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

基于口腔癌干细胞和肿瘤微环境的细胞和生物学特征的基因靶向治疗的开发。

• 批准号: 20249079
• 负责人: TOTSUKA Yasunori
• 金额: $ 19.47万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-20249079/
• 关键词: 口腔癌; 癌の微小環境; 癌幹細胞; 上皮間葉移行; 口腔がん; がん幹細胞; がんの微小環境; がん微小環境; EMT; cancer stem cell; cancer stem sell; ニッチ

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

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

项目成果

RANKL upregulaters integrin α2expression and cell adhesion in oral cancer cells

RANKL上调口腔癌细胞中整合素α2的表达和细胞粘附

• 发表时间: 2011
• 作者: Ohba Y;Yamada T;Fujioka Y;KaibaraT;Totsuka Y;Shindoh M;Tsuda M
• 通讯作者: Tsuda M

転移能の異なる腫瘍から分離された腫瘍血管内皮細胞の比較検討

不同转移潜能肿瘤分离肿瘤血管内皮细胞的比较研究

• 发表时间: 2011
• 作者: 大賀則孝;石川修平;樋田泰浩;秋山廣輔;間石奈湖;近藤美弥子;川本泰輔;進藤正信;樋田京子
• 通讯作者: 樋田京子

RNA 結合タンパクHuR の発現を介した口腔がん細胞の浸潤能の亢進

通过RNA结合蛋白HuR的表达增强口腔癌细胞的侵袭能力

• 发表时间: 2011
• 作者: Iwase M;Nakatani T;Saito F;et al;前田健康;黒嶋雄志;格口渉;今待賢治;黒嶋雄志;格口渉;格口 渉
• 通讯作者: 格口 渉

HuR keeps on angiogenic switch on by stabilizing mRNA of VEGF and COX-2 in tumor endothelium.

HuR 通过稳定肿瘤内皮细胞中 VEGF 和 COX-2 的 mRNA 来保持血管生成的开启。

• 发表时间: 2011
• 期刊: Br J Cancer 104
• 作者: Kurosu T;Ohga N;Hida Y;Maishi N;Akiyama K;Kakuguchi W;Kuroshima T;Kondo M;Akino T;Totsuka Y;Shindoh M;Higashino F;Hida K
• 通讯作者: Hida K

口腔癌周囲環境により誘導される癌細胞接着能を制御する因子の機能解析

口腔癌周围环境诱导的癌细胞粘附控制因素的功能分析

• 发表时间: 2009
• 作者: 山田珠樹;進藤正信;戸塚靖則
• 通讯作者: 戸塚靖則