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

我们对500个口腔鳞状细胞癌相关基因进行了基因表达谱分析，建立了口腔鳞状细胞癌诊断系统。为了消除肿瘤或测量结果之间的差异造成的偏差，我们选择了所有口腔鳞癌病例中增加和减少的基因。正常口腔黏膜组织中视黄酸受体γ、角蛋白家族基因和桥粒部分分子的基因表达比无明显变化。细胞外基质(ECM)降解酶如MMPs、uPA；ECM如Tenascin C和FN-1；由生长因子诱导的趋化因子或转录因子如MIG、IP-10、STAT1、BIGH3呈规律性增加。聚类分析的结果表明，这些基因之间的基因表达模式是相似的。口腔鳞癌组织中癌相关基因的表达谱似乎反映了上皮细胞特性的丧失、激活的组织破坏和癌链…的形成。更多的OMA，以及信号传输系统中的干扰相位。有无淋巴结转移组间比较，MMP1、uPA、CD44、整合素α3、Paxlin表达显著增加，CD9、IGFBP2mRNA表达显著降低。为了证实基因表达分析的结果，我们对被认为与口腔鳞癌转移行为相关的基因进行了免疫组织化学研究。MMP1、MMP3和uPA广泛分布于炎症细胞、内皮细胞和细胞外基质结构中，但在肿瘤细胞中未见定位。这些基因产物在嗜酸性圆形单核细胞上有明显的染色，与周围胶原纤维和毛细血管结构的降解有关。这些组织学发现证实了基因表达分析中预期的那些ECM降解酶的共同调节表达和合作功能。MMP1mRNA的表达与淋巴结转移显著相关(U=0.001，p=0.00)。MMP1可作为预测口腔鳞癌淋巴结转移的独立、准确的预后因子。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大量的临床数据进行比较，然后通过针对重要基因的子集进行免疫组织化学，可以使具有不同背景的手术标本能够提取有价值的基因，而不需要事先解剖肿瘤组织的组成部分。较少

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