Expression Profile of CDC45 as a Potential Therapeutic Target in HPV-Associated Cervical Cancer and Pan-Cancer Prognostic Heterogeneity

Abstract

Objective: This study aimed to elucidate the expression profile, clinical relevance, and mechanistic role of cell division cycle protein 45 (CDC45) in cervical carcinoma (CC) pathogenesis, while assessing its pan-cancer prognostic significance.
Methods: Multi-cohort transcriptomic analysis of CDC45 was performed using TCGA-CESC (306 tumors, 18 normal), GEO datasets (GSE63514: 152 samples; GSE67522: 42 samples), and experimental validation with 4 clinical CC/normal pairs. In addition, CDC45 expression and human papilloma virus (HPV) positivity and negativity were analyzed in CC, oral squamous cell carcinoma (OSCC), head and neck squamous cell carcinoma (HNSCC) from GEO database (GSE39001-CESCC, GSE67522-CESCC, GSE40774-HNSCC, GSE55542-OSCC). Differential expression, survival correlations, and pathway enrichment (GSEA) were analyzed. A prognostic nomogram integrating CDC45 expression and clinical variables was developed. Pan-cancer profiling across 34 malignancies (TCGA/TARGET/GTEx, N=19,131) evaluated CDC45’s prognostic utility.
Results: CDC45 was significantly overexpressed in CC tissues versus normal (TCGA: p<0.0001; GEO: p<0.0001), validated experimentally (mRNA: p<0.01; protein: p<0.05). HPV-positive CC, OSCC, and HNSCC exhibited higher CDC45 levels than HPV-positive/negativity samples (CC: p<0.0001; OSCC: p<0.01; HNSCC: p<0.001). GSEA revealed CDC45’s association with DNA repair (mismatch/homologous recombination), replication, and cell cycle pathways (FDR<0.25). High CDC45 expression correlated with prolonged overall survival (HR=0.58, p=0.022) and progression-free survival (HR=0.56, p=0.016). A nomogram incorporating CDC45 and p-TNM stage (I vs IV) status predicted 1-/3-/5-year survival (C-index=0.702). Pan-cancer analysis identified CDC45 as a dual-context prognostic marker: high expression conferred poor survival in glioblastoma, renal/liver cancers (HR>1, p<0.05), while low expression predicted adverse outcomes in ovarian/lymphoid malignancies (HR<1, p<0.05).
Conclusion: CDC45 overexpression in CC is linked to HPV-driven carcinogenesis, genomic instability, and replication stress, serving as an independent prognostic indicator. Its pan-cancer dichotomy underscores tissue-specific oncogenic roles. These findings nominate CDC45 as a potential therapeutic target and predictive biomarker for cervical and other malignancies.