Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.
Department of General Medicine, Gunma University, Gunma, Japan.
Clin Cancer Res. 2017 Jul 1;23(13):3442-3452. doi: 10.1158/1078-0432.CCR-16-1815. Epub 2017 Jan 13.
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 an 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. We carried out a clinicopathologic 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 SCC cells. Significantly higher levels of STXBP4 expression were correlated with accumulations of ΔNp63 in clinical lung SCC specimens (Spearman rank correlation = 0.219). Notably, STXBP4-positive tumors correlated with three important clinical parameters: T factor ( < 0.001), disease stage ( = 0.030), and pleural involvement ( = 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 and knockdown suppressed tumor growth in soft-agar and xenograft assays. 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. .
ΔN 型 p63（ΔNp63）的表达是肺鳞状细胞癌（SCC）高度特异的诊断标志物。我们之前发现Syntaxin Binding Protein 4（STXBP4）调节ΔNp63的泛素化，这表明 STXBP4 也可能是 SCC 的生物标志物。为了解决这个问题，我们研究了 STXBP4 表达在 SCC 生物学中的作用以及 STXBP4 表达对 SCC 预后的影响。我们对 87 例肺 SCC 患者的 STXBP4 表达进行了临床病理分析。对肺 SCC 中 STXBP4 阳性和 STXBP4 阴性肿瘤进行了全转录组 RNA-seq 分析。使用过表达或敲低 SCC 细胞进行软琼脂实验和异种移植实验。在临床肺 SCC 标本中，STXBP4 表达水平的显著升高与 ΔNp63 的积累相关（Spearman 秩相关系数 = 0.219）。值得注意的是，STXBP4 阳性肿瘤与三个重要的临床参数相关：T 因子（<0.001）、疾病分期（=0.030）和胸膜受累（=0.028）。全转录组测序后进行通路分析表明，STXBP4 参与调节细胞生长、增殖、细胞死亡和存活的功能基因网络。血小板衍生生长因子受体α（PDGFRα）是 STXBP4 功能的关键下游介质。与此一致，shRNA 介导的 和 敲低抑制了软琼脂和异种移植实验中的肿瘤生长。STXBP4 在驱动 SCC 生长中起着至关重要的作用，是预测肺 SCC 不良结局的独立预后因素。这些数据表明，STXBP4 是肺 SCC 患者的一个相关治疗靶点。
