Integrative Transcriptomic and Network-Based Analysis of the Potential ZNF695–miR-3689d–MCM8 Regulatory Axis in HNSC

Background A high proportion of local relapses is a common feature of HNSC. Numerous investigations have shown that the primary etiologic factors of HNSC mostly produce genetic and gene expression abnormalities in the mucosa of patients with the condition. Methods TCGA-HNSC mRNA expression data were analyzed using an integrative transcriptomic and network-based workflow comprising DEA, WGCN, PPIN analysis, functional enrichment analysis, and TF–miRNA–mRNA regulatory network analysis. Results A total of 1703 HNSC-specific DEGs were obtained followed by noisy genes removal and establishment of WGCN which resulted in a total of five modules and a hub module comprising 98 DEGs. PPIN comprised 45 nodes and 97 edges whereas top-scoring PPIN hub cluster comprised 8 nodes and 23 edges. Most significant pathway, GO-BP, GO-CC, GO-MF terms were activation of pre-replicative complex ( BH − p − value = 6.84 × 10 −15 ), DNA duplex unwinding ( BH − p − value = 9.71 × 10 −11 ), CMG complex ( BH − p − value = 4.53 × 10 −8 ), single-stranded DNA binding ( BH − p − value = 3.87 × 10 −7 ). Network centrality analysis prioritized a 3-node FFL comprising ZNF695 , miR-3689d, and MCM8 as a candidate regulatory motif. Conclusion The integrative network analysis identified the ZNF695–miR-3689d–MCM8 FFL as a potential regulatory axis associated with HNSC. These findings provide a computational basis for further investigation of the molecular interactions underlying HNSC and require independent validation and experimental confirmation.