Characterization of Tumor-Suppressive Function of SOX6 in Human Esophageal Squamous Cell Carcinoma
Characterization of Tumor-Suppressive Function of SOX6 in Human Esophageal Squamous Cell Carcinoma
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SOX6 在人食管鳞状细胞癌中的抑癌功能特征
DOI：
10.1158/1078-0432.ccr-10-1155
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发表时间：
2011-01-01
影响因子：
11.5
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Qin, Yan-Ru;Tang, Hong;Guan, Xin-Yuan
目的：通过基因芯片分析，我们发现一个转录因子SOX6在食管鳞状细胞癌（ESCC）中经常下调。本研究旨在探讨SOX6在人类食管癌发生发展中的作用，并探讨SOX6下调在ESCC中的患病率及临床意义。实验设计：采用半定量RT-PCR和免疫组织化学方法分别检测50例escc中SOX6 mRNA和300例escc中SOX6蛋白的表达。通过细胞生长、病灶形成、创面愈合和细胞侵袭实验以及肿瘤异种移植实验表征SOX6的肿瘤抑制功能。Western blot检测蛋白表达水平。结果：SOX6在原发性escc中mRNA水平（29/50,58%）和蛋白水平（149/219,68.0%）均下调，与分化不良（P = 0.029）、淋巴结转移（P = 0.014）、TNM分期（P = 0.000）和疾病特异性生存率（P < 0.001）显著相关。多因素分析显示，SOX6下调（P = 0.000）是ESCC的重要独立预后因素。功能研究表明，SOX6在体外和体内均能抑制ESCC细胞的致瘤能力。SOX6的肿瘤抑制机制可能通过上调p53和p21WAF1/CIP1的表达，下调cyclin D1/CDK4、cyclin A和β-catenin的表达而参与G1/S细胞周期阻滞。结论：我们首次证明SOX6在ESCC的发展中是一种新的肿瘤抑制基因，并且是ESCC的潜在预后标志物。临床癌症研究；17 (1);46-55。AACR©2010。
Purpose: By using cDNA microarray analysis, we identified a transcriptional factor, SOX6, was frequently downregulated in esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the role of SOX6 in human esophageal cancer development, and to examine the prevalence and clinical significance of SOX6 downregulation in ESCC. Experimental Design: Expressions of SOX6 mRNA in 50 ESCCs and SOX6 protein in 300 ESCCs were investigated by semiquantitative RT-PCR and immunohistochemistry, respectively. The tumor-suppressive function of SOX6 was characterized by cell growth, foci formation, wound-healing and cell invasive assays, and tumor xenograft experiment. Western blot analysis was applied to detect protein expression levels. Results: SOX6 was frequently downregulated in primary ESCCs in both mRNA level (29/50, 58%) and protein level (149/219, 68.0%), which was significantly associated with the poor differentiation (P = 0.029), lymph node metastases (P = 0.014), advanced TNM stage (P = 0.000), and disease-specific survival (P < 0.001). Multivariate analysis indicated that the downregulation of SOX6 (P = 0.000) was a significant independent prognostic factors for ESCC. Functional studies showed that SOX6 was able to suppress both in vitro and in vivo tumorigenic ability of ESCC cells. The tumor-suppressive mechanism of SOX6 was associated with its role in G1/S cell-cycle arrest by upregulating expressions of p53 and p21WAF1/CIP1 and downregulating expressions of cyclin D1/CDK4, cyclin A, and β-catenin. Conclusions: We provided the first evidence that SOX6 is a novel tumor-suppressor gene in ESCC development and is a potential prognostic marker in ESCC. Clin Cancer Res; 17(1); 46–55. ©2010 AACR.