Molecular analysis of bone invasion mechanism in oral carcinoma.

我们利用微阵列分析研究了口腔鳞状细胞癌（OSCC）的骨侵袭。对人类OSCC标本进行的芯片分析显示，许多标本过表达PTHrP mRNA，但少数过表达IL-6 mRNA。免疫组化分析显示，IL-6不仅在癌细胞中表达，也在肿瘤-骨界面的成纤维细胞和破骨细胞中表达。将HSC3细胞移植到胸腺小鼠的顶骨骨膜区，其组织学和RANKL和IL-6的表达谱与骨侵袭性人OSCC标本相似。这些结果表明，OSCC不仅通过产生IL-6和PTHrP，而且通过刺激基质细胞合成IL-6，为破骨细胞的形成提供了合适的微环境。随着FADD基因在OSCC微阵列分析中的表达上调，以及11q13.3基因在口腔鳞状细胞细胞系的比较基因组杂交（Comparative Genomic Hybridization， CGH）数据库中的扩增，我们对FADD基因的基因组扩增和表达水平进行了研究。在44.3%的病例中观察到FADD的DNA扩增，并与SCCs的组织病理分化等级显著相关。FADD表达水平较匹配的相邻上皮明显升高。FADD阳性表达与SCCs淋巴结转移及5年疾病特异性生存率显著相关。因此，表达FADD的SCC细胞可能更容易发生转移并降低生存率。如前所述，FADD在细胞凋亡和增殖过程中都是细胞表面受体传递信号的必要条件。因此，过去许多关于FADD的研究都局限于其在细胞质内的功能；然而，最近的研究表明，FADD位于细胞核和细胞质中。在本研究中，FADD在口腔SCCs中的免疫反应模式清楚地显示出主要的核定位模式。由于FADD在细胞核中的功能尚未明确，目前正在研究FADD在细胞核中的定位。少

We investigated the bone invasion in oral squamous cell carcinoma (OSCC) using microarray analyses. Microarray analyses performed on human OSCC specimens revealed that many of the specimens overexpressed PTHrP mRNA, but a few overexpressed IL-6 mRNA. Immunohistochemical analysis revealed that IL-6 was expressed not only in cancer cells but also in fibroblasts and osteoclasts at the tumor-bone interface. Xenografts of HSC3 cells onto the periosteal region of the parietal bone in athymic mice presented histology and expression profiles of RANKL and IL-6 similar to those observed in bone-invasive human OSCC specimens. These results indicate that OSCC provides a suitable microenvironment for osteoclast formation not only by producing IL-6 and PTHrP but also by stimulating stromal cells to synthesize IL-6. As the up-regulation of FADD expression in OSCC microarray analyses and the amplification of 11q13.3 in oral SCC cell lines on the Comparative Genomic Hybridization (CGH) database have be … More come available, genomic amplifications and expression levels of FADD were investigated. The DNA amplifications of FADD were observed in 44.3% cases and were significantly correlated with the histopathological differentiation grade of SCCs. FADD expression levels compared with the matched adjacent epithelium increased significantly. Additionally, the positive expressions of FADD were significantly correlated with lymph node metastasis of SCCs and the 5-year diseasespecific survival rates. Thus, SCC cells with the expression of FADD are possibly more likely to become metastatic and to worsen survival rates. As previously mentioned, FADD is imperative for transmitting signals from cell surface receptors in both cell apoptosis and proliferation. Therefore, many past studies investigating FADD were confined to its function within the cytoplasm; however, recent studies have demonstrated that FADD is located in both the nucleus and the cytoplasm. In this study, the immunoreactivity pattern of FADD in oral SCCs clearly demonstrated a predominant nuclear localization pattern. As the function of FADD in the nucleus has not been clarified, a meaningful localization of FADD in the nucleus is currently under investigation. Less