STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma.
STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma.
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DOI：
10.1158/1078-0432.ccr-16-1815
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发表时间：
2017-07-01
期刊：
影响因子：
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通讯作者：
Nishiyama M
中科院分区：
文献类型：
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作者：
Otaka Y;Rokudai S;Kaira K;Fujieda M;Horikoshi I;Iwakawa-Kawabata R;Yoshiyama S;Yokobori T;Ohtaki Y;Shimizu K;Oyama T;Tamura J;Prives C;Nishiyama M
p63的ΔN亚型（Δ Np 63）的表达是肺鳞状细胞癌（SCC）的高度特异性诊断标志物。我们之前发现，突触融合蛋白结合蛋白4（STXBP 4）调节Δ Np 63泛素化，这表明STXBP 4也可能是SCC生物标志物。为了解决这个问题，我们研究了STXBP 4表达在SCC生物学中的作用以及STXBP 4表达对SCC预后的影响。我们对87例肺鳞癌患者进行了STXBP 4表达的临床病理分析。在肺SCC的STXBP 4阳性和STXBP 4阴性肿瘤中使用RNA-seq进行全转录组分析。使用过表达或敲低SCC细胞进行软琼脂测定和异种移植测定。在临床肺SCC标本中，STXBP 4表达水平显著升高与Δ Np 63积累相关（斯皮尔曼等级相关性ρ=0.219）。值得注意的是，STXBP 4阳性肿瘤与三个重要的临床参数相关：T因子（P<0.001）、疾病分期（P=0.030）和胸膜受累（P=0.028）。全转录组测序和随后的通路分析表明，STXBP 4参与调节癌症中细胞生长、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STXBP 4功能的关键下游介质。与此一致，shRNA介导的STXBP 4和PDGFRA敲低在软琼脂和异种移植试验中抑制肿瘤生长。STXBP 4在驱动SCC生长中起着至关重要的作用，并且是预测肺SCC预后不良的独立预后因素。这些数据表明STXBP 4是肺SCC患者的相关治疗靶标。
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. 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 SCC cells. 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. 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.