Microarray gene expression analysis for development prognostic factors for oral squamous cell carcinoma

我们对500个癌相关基因进行基因表达谱分析，建立口腔鳞状细胞癌（OSCC）的诊断系统。为了消除肿瘤或测量差异引起的偏差，我们在所有OSCC病例中选择了增加和减少的基因。维甲酸受体γ、角蛋白家族基因及桥粒组分部分分子对正常口腔黏膜的基因表达比例不变。细胞外基质（ECM）降解酶如MMPs、uPA有规律地增加；ecm如Tenascin C和Fibronectin 1；生长因子诱导的趋化因子或转录因子，如MIG、IP-10、STAT1、BIGH3。聚类分析结果表明，这些基因之间的基因表达模式相似。癌相关基因在OSCC组织中的表达谱似乎反映了上皮特征的丧失，激活的组织破坏和癌结构的形成，以及信号传递系统中的紊乱阶段。与未发生淋巴结转移的组相比，MMP-1、uPA、CD44、Integrin α 3和Paxillin的表达显著增加，CD9和IGFBP2的mRNA水平显著降低。为了证实基因表达分析的结果，我们对被认为与oscc转移行为相关的基因进行了免疫组化。MMP-1、MMP-3和uPA在炎症细胞、内皮细胞和ECM结构中广泛共定位，但在肿瘤细胞中未发现定位。在与周围胶原纤维和毛细血管结构降解有关的嗜酸性圆形单核细胞上观察到这些基因产物的显著染色。这些组织学结果证实了基因表达分析中预期的ecm降解酶的共调控表达和协同功能。MMP-1 mRNA水平与淋巴结转移有显著相关性（U=0, p=0.001）。MMP-1可能是OSCC淋巴结转移的独立、准确的预后因素。通过识别共同调控和特征的共表达基因簇，通过将基因表达数据与广泛的临床数据进行比较，然后通过对重要基因子集使用免疫组织化学，可以获得具有不同背景的手术标本，以提取有价值的基因，而无需事先解剖肿瘤组织的组成部分。少

We performed gene expression profiling with 500 of the cancer related genes to develop diagnostic system of oral squamous cell carcinoma (OSCC). To eliminate biases caused by difference between tumors or measurements, we selected increased arid decreased genes in all OSCC cases. Unchangeable decreases were observed in gene expression ratio of Retinoic acid receptor gamma, Keratin family genes, and some molecules of desmosomes components against normal oral mucosa. Regular increases were observed in extracellular matrix (ECM)-degrading enzymes such as MMPs, uPA; ECMs such as Tenascin C and Fibronectin 1; Chemokines or transcription factors, such as MIG, IP-10, STAT1, BIGH3, that were induced by growth factors. Results of a cluster analysis indicated the similarity in gene expression patterns between those genes. The expression profile of cancer related genes in OSCC tissues seemed to reflect loss of epithelial characteristics, activated tissue destruction and formation of the cancer str … More oma, and disturbed phases in signal transudation systems. Comparison between groups with or without the involvement of lymphnode metastasis revealed significantly increased expression of MMP-1, uPA, CD44, Integrin alpha 3 and Paxillin as well as decreased mRNA levels of CD9 and IGFBP2. To confirm the results of gene expression analysis, we preformed immunohistochemistry for the genes that were suggested to associate with metastatic behavior of OSCCs. MMP-1, MMP-3 and uPA were co-localized extensively in inflammatory cells, endotherial cells and ECM structure, but no localization was indicated in tumor cells. Prominent staining of those gene products were observed on eosinophilic, round shaped mononuclear cells that were associated with degrading of surrounding collagen fibers and capillary structures. These histological findings corroborate the co-regulated expression and cooperative function of those ECM-degrading enzymes that were expected in gene expression analyzes. Striking correlation was demonstrated between MMP-1 mRNA revel and lymph node metastasis (U=0, p=0.001). MMP-1 could be an independent and accurate prognostic factor of lymph node metastasis for OSCC. By identifying commonly regulated and characteristic clusters of coexpressed genes, and by compeering the gene expression data with the extensive clinical data, and then by using immunohistochemistry against a subset of significant genes, surgical specimens with diverse backgrounds can be made accessible to extract valuable genes without prior dissection into components of tumor tissue. Less