Sriharikrishnaa S, Jishnu Padacherri Vethil, Varghese Vinay Koshy, Shukla Vaibhav, Mallya Sandeep, Chakrabarty Sanjiban, Sharan Krishna, Pandey Deeksha, Kabekkodu Shama Prasada
Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Discov Oncol. 2025 Feb 13;16(1):172. doi: 10.1007/s12672-025-01946-0.
Aberrant miRNA expression has been associated with cervical cancer (CC) progression. The present study aimed to identify the miRNA clusters (MCs) altered in CC, identify their clinical utility, and understand their biological functions via computational analysis.
We used small RNA sequencing and qRT‒PCR to identify and validate abnormally expressed MCs in cervical squamous cell carcinoma (CSCC) samples. We compared our data with publicly available CC datasets to identify the differentially expressed MCs in CC. The potential targets, pathways, biological functions, and clinical utility of abnormally expressed MCs were predicted via several computational tools.
Small RNA sequencing revealed that 229 miRNAs belonging to 48 MCs were significantly differentially expressed in CSCC (p-value ≤ 0.05). Validation by qRT‒PCR confirmed the downregulation of members of the miR-379/656, namely, hsa-miR-376c-3p (2.8-fold; p-value 0.03), hsa-miR-494-3p (3.4-fold; p-value 0.02), hsa-miR-495-3p (eightfold; p-value 0.01), and hsa-miR-409-3p (fivefold; p-value 0.03), in CSCC samples compared with normal samples. The prognostic model generated via miRNA expression and random forest analysis showed robust sensitivity and specificity (0.88 to 0.92) in predicting overall survival. In addition, we report 22 prognostically important miRNAs in CC. Pathway analysis revealed the enrichment of several cancer-related pathways, notably p53, the cell cycle, viral infection and MAPK signalling. CDC25A, CCNE1, E2F1, CCNE2, RBL1, E2F3, CDK2, RBL2, E2F2 and CCND2 were identified as the top ten gene targets of MC. Drug‒gene interaction analysis revealed enrichment of 548 approved drugs and 62 unique genes.
Our study identified MCs, their target genes, their prognostic utility, and their potential functions in CC and recommended their usefulness in CC management.
异常的微小RNA（miRNA）表达与宫颈癌（CC）进展相关。本研究旨在通过计算分析鉴定CC中改变的miRNA簇（MC），确定其临床应用价值，并了解其生物学功能。
我们使用小RNA测序和qRT-PCR来鉴定和验证宫颈鳞状细胞癌（CSCC）样本中异常表达的MC。我们将我们的数据与公开可用的CC数据集进行比较，以鉴定CC中差异表达的MC。通过几种计算工具预测异常表达的MC的潜在靶标、途径、生物学功能和临床应用价值。
小RNA测序显示，属于48个MC的229个miRNA在CSCC中显著差异表达（p值≤0.05）。qRT-PCR验证证实，与正常样本相比，CSCC样本中miR-379/656成员，即hsa-miR-376c-3p（2.8倍；p值0.03）、hsa-miR-494-3p（3.4倍；p值0.02）、hsa-miR-495-3p（8倍；p值0.01）和hsa-miR-409-3p（5倍；p值0.03）下调。通过miRNA表达和随机森林分析生成的预后模型在预测总生存期方面显示出强大的敏感性和特异性（0.88至0.92）。此外，我们报告了CC中22个具有预后重要性的miRNA。通路分析显示富集了几种与癌症相关的通路，特别是p53、细胞周期、病毒感染和MAPK信号通路。CDC25A、CCNE1、E2F1、CCNE2、RBL1、E2F3、CDK2、RBL2、E2F2和CCND2被确定为MC的前十大基因靶标。药物-基因相互作用分析显示富集了548种获批药物和62个独特基因。
我们的研究鉴定了MC、其靶基因、其预后应用价值及其在CC中的潜在功能，并推荐其在CC管理中的有用性。
