Exploitation of gene-targeting therapy based on the cellular and biological features of oral-carcinoma stem cell and tumor microenvironment.

我们已经证明，存在于癌间质中的肿瘤内皮细胞具有与正常内皮细胞不同的基因背景。上皮-间质转化（EMT）在肿瘤侵袭和转移中的作用日益明显。由于间质细胞具有向肿瘤提供营养和氧气的能力，因此，期望对上皮性质的口腔鳞状细胞癌细胞和间质细胞的相互作用的研究将有助于建立有效的治疗方法。HuR蛋白通常存在于细胞核中，并参与稳定富含AU的元件（ARE）mRNA。我们发现ARE mRNA通过HuR通过涉及细胞转化的病毒致癌系统而稳定。口腔环境具有独特的特征，包括不同的器官，如唾液腺。我们发现RANKL，破骨细胞诱导剂，在口腔环境中表达更高。此外，当口腔癌细胞植入裸鼠口腔区域时，癌细胞有意地增殖，并且观察到EMT。肿瘤微环境与肿瘤细胞增殖和侵袭转移密切相关。我们分离了肿瘤间质中的内皮细胞，并研究了肿瘤内皮细胞的生物学特性。结果，通过抑制考克斯-2（也已知为诱导炎症因子）来抑制肿瘤血管生成，并且通过VEGF信号传导引起MDR 1上调来获得对化疗抗性

We have shown that the tumor endothelial cells which exist in cancer stroma have a different gene background from normal endothelial cells. It has been becoming clear that epithelial-mesenchymal transition (EMT) plays an important role in tumor invasion and metastasis. It is expected that the investigation on the interaction of the oral squamous cell carcinoma cell in epithelium nature and a mesenchymal cell will contribute to the establishment of effective therapeutic method because stromal cells have the ability to supply nutrition and oxygen to a tumor. HuR protein usually exists in the nucleus, and HuR is participating to stabilize AU-rich element (ARE) mRNA. We showed that ARE mRNA is stabilized through HuR by a viral carcinogenesis system that concerns cell transformation. Oral environment has a unique features including distinct organs such as salivary glands. We identified that RANKL, an osteoclast inducer, expression was higher in oral environment. Furthermore, when oral cancer cells were implanted in oral region of nude mice, cancer cells proliferated intentionally, and EMT was observed. Tumor microenvironment is deeply correlated with cancer cell proliferation and invasion/metastasis. We have isolated endothelial cells in tumor stroma, and investigated the biological feature of tumor endothelial cells. As a result, tumor angiogenesis was suppressed by inhibiting Cox-2 known also for the factor inducing inflammation, and the resistance for chemothrapy was acquired by MDR1 upregulatin caused by VEGF signaling