2024-08-08 DOI:10.1002/cnr2.2152

Ata Moghimi, Nasrin Bani Hosseinian, Mahdi Mahdipour, Ehsan Ahmadpour, Alberto Miranda-Bedate, Saeid Ghorbian

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Abstract

Background

Hepatocellular carcinoma (HCC) represents a primary liver tumor characterized by a bleak prognosis and elevated mortality rates, yet its precise molecular mechanisms have not been fully elucidated. This study uses advanced bioinformatics techniques to discern differentially expressed genes (DEGs) implicated in the pathogenesis of HCC. The primary objective is to discover novel biomarkers and potential therapeutic targets that can contribute to the advancement of HCC research.

Methods

The bioinformatics analysis in this study primarily utilized the Gene Expression Omnibus (GEO) database as data source. Initially, the Transcriptome analysis console (TAC) screened for DEGs. Subsequently, we constructed a protein–protein interaction (PPI) network of the proteins associated to the identified DEGs with the STRING database. We obtained our hub genes using Cytoscape and confirmed the results through the GEPIA database. Furthermore, we assessed the prognostic significance of the identified hub genes using the GEPIA database. To explore the regulatory interactions, a miRNA-gene interaction network was also constructed, incorporating information from the miRDB database. For predicting the impact of gene overexpression on drug effects, we utilized CANCER DP.

Results

A comprehensive analysis of HCC gene expression profiles revealed a total of 4716 DEGs, consisting of 2430 upregulated genes and 2313 downregulated genes in HCC sample compared to healthy control group. These DEGs exhibited significant enrichment in key pathways such as the PI3K-Akt signaling pathway, nuclear receptors meta-pathway, and various metabolism-related pathways. Further exploration of the PPI network unveiled the P53 signaling pathway and pyrimidine metabolism as the most prominent pathways. We identified 10 hub genes (ASPM, RRM2, CCNB1, KIF14, MKI67, SHCBP1, CENPF, ANLN, HMMR, and EZH2) that exhibited significant upregulation in HCC samples compared to healthy control group. Survival analysis indicated that elevated expression levels of these genes were strongly associated with changes in overall survival in HCC patients. Lastly, we identified specific miRNAs that were found to influence the expression of these genes, providing valuable insights into potential regulatory mechanisms underlying HCC progression.

Conclusion

The findings of this study have successfully identified pivotal genes and pathways implicated in the pathogenesis of HCC. These novel discoveries have the potential to significantly enhance our understanding of HCC at the molecular level, opening new ways for the development of targeted therapies and improved prognosis evaluation.

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解密肝细胞癌的分子复杂性：通过先进的生物信息学分析揭示新型生物标记物和治疗靶点。

背景：肝细胞癌（HCC）是一种原发性肝脏肿瘤，其特点是预后不良、死亡率高，但其确切的分子机制尚未完全阐明。本研究利用先进的生物信息学技术来识别与 HCC 发病机制有关的差异表达基因 (DEG)。其主要目的是发现新的生物标志物和潜在的治疗靶点，从而推动 HCC 研究的发展：本研究的生物信息学分析主要利用基因表达总库（GEO）数据库作为数据源。首先，转录组分析控制台（TAC）筛选出 DEGs。随后，我们利用 STRING 数据库构建了一个蛋白质-蛋白质相互作用（PPI）网络，其中包含了与已识别 DEGs 相关的蛋白质。我们利用 Cytoscape 获得了中心基因，并通过 GEPIA 数据库确认了结果。此外，我们还利用 GEPIA 数据库评估了所发现的中心基因的预后意义。为了探索调控相互作用，我们还结合 miRDB 数据库的信息构建了 miRNA 基因相互作用网络。为了预测基因过表达对药物效果的影响，我们使用了CANCER DP：对HCC基因表达谱的全面分析显示，与健康对照组相比，HCC样本中共有4716个DEGs，其中包括2430个上调基因和2313个下调基因。这些DEGs在PI3K-Akt信号通路、核受体元通路和各种代谢相关通路等关键通路中表现出明显的富集。对 PPI 网络的进一步探索发现，P53 信号通路和嘧啶代谢是最重要的通路。与健康对照组相比，我们发现有10个枢纽基因（ASPM、RRM2、CCNB1、KIF14、MKI67、SHCBP1、CENPF、ANLN、HMMR和EZH2）在HCC样本中表现出显著上调。生存期分析表明，这些基因表达水平的升高与 HCC 患者总生存期的变化密切相关。最后，我们确定了影响这些基因表达的特定 miRNA，为了解 HCC 进展的潜在调控机制提供了有价值的见解：本研究的结果成功鉴定了与 HCC 发病机制有关的关键基因和通路。这些新发现有可能在分子水平上大大提高我们对 HCC 的认识，为开发靶向疗法和改善预后评估开辟新的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.