SOX2表达缺失通过上调波形蛋白诱导细胞迁移，并且是头颈部鳞状细胞癌患者生存的不良风险因素。
Loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma.
作者信息
Bayo Pilar, Jou Adriana, Stenzinger Albrecht, Shao Chunxuan, Gross Madeleine, Jensen Alexandra, Grabe Niels, Mende Christel Herold, Rados Pantelis Varvaki, Debus Juergen, Weichert Wilko, Plinkert Peter K, Lichter Peter, Freier Kolja, Hess Jochen
机构信息
Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany; Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany.
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, D-69120, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany; Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, CEP: 90035-003, Brazil.
出版信息
Mol Oncol. 2015 Oct;9(8):1704-19. doi: 10.1016/j.molonc.2015.05.006. Epub 2015 May 20.
Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up-regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down-regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression-free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure.
3号染色体q26区域的复发性增益包含转录因子SOX2的基因座，这在人类鳞状细胞癌中是常见事件，包括头颈部鳞状细胞癌（HNSCC）。大量研究表明，SOX2的表达和功能与肿瘤细胞病理生理学的不同方面相关。然而，其潜在的分子机制尚不清楚，并且SOX2表达与临床结果之间的相关性显示出相互矛盾的数据。在一种HNSCC细胞系中沉默SOX2表达后的转录谱分析确定了一组与细胞运动相关的上调基因（例如波形蛋白、纤连蛋白1、钙黏蛋白2）。SOX2与上述基因的反向调节在来自不同解剖部位的18个独立HNSCC细胞系中得到验证。通过持续或条件性基因沉默证实了SOX2对细胞迁移和侵袭的抑制作用，并且在波形蛋白下调部分逆转SOX2沉默后，HNSCC细胞的运动性加速。在一项回顾性研究中，通过免疫组织化学染色在包含两个独立HNSCC患者队列原发性肿瘤标本的组织微阵列上确定了SOX2表达。在原发性肿瘤标本中分别发现19.3%和44.9%的标本SOX2表达较低。单变量分析表明，低SOX2蛋白水平与无进展生存期缩短（队列I：51个月对16个月；队列II：33个月对12个月）和总生存期缩短（队列I：150个月对37个月；队列II：33个月对16个月）之间存在统计学上的显著相关性。多变量Cox比例风险模型分析证实，低SOX2表达是HNSCC患者的独立预后标志物。我们得出结论，SOX2抑制HNSCC细胞中的肿瘤细胞运动，并且低SOX2表达可作为一种预后指标，用于识别治疗失败风险高的HNSCC患者。
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