Department of Surgery, Northwestern University Feinberg Medical School, Chicago, Illinois, USA.
Mol Cancer Res. 2010 Feb;8(2):145-58. doi: 10.1158/1541-7786.MCR-09-0045. Epub 2010 Feb 9.
Oral squamous cell carcinoma (OSCC) has 50% 5-year survival rate, highlighting our limited understanding of the molecular events that contribute to disease progression. Microarray analyses of primary oral tumors have identified urinary-type plasminogen activator (uPA) and its receptor (uPAR) as key genes associated with human OSCC progression. The uPAR functions as both a proteinase receptor and an integrin ligand, modifying proteolysis, migration, integrin signaling, and cellular transcription. In the current study, uPAR expression levels were modified in OSCC cells followed by analysis of tumor growth in an in vivo orthotopic xenograft model and by transcriptional profiling. Overexpression of uPAR resulted in more infiltrative and less differentiated tumors, with ill-defined borders, cytologic atypia, and enhanced vascularity. Analysis of serial sections of both murine experimental tumors and microarrayed human OSCC showed a statistically significant association between uPAR and alpha(3) integrin colocalization in areas exhibiting extracellular signal-regulated kinase phosphorylation, suggesting that uPAR/alpha(3) integrin interaction potentiates extracellular signal-regulated kinase signaling in vivo. This is supported by cDNA microarray analysis, which showed differential expression of 148 genes (113 upregulated and 35 downregulated). Validation of gene expression changes in human OSCC using immunohistochemistry and quantitative real-time PCR showed increased growth factors, proteinases/inhibitors, and matrix components in uPAR-overexpressing tumors. Together, these results support a model wherein increased uPAR expression promotes alpha(3)beta(1) integrin association, resulting in increased mitogen-activated protein kinase signaling and transcriptional activation, leading to the formation of more aggressive tongue tumors. This combined approach has efficacy to identify additional biomarkers and/or prognostic indicators associated with aggressive human OSCC.
口腔鳞状细胞癌 (OSCC) 的 5 年生存率为 50%，这突出表明我们对导致疾病进展的分子事件的了解有限。对原发性口腔肿瘤的微阵列分析已经确定尿激酶型纤溶酶原激活物 (uPA) 和其受体 (uPAR) 是与人类 OSCC 进展相关的关键基因。uPAR 作为蛋白水解酶受体和整合素配体发挥作用，改变蛋白水解、迁移、整合素信号和细胞转录。在本研究中，对 OSCC 细胞中的 uPAR 表达水平进行了修饰，然后在体内原位异种移植模型中分析肿瘤生长，并进行转录谱分析。uPAR 的过表达导致侵袭性更强、分化程度更低的肿瘤，边界不清晰，细胞异型性增加，血管生成增强。对小鼠实验性肿瘤的连续切片和微阵列分析的人类 OSCC 进行分析表明，uPAR 与在细胞外信号调节激酶磷酸化区域表现出共定位的 alpha(3) 整合素之间存在统计学显著关联，表明 uPAR/alpha(3) 整合素相互作用在体内增强细胞外信号调节激酶信号。这得到了 cDNA 微阵列分析的支持，该分析显示 148 个基因（113 个上调和 35 个下调）的差异表达。使用免疫组织化学和定量实时 PCR 对人类 OSCC 中的基因表达变化进行验证，显示 uPAR 过表达肿瘤中生长因子、蛋白水解酶/抑制剂和基质成分增加。总之，这些结果支持这样一种模型，即 uPAR 表达增加促进 alpha(3)beta(1) 整合素的关联，导致有丝分裂原激活的蛋白激酶信号和转录激活增加，导致更具侵袭性的舌肿瘤的形成。这种联合方法具有识别与侵袭性人类 OSCC 相关的其他生物标志物和/或预后指标的功效。
