Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
BMC Cancer. 2022 Jul 30;22(1):835. doi: 10.1186/s12885-022-09931-4.
A deep understanding of potential molecular biomarkers and therapeutic targets related to the progression of colorectal cancer (CRC) from early stages to metastasis remain mostly undone. Moreover, the regulation and crosstalk among different cancer-driving molecules including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs) in the transition from stage I to stage IV remain to be clarified, which is the aim of this study.
We carried out two separate differential expression analyses for two different sets of samples (stage-specific samples and tumor/normal samples). Then, by the means of robust dataset analysis we identified distinct lists of differently expressed genes (DEGs) for Robust Rank Aggregation (RRA) and weighted gene co-expression network analysis (WGCNA). Then, comprehensive computational systems biology analyses including mRNA-miRNA-lncRNA regulatory network, survival analysis and machine learning algorithms were also employed to achieve the aim of this study. Finally, we used clinical samples to carry out validation of a potential and novel target in CRC.
We have identified the most significant stage-specific DEGs by combining distinct results from RRA and WGCNA. After finding stage-specific DEGs, a total number of 37 DEGs were identified to be conserved across all stages of CRC (conserved DEGs). We also found DE-miRNAs and DE-lncRNAs highly associated to these conserved DEGs. Our systems biology approach led to the identification of several potential therapeutic targets, predictive and prognostic biomarkers, of which lncRNA LINC00974 shown as an important and novel biomarker.
Findings of the present study provide new insight into CRC pathogenesis across all stages, and suggests future assessment of the functional role of lncRNA LINC00974 in the development of CRC.
对大肠癌（CRC）从早期到转移的潜在分子生物标志物和治疗靶点的深入了解仍大多未被揭示。此外，信使 RNA（mRNA）、长非编码 RNA（lncRNA）和 microRNA（miRNA）等不同癌症驱动分子在从 I 期到 IV 期的转变过程中的调控和相互作用仍有待阐明，这也是本研究的目的。
我们对两组不同的样本（特定阶段样本和肿瘤/正常样本）进行了两次独立的差异表达分析。然后，通过稳健数据集分析，我们确定了用于稳健秩聚合（RRA）和加权基因共表达网络分析（WGCNA）的不同差异表达基因（DEGs）的不同列表。然后，还进行了综合计算系统生物学分析，包括 mRNA-miRNA-lncRNA 调控网络、生存分析和机器学习算法，以实现本研究的目的。最后，我们使用临床样本对 CRC 中的一个潜在的新靶标进行了验证。
我们通过结合 RRA 和 WGCNA 的不同结果，确定了最显著的阶段特异性 DEGs。找到阶段特异性 DEGs 后，我们共鉴定出 37 个在 CRC 的所有阶段都保守的 DEGs（保守 DEGs）。我们还发现与这些保守 DEGs 高度相关的 DE-miRNAs 和 DE-lncRNAs。我们的系统生物学方法确定了几个潜在的治疗靶点、预测和预后生物标志物，其中 lncRNA LINC00974 是一个重要的新标志物。
本研究的结果为 CRC 所有阶段的发病机制提供了新的见解，并提示未来评估 lncRNA LINC00974 在 CRC 发展中的功能作用。
