Cervical cancer (CC) remains high morbidity and mortality. We aimed to identify critical pathways underlying cervical carcinogenesis and establish a prognostic signature. Six datasets from the gene expression omnibus (GEO) database were used to screen the differentially expressed genes (DEGs) between CC and normal tissues. We used the unions of the DEGs to perform functional analysis. The 108 overlapped DEGs were analyzed to determine a prognostic signature by Cox regression and Lasso analysis based on The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) and Immune Cell Abundance Identifier (ImmuCellAI) were used to determine the relationships between the signature and biological functions. The PI3K-Akt signaling pathway, the Ras signaling pathway, and the viral carcinogenesis pathway may be critical for CC development. We identified seven genes (PLOD2, DSG2, SPP1, CXCL8, MCM5, HLTF, and KLF4) to construct a risk score formula. Survival analysis showed that the high-risk group indicated a worse prognosis than the low-risk group p < 0.0001 . The AUC of the prognostic signature was 0.7449, 0.7641, and 0.8146 at 1, 3, and 5 years. We also identified that the signature is an independent prognostic factor. GSEA showed five pathways were relevant to the signature, such as the adherens junction pathway. The signature also affected the abundances of various types of immune cells, such as B cell, CD4+ T cell, and CD8+ T cell. Further, we found that SPP1 was co-expressed with HK3, CD163, CCL3, CLEC5A, MMP8, TREM1, OLR1, and TREM2. The results of Gene Ontology analysis showed that SPP1 and its co-expressed related proteins mainly affected metabolic process, multicellular organismal process, cell communication, cell proliferation, protein binding, and transporter activity. In conclusion, the present study explored the key pathways for CC development and the seven-gene signature can effectively make the prognosis evaluation of CC patients.
Background: Cervical cancer is the most common malignant tumor in the female reproductive system, while the efficacy of routine screening strategy is unsatisfied. New molecular tests need to be developed. miRNAs participate in many pathologic processes, and circulating miRNAs are promising non-invasive biomarkers in tumors. Objectives: This study aimed to identify the circulating miRNAs associated with both cervical cancer and cervical intraepithelial neoplasia (CIN), and establish a non-invasive classifier for cervical lesions using circulating miRNAs. Methods: This study consisted of 5 steps: miRNAs screening, miRNAs validation, classifier establishment, independent validation and in silico analyses. Three cohorts were included in our study: In screening stage, 24 samples including 14 cases and 10 controls were retrieved; In validation stage, 380 samples including 200 cases and 180 controls were recruited; In independent validation stage, 47 samples comprising 26 cases and 21 controls were included. miRNAs were quantified by RT-qPCR. A classifier was built with random forest algorithm using validation samples and selected miRNAs, which were then validated in an independent cohort. To explore the function of selected miRNAs, in silico analyses were performed. Target genes of selected miRNAs were predicted by the overlap of three online tools. Enrichment analyses were executed with predicted target genes. Differential analysis of target genes was carried out with open access expression assay datasets of cervical tissues. Results: 6 miRNAs (hsa-miR-26b-5p, hsa-miR-146b-5p, hsa-miR-191-5p, hsa-miR-484, hsa-miR-574-3p, hsa-miR-625-3p) were screened out from 754 miRNAs. They were associated with cervical lesions and were selected to establish a classifier. The accuracy of the classifier were 0.7218 (0.7117, 0.7319) in validation samples, which was 0.7021 in the independent cohort. 958 target genes were predicted and enriched in 23 pathways (MAPK, human papillomavirus infection and Wnt signaling pathway, etc.). 55 genes were identified as the most likely target genes by differential analysis. Conclusion: The 6 circulating miRNAs were related to cervical lesions and could serve as non-invasive biomarkers.
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