Abstract
Background: Persistent HPV infection is the primary cause of cervical carcinogenesis. While HPV testing as a screening modality has reduced cervical cancer incidence, standalone HPV screening cannot distinguish persistent infections, necessitating novel molecular markers to identify effective HPV infection in cervical epithelial cells. Methods: Genes associated with HPV-positive cervical lesions were screened using GEO databases, with SYCP2's diagnostic potential evaluated by ROC curve analysis. TCGA data were analyzed for SYCP2-clinicopathological correlations and prognostic significance. RNA-seq following SYCP2 silencing identified differentially expressed genes, with functional characterization via GO/KEGG enrichment. Downstream effector IL13RA2 was validated at RNA/protein levels. SYCP2-immunological parameter correlations were investigated using the TISIDB repository. Results: Integrated analysis of four GEO datasets identified SYCP2 as a key upregulated gene in HPV16-positive cervical cancer compared to HPV-negative tissues. Clinical analyses revealed SYCP2 overexpression correlated with lymph node metastasis and worse disease-free survival (HR (high) = 2.1, P = 0.0096). ROC curves demonstrated diagnostic efficacy for cervical lesions (CIN2+: AUC = 0.846(95%C1 0.777, 0.915); CIN3+: AUC = 0.806(95%C1 0.731, 0.881)). RNA-seq of SYCP2-knockdown cells identified 68 differentially expressed genes, with GO/KEGG analyses linking SYCP2 to viral response pathways (e.g., influenza A, measles) and extracellular matrix remodeling. Alternative splicing analysis revealed enrichment in viral carcinogenesis pathways. SYCP2 silencing significantly downregulated IL13RA2 expression, validated via RT-PCR, Western blot, and IL13 rescue experiments. Correlation analyses revealed that SYCP2 expression levels showed statistically significant negative correlations with the abundance of Activated Dendritic Cells (rho = - 0.347, P < 0.001), Regulatory T cells (rho = - 0.351, P < 0.001), Monocytes (rho = -0.363, P < 0.001), Macrophages (rho = - 0.327, P < 0.001), Myeloid-Derived Suppressor Cells (rho = - 0.313, P < 0.001), and Gamma Delta T cells (Tgd, rho = - 0.433, P < 0.001). Pan-cancer analysis showed SYCP2 upregulation in cervical squamous carcinoma but downregulation in testicular/thyroid cancers. Conclusions: SYCP2 emerges as a critical biomarker for HPV-driven cervical carcinogenesis, with diagnostic potential for high-grade lesions and prognostic value for metastasis risk. Its regulatory role in IL13RA2-mediated signaling and association with viral response pathways suggest mechanistic involvement in tumor microenvironment remodeling. The dual context-dependent expression (upregulated in cervical cancer vs. downregulated in other malignancies) highlights tissue-specific oncogenic functions. These findings position SYCP2 as a promising target for HPV-associated cervical cancer screening and therapeutic strategies.