Research on factors involved in prognosis of oral carcinoma.

口腔癌预后影响因素的研究.

• 批准号: 14370654
• 负责人: SHINDOH Masanobu
• 金额: $ 9.6万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370654/
• 关键词: Oral carcinoma; Immortalization; Invasion and metastasis; Protein-protein interaction; Gene therapy; ets oncogene; E1AF; MMP; TIMP; 口腔扁平上皮がん; 浸潤; 転移

EWS/ETS is a chimeric protein identified in most Ewing's sarcomas. We demonstrate that telomerase is a new target of EWS/ETS fusions TERT mRNA were up-regulated by EWS/Ets ; however, EWS/Ets function in an EBS-independent manner and EWS/ETS fusion proteins were shown to activate human telomerase activity as a transcriptional co-activator. The adenovirus E4orf6 is a viral oncoprotein and it has been shown to inhibit the apoptotic activities of p53 and p73. We demonstrate that the adenovirus E4ort6 protein directly inhibits apoptosis mediated by BNIP3 and Bik, which are BH3-only proteins of the Bcl-2 family and that the export signal of E4orf6 from the nucleus to the cytoplasm was shown to be important for the inhibition of apoptotic activity.We investigated the activation mechanism of MMP-2 in oral squamous cell carcinomas. CAT assay revealed that MT1-MMP promoter was activated by E1AF and Real-time RT-PCR study in 25 patients with tongue squamous cell carcinoma showed synergistical increasing expression of E1AF and MT1-MMP. These results indicate that E1AF positively regulates transcription from MT1-MMP genes, which plays an important role in invasion and metastasis of squamous cell carcinoma of the tongue by converting pro-MMP-2. into active-MMP-2 We investigated expression levels of VEGF-C mRNA in 48 cases of 0SCC by real-time RT-PCR. High levels of VEGF-C expression were identified 20 of 48 cases examined Expression level of VEGF-C was significantly associated with cancer cell metastasis in cervical lymph node. These results suggest that high expression of VEGF-C would be a predictive parameter for cervical lymph node metastasis of 0SCC, especially in the early stage tumors.

EWS/ETS 是在大多数尤文氏肉瘤中发现的嵌合蛋白。我们证明端粒酶是 EWS/ETS 融合的新靶标，EWS/Ets 上调 TERT mRNA；然而，EWS/Ets 以不依赖于 EBS 的方式发挥作用，并且 EWS/ETS 融合蛋白被证明可以作为转录共激活剂激活人端粒酶活性。腺病毒 E4orf6 是一种病毒癌蛋白，已被证明可以抑制 p53 和 p73 的凋亡活性。我们证明腺病毒E4ort6蛋白直接抑制BNIP3和Bik介导的细胞凋亡，BNIP3和Bik是Bcl-2家族中仅BH3的蛋白，并且E4orf6从细胞核到细胞质的输出信号对于抑制细胞凋亡活性很重要。我们研究了口腔鳞状细胞中MMP-2的激活机制 癌。 CAT检测显示MT1-MMP启动子被E1AF激活，并且对25例舌鳞状细胞癌患者的实时RT-PCR研究显示E1AF和MT1-MMP的表达协同增加。这些结果表明E1AF正向调节MT1-MMP基因的转录，通过转化pro-MMP-2在舌鳞状细胞癌的侵袭和转移中发挥重要作用。转化为活性-MMP-2 我们通过实时RT-PCR研究了48例0SCC中VEGF-C mRNA的表达水平。 48例检查中发现20例VEGF-C高表达。VEGF-C的表达水平与颈部淋巴结癌细胞转移显着相关。这些结果表明，VEGF-C 的高表达可能是 0SCC 颈部淋巴结转移的预测参数，尤其是在早期肿瘤中。

项目成果

Aoyagi M, Higashino F, Kobayashi M, Shindoh M, et al.: "Nuclear export of the adenovirus E4orf6 protein is necessary for its ability to antagonize the apoptotic activity of the BH3-only proteins"Oncogene. 22. 6919-6927 (2003)

Aoyagi M、Higashino F、Kobayashi M、Shindoh M 等人：“腺病毒 E4orf6 蛋白的核输出对于其拮抗 BH3-only 蛋白的凋亡活性的能力是必需的”癌基因。

Takahashi A, Higashino F, Kobayashi M, Shindoh M et al.: "EWS/ETS fusions activate telomerase in Ewing's tumors"Cancer Res. 63. 8338-8344 (2003)

Takahashi A、Higashino F、Kobayashi M、Shindoh M 等人：“EWS/ETS 融合激活尤因肿瘤中的端粒酶”Cancer Res。

Takahashi A, Higashino F, Kobayashi M, Shindoh M, et al.: "EWS/ETS fusions activate telomerase in Ewing's tumors."Cancer Res. 63. 8338-8344 (2003)

Takahashi A、Higashino F、Kobayashi M、Shindoh M 等人：“EWS/ETS 融合激活尤因肿瘤中的端粒酶。”癌症研究。

泉山ゆり, 進藤正信, 大廣洋一, 東野史裕, 向後隆男, 戸塚靖則: "舌扁平上皮がんにおけるE1AFによるMT1-MMPの発現亢進と悪性形質の関連"北海道歯誌. 24. 142-150 (2003)

Yuri Izumiyama、Masanobu Shindo、Yoichi Ohhiro、Fumihiro Higashino、Takao Kogo、Yasunori Totsuka：“E1AF 增加的 MT1-MMP 表达与舌鳞状细胞癌恶性特征之间的关系”北海道牙科杂志 24. 142-150（2003）。

Chen J, Shindo M, Higashino F, Kobayashi M, et al.: "Dominant-negative hypoxia-inducible factor-1a reduces tumorigenisity of Pancreatic cancer cells through suppression of glucose metabolism."Am J Pathol. 162. 1282-1291 (2003)

Chen J、Shindo M、Higashino F、Kobayashi M 等人：“显性负性缺氧诱导因子 1a 通过抑制葡萄糖代谢来降低胰腺癌细胞的致瘤性。”Am J Pathol。