Abstract
Background
Lung squamous cell carcinoma (LSCC) remains a challenging disease to treat, and further improvements in prognosis are dependent upon the identification of LSCC-specific therapeutic biomarkers and/or targets. We previously found that Syntaxin Binding Protein 4 (STXBP4) plays a crucial role in lesion growth and, therefore, clinical outcomes in LSCC patients through regulation of tumor protein p63 (TP63) ubiquitination.
Methods
To clarify the potential of STXBP4 as a novel therapeutic target and/or a predictive biomarker of therapeutic response, we assessed its prognostic impact of the protein in 144 LSCC patients and examined whether its action pathway is distinct from those of currently used drugs in in vitro experiments including RNA-seq analysis through comparison with the other putative exploratory targets and/or markers.
Results
Kaplan–Meier analysis revealed that, along with ΔNp63 (an isoform of TP63) and vascular endothelial growth factor receptor 2 (VEGFR2), STXBP4 expression signified a worse prognosis in LSCC patients, both in terms of overall survival (OS, P = 0.002) and disease-free survival (DFS, P = 0.041). Multivariate analysis demonstrated STXBP4 to be an independent prognostic factor for poor DFS, while VEGFR2 (P < 0.001) and TP63 (ΔNp63, P < 0.05) were independent prognostic factors for poor OS. The action pathway of STXBP4 on suppression of TP63 (ΔNp63), which results in the and inhibits tumor growth, was unique: Ingenuity pathway analysis using the knowledge database and our RNA-seq analysis in human LSCC cell lines indicated that 35 pathways were activated or inactivated in association with STXBP4, but the action pathway of STXBP4 was distinct from those of other current drug targets: STXBP4, TP63 and KDR (VEGFR2 gene) formed a cluster independent from other target genes of tumor protein p53 (TP53), tubulin beta 3 (TUBB3), stathmin 1 (STMN1) and cluster of differentiation 274 (CD274: programmed cell death 1 ligand 1, PD-L1). STXBP4 itself appeared not to be a potent predictive marker of individual drug response, but we found that TP63, main action target of STXBP4, might be involved in drug resistance mechanisms of LSCC.
Conclusion
STXBP4 could afford a unique therapeutic target and a key to the development of precision medicine for LSCC patients.
Syntaxin binding protein 4 as a novel therapeutic target and an effective biomarker for better treatment selection in lung squamous cell carcinoma: A theranostic study
