Urinary-type plasminogen activator receptor/alpha 3 beta 1 integrin signaling, altered gene expression, and oral tumor progression.
Urinary-type plasminogen activator receptor/alpha 3 beta 1 integrin signaling, altered gene expression, and oral tumor progression.
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DOI：
10.1158/1541-7786.mcr-09-0045
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Stack MS
中科院分区：
文献类型：
--
作者：
Ghosh S;Koblinski J;Johnson J;Liu Y;Ericsson A;Davis JW;Shi Z;Ravosa MJ;Crawford S;Frazier S;Stack MS
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理解有限。原发性口腔肿瘤的微阵列分析已确定尿型纤溶酶原激活物（uPA）及其受体（uPAR）作为与人类口腔鳞癌进展相关的关键基因。uPAR作为蛋白酶受体和整联蛋白配体发挥作用，调节蛋白水解、迁移、整联蛋白信号传导和细胞转录。在目前的研究中，uPAR的表达水平在口腔鳞癌细胞中进行了修改，然后在体内原位异种移植模型中进行肿瘤生长分析和转录谱分析。uPAR的过表达导致更多的浸润性和低分化的肿瘤，边界不清，细胞学异常，并增强血管。对小鼠实验性肿瘤和微阵列人OSCC连续切片的分析表明，在ERK磷酸化区域，uPAR和α3整合素共定位之间存在统计学显著相关性，表明uPAR/α3整合素相互作用增强体内ERK信号传导。这得到了cDNA微阵列分析的支持，该分析显示了148个基因的差异表达（113个上调，35个下调）。使用免疫组化和定量实时PCR验证人OSCC中的基因表达变化，显示在uPAR过表达肿瘤中生长因子、蛋白酶/抑制剂和基质成分增加。这些结果共同支持了一种模型，其中增加的uPAR表达促进α3β1整联蛋白缔合，导致增加的MAPK信号传导和转录激活，导致形成更具侵袭性的舌肿瘤。这种组合方法具有鉴定与侵袭性人OSCC相关的其他生物标志物和/或预后指标的功效。
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 both as 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 demonstrated a statistically significant association between uPAR and α3 integrin co-localization in areas exhibiting ERK phosphorylation, suggesting that uPAR/α3 integrin interaction potentiates ERK signaling in vivo. This is supported by cDNA microarray analysis which showed differential expression of 148 genes (113 up, 35 down). Validation of gene expression changes in human OSCC using immunohistochemistry and quantitative real-time PCR showed increased growth factors, proteinases/inhibitor and matrix components in uPAR-overexpressing tumors. Together these results support a model wherein increased uPAR expression promotes α3β1 integrin association, resulting in increased MAPK 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.