Validating S100A16 as a prognostic and immunological biomarker in pan-cancer and lung adenocarcinoma through integrated Single-cell Sequencing Analysis

Abstract

Abstract Background S100A16 belongs to the S100 protein family, exhibiting different expression levels across several human tumors. S100A16 upregulation in many malignancies suggests its potential role in malignant transformation. However, the specific involvement of S100A16 in lung adenocarcinoma (LUAD) remains unclear. Methods This study utilized RNA sequencing and protein expression data from the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (THPA) databases to scrutinize the expression of S100A16 and its associations with patients’ prognosis, clinicopathological characteristics, tumor microenvironment (TME), immune cell infiltration, expression of immune checkpoint genes, and relevant signaling pathways in LUAD. Employing ESTIMATE and CIBERSORT algorithms alongside Gene Set Enrichment Analysis (GSEA), we investigated the underlying mechanisms by which LUAD is involved in the TME. Additionally, we used single-cell sequencing to measure the role of S100A16 at the cellular level and dissect the effect on treatment response in LUAD. Results S100A16 was highly expressed in LUAD. As an independent prognostic marker, S100A16 expression was correlated with adverse outcomes. Its expression levels were positively correlated with the clinical TN stage and LUAD grade. GO and KEGG analyses revealed the predominance of molecules positively associated with S100A16 expression in LUAD, concentrating on pathways related to cellular signaling, motility, morphology, and cell interactions. The high S100A16 group showed a significantly higher TME score compared with the low S100A16 expression group. Immune cells, including M1 macrophages, memory B cells, activated NK cells, plasma cells, and naive B cells, were positively associated with S100A16 expression in LUAD. Furthermore, a positive correlation was observed between S100A16 and the expression of most immune checkpoint genes. Patients with high S100A16 expression demonstrated lower IC50 values for drugs such as 5-fluorouracil, bortezomib, cisplatin, cytarabine, docetaxel, doxorubicin, etoposide, and vinorelbine, suggesting that S100A16 overexpression increased sensitivity to these treatments in LUAD. This study provides novel insights into the role of S100A16 in LUAD and associated signaling pathways. Conclusions S100A16 is an independent prognostic marker in LUAD, intricately linked to the TME, immune cell infiltration, immune checkpoint expression, and response to treatment. This study underscores the potential of S100A16 as a prognostic marker in LUAD, advancing cancer treatment.