STXBP4 drives tumor growth and is associated with poor prognosis through PDGF Receptor signaling in lung squamous cell carcinoma
A partir d'échantillons tumoraux prélevés sur 87 patients atteints d'un carcinome épidermoïde du poumon, puis menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels une surexpression de la protéine STXBP4 favorise la croissance tumorale
Purpose: Expression of the ΔN isoform of p63 (ΔNp63) is a diagnostic marker highly specific for lung squamous cell carcinoma (SCC). We previously found that Syntaxin Binding Protein 4 (STXBP4) regulates ΔNp63 ubiquitination, suggesting that STXBP4 may also be a SCC biomarker. To address this issue, we investigated the role of STXBP4 expression in SCC biology and the impact of STXBP4 expression on SCC prognosis. Experimental design: We carried out a clinicopathological analysis of STXBP4 expression in 87 lung SCC patients. Whole transcriptome analysis using RNA-seq was performed in STXBP4-positive and STXBP4-negative tumors of lung SCC. Soft agar assay and xenograft assay were performed using overexpressing or knockdown SCCcells. Results: Significantly higher levels of STXBP4 expression were correlated with accumulations of ΔNp63 in clinical lung SCC specimens (Spearman's rank correlation ρ=0.219). Notably, STXBP4-positive tumors correlated with three important clinical parameters: T factor (P<0.001), disease stage (P=0.030) and pleural involvement (P=0.028). Whole transcriptome sequencing followed by pathway analysis indicated that STXBP4 is involved in functional gene networks that regulate cell growth, proliferation, cell death and survival in cancer. Platelet-Derived Growth Factor Receptor alpha (PDGFRα) was a key downstream mediator of STXBP4 function. In line with this, shRNA mediated STXBP4 and PDGFRA knockdown suppressed tumor growth in soft agar and xenograft assays. Conclusions: STXBP4 plays a crucial role in driving SCC growth and is an independent prognostic factor for predicting worse outcome in lung SCC. These data suggest that STXBP4 is a relevant therapeutic target for patients with lung SCC.