Table9_Identification of Potential Hub Genes and miRNA-mRNA Pairs Related to the Progression and Prognosis of Cervical Cancer Through Integrated Bioinformatics Analysis.XLSX

In recent years, the incidence and mortality of cervical cancer have increased worldwide. At the same time, increasing data have confirmed that miRNA-mRNA plays a positive or negative regulatory role in many cancers. This study attempted to screen effective miRNA-mRNA in the progression of cervical cancer, and to study the mechanism of miRNA-mRNA in the progression of cervical cancer. The expression profile data of GSE7410, GSE 63514, GSE 86100 and TCGA-CESC were downloaded, and 34 overlapping differentially expressed genes (22 up-regulated and 12 down-regulated) and 166 miRNAs (74 down-regulated and 92 up-regulated) were screened through limma package. Then, miR-197-3p/TYMS pairs were obtained by PPI, functional enrichment, Kaplan-Meier plotter analysis, Cox univariate and multivariate analysis, risk modeling, WGCNA, qPCR and dual-luciferase experiments. The results showed that TYMS was an independent prognostic factor of cervical cancer, and its expression level was negatively correlated with cervical cancer tissue grade (TMN), tumor grade, age, microsatellite stability and tumor mutation load, and positively correlated with methyl expression in DNMT1, DNMT2, DNMT3A and DNMT3B. Functional experiments showed that TYMS knockout could promote the proliferation, migration and invasion of HeLa cells and reduce apoptosis. Overexpression of TYMS showed the opposite trend, miR-197-3p was negatively correlated with the expression of TYMS. MiR-197-3p inhibitor reversed the effect of si-TYMS on the proliferation of HeLa cells. In conclusion, these results reveal that TYMS plays a very important role in the prognosis and progression of cervical cancer, and has the potential to be thought of as cervical cancer biomarkers. At the same time, miR-197-3p/TYMS axis can regulate the deterioration of cervical cancer cells, which lays a foundation for the molecular diagnosis and treatment of cervical cancer.

近年来，全球范围内宫颈癌的发病率和死亡率均有上升。与此同时，越来越多的数据证实了miRNA-mRNA在多种癌症中发挥着正负双向的调控作用。本研究旨在筛选出在宫颈癌进展过程中具有调控功能的miRNA-mRNA，并探讨miRNA-mRNA在宫颈癌进展中的调控机制。下载了GSE7410、GSE 63514、GSE 86100和TCGA-CESC的表达谱数据，通过limma软件包筛选出34个重叠的差异表达基因（其中22个上调和12个下调）以及166个miRNA（其中74个下调和92个上调）。随后，通过蛋白质互作网络（PPI）、功能富集分析、Kaplan-Meier生存分析、Cox单因素和多因素分析、风险建模、加权基因共表达网络分析（WGCNA）、实时荧光定量PCR（qPCR）和双荧光素酶实验，获得了miR-197-3p/TYMS的配对。结果显示，TYMS是宫颈癌独立预后因素，其表达水平与宫颈癌组织分级（TMN）、肿瘤分级、年龄、微卫星不稳定性以及肿瘤突变负荷呈负相关，与DNA甲基转移酶1（DNMT1）、DNMT2、DNMT3A和DNMT3B中的甲基表达呈正相关。功能实验表明，TYMS基因敲除可促进HeLa细胞的增殖、迁移和侵袭，并减少细胞凋亡。TYMS的过表达表现出相反的趋势，miR-197-3p与TYMS的表达呈负相关。miR-197-3p抑制剂逆转了si-TYMS对HeLa细胞增殖的影响。综上所述，这些研究结果揭示了TYMS在宫颈癌的预后和进展中发挥着至关重要的作用，并具有作为宫颈癌生物标志物的潜力。同时，miR-197-3p/TYMS轴可调节宫颈癌细胞的恶化，为宫颈癌的分子诊断和治疗奠定了基础。