Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: a theranostic study for the precision medicine.
Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: a theranostic study for the precision medicine.
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突触融合蛋白结合蛋白 4 及其作用靶标 TP63 在肺鳞状细胞癌中的独特作用：精准医学的治疗诊断研究。
DOI：
10.1186/s12885-020-07448-2
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发表时间：
2020-09-29
期刊：
影响因子：
3.8
通讯作者：
Nishiyama M
中科院分区：
文献类型：
--
作者：
Bilguun EO;Kaira K;Kawabata-Iwakawa R;Rokudai S;Shimizu K;Yokobori T;Oyama T;Shirabe K;Nishiyama M
肺鳞状细胞癌（LSCC）仍然是一种治疗具有挑战性的疾病，并且预后的进一步改善取决于LSCC特异性治疗生物标志物和/或靶标的鉴定。我们先前发现，突触融合蛋白结合蛋白4（STXBP 4）在病变生长中起着至关重要的作用，因此，通过调节肿瘤蛋白p63（TP 63）泛素化，在喉鳞状细胞癌患者的临床结果。为了阐明STXBP 4和TP 63对LSCC治疗的影响，我们评估了这些蛋白质与144例LSCC患者结果的相关性，并通过与其他假定的探索性靶点和/或标志物进行比较，检查其作用途径是否与体外实验中目前使用的药物不同，包括RNA-seq分析。Kaplan-Meier分析显示，沿着血管内皮生长因子受体2（VEGFR 2），STXBP 4表达在喉鳞状细胞癌患者中意味着更差的预后，在总生存期（OS，p = 0.002）和无病生存期（DFS，p = 0.041）方面。STXBP 4的这些预后影响在单变量考克斯回归分析中得到证实，但在多变量分析中没有得到证实。而TP 63（Δ Np 63）与OS密切相关（p = 0.013），在多因素分析中显示TP 63（Δ Np 63）是OS差的独立预后因素（p = 0.0324）。STXBP 4对TP 63（Δ Np 63）抑制的作用途径是独特的：使用知识数据库和我们在人喉鳞状细胞癌细胞系中的RNA-seq分析进行的免疫途径分析表明，35条途径与STXBP 4相关被激活或失活，但STXBP 4的作用途径与其他当前药物靶点的作用途径不同：STXBP 4、TP 63和KDR（VEGFR 2基因）形成独立于肿瘤蛋白p53（TP 53）、微管蛋白β 3（TUBB 3）、stathmin 1（STMN 1）和分化簇274（CD 274：程序性细胞死亡1配体1，PD-L1）的其它靶基因的簇。STXBP 4本身似乎不是一个有效的预测个体药物反应的标志物，但我们发现，TP 63，STXBP 4的主要作用靶标，可能参与了LSCC的耐药机制。STXBP 4及其作用靶点TP 63可能成为喉鳞癌精准治疗的关键。
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.
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影响因子：
10.1
作者：
Goodman, Aaron M.;Kato, Shumei;Kurzrock, Razelle
通讯作者：
Kurzrock, Razelle
影响因子：
2.6
作者：
Ratovitski EA
通讯作者：
Ratovitski EA
影响因子：
8.8
作者：
Bai T;Yokobori T;Altan B;Ide M;Mochiki E;Yanai M;Kimura A;Kogure N;Yanoma T;Suzuki M;Bao P;Kaira K;Asao T;Katayama A;Handa T;Gombodorj N;Nishiyama M;Oyama T;Ogata K;Kuwano H
通讯作者：
Kuwano H
影响因子：
5.3
作者：
Li, Yingchun;Peart, Melissa J.;Prives, Carol
通讯作者：
Prives, Carol
DOI：
10.1158/1078-0432.ccr-16-1815
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
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
通讯作者：
Nishiyama M