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-间充质转化(EMT)在肿瘤的侵袭和转移中起着重要的作用。由于间质细胞具有为肿瘤提供营养和氧气的能力，因此研究口腔鳞状细胞上皮性癌细胞与间充质细胞的相互作用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，HUR参与稳定富含AU元素(ARE)的mRNA。我们证明了ARE mRNA是通过HUR通过与细胞转化有关的病毒致癌系统稳定的。口腔环境具有独特的特点，包括唾液腺等器官的独特之处。我们发现破骨细胞诱导剂RANKL在口腔环境中有较高的表达。此外，当口腔癌细胞移植到裸鼠口腔区域时，癌细胞故意增殖，并观察到EMT。肿瘤微环境与癌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，并对肿瘤内皮细胞的生物学特性进行了研究。其结果是，通过抑制COX-2抑制肿瘤血管生成，该因子也是已知的诱导炎症的因素，并且通过由血管内皮生长因子信号引起的mdr1上调糖蛋白而获得对化疗药物的抵抗。

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