Multi-omic discovery of SCG5 as a shared driver and prognostic biomarker in head-neck and non-small cell lung cancers

Abstract

Patients with head and neck squamous cell carcinoma (HNSC) face a high risk of developing non-small cell lung cancer (NSCLC). However, the shared molecular drivers linking these two malignancies remain poorly defined. We integrated TCGA and GEO datasets to identify shared differentially expressed genes (DEGs) between HNSC and NSCLC, subsequently evaluating their prognostic value, immune infiltration patterns (ssGSEA), and enriched pathways. Clinical validation of SCG5 protein expression was comprehensively performed using tissue microarrays (TMA) via immunohistochemistry. in vitro assays, including siRNA-mediated knockdown, CCK-8, colony formation, and Western blotting, were conducted in both HNSC (SCC-25) and NSCLC (A549) cell lines to ascertain its oncogenic functions and underlying molecular mechanisms. SCG5 was identified as a consistently upregulated, independent predictor of poor survival in both cancers. IHC confirmed SCG5 protein overexpression, correlating with lymph node metastasis and advanced clinical stages. GSEA revealed that SCG5-associated genes were significantly enriched in focal adhesion and the PI3K/AKT signaling pathway in both HNSC and NSCLC. SCG5 expression correlated positively with tumor-infiltrating macrophages (P < 0.001) and with PDCD1LG2, HAVCR2 and SIGLEC15 (P < 0.05). SCG5 knockdown significantly suppressed cell proliferation and colony formation in both SCC-25 and A549 cells, concurrently attenuating PI3K and AKT phosphorylation. SCG5 is a novel shared oncogenic driver and prognostic biomarker for HNSC and NSCLC. Downregulation of SCG5 suppresses the growth of HNSC and NSCLC cells, potentially through modulating the PI3K/AKT signaling pathway, thereby presenting a potential therapeutic target for both malignancies.