Department of General Surgical Science, Gunma University Graduate School of Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
BMC Cancer. 2020 Sep 29;20(1):935. doi: 10.1186/s12885-020-07448-2.
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.
To clarify the impact of STXBP4 and TP63 for LSCC therapeutics, we assessed relevance of these proteins to outcome of 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.
Kaplan-Meier analysis revealed that, along with 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). These prognostic impacts of STXBP4 were confirmed in univariate Cox regression analysis, but not in the multivariate analysis. Whereas, TP63 (ΔNp63) closely related to OS (p = 0.013), and shown to be an independent prognostic factor for poor OS in the multivariate analysis (p = 0.0324). The action pathway of STXBP4 on suppression of TP63 (ΔNp63) 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.
STXBP4 and the action target, TP63, could afford a key to the development of precision medicine for LSCC patients.
肺鳞状细胞癌（LSCC）的治疗仍然具有挑战性，进一步改善预后取决于鉴定 LSCC 特异性治疗生物标志物和/或靶标。我们之前发现，通过调节肿瘤蛋白 p63（TP63）泛素化，突触结合蛋白 4（STXBP4）在病变生长和因此 LSCC 患者的临床结局中发挥关键作用。
为了阐明 STXBP4 和 TP63 对 LSCC 治疗的影响，我们评估了这些蛋白与 144 名 LSCC 患者结局的相关性，并通过与其他推定的探索性靶标和/或标志物进行比较，通过 RNA-seq 分析等体外实验来检查其作用途径是否与目前使用的药物不同。
Kaplan-Meier 分析显示，STXBP4 表达与血管内皮生长因子受体 2（VEGFR2）一起，在 LSCC 患者的总生存期（OS，p=0.002）和无病生存期（DFS，p=0.041）方面均预示着预后较差。STXBP4 的这些预后影响在单因素 Cox 回归分析中得到证实，但在多因素分析中没有得到证实。相比之下，TP63（ΔNp63）与 OS 密切相关（p=0.013），并在多因素分析中被证明是 OS 不良的独立预后因素（p=0.0324）。STXBP4 对 TP63（ΔNp63）的抑制作用的作用途径是独特的：使用知识数据库和我们在人 LSCC 细胞系中的 RNA-seq 分析进行的 Ingenuity 途径分析表明，有 35 条途径与 STXBP4 相关联而被激活或失活，但 STXBP4 的作用途径与其他当前药物靶标不同：STXBP4、TP63 和 KDR（VEGFR2 基因）形成了一个与肿瘤蛋白 p53（TP53）、微管蛋白 β3（TUBB3）、微管蛋白 1（STMN1）和分化簇 274（CD274：程序性细胞死亡 1 配体 1，PD-L1）等其他靶基因不同的簇。STXBP4 本身似乎不是个体药物反应的有力预测标志物，但我们发现，STXBP4 的主要作用靶标 TP63 可能参与 LSCC 耐药机制。
STXBP4 和作用靶标 TP63 可能为 LSCC 患者精准医学的发展提供关键。
