权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Alterations of ERK gene and the signal transduction pathway in oral squamous cell carcinoma and the roles in the genesis of the cancer

口腔鳞癌中ERK基因及信号转导通路的改变及其在癌症发生中的作用

基本信息

批准号：
12470381
负责人：
TSUCHIDA Nobuo
金额：
$ 9.34万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

This grant research was aimed to find abnormalities of signal transduction pathway of ERK2 in oral cancers, and to elucidate roles of the signals in the genesis of this cancer. Results obtained were(1) by CGH analyzes we found that 3 oral squamous cell carcinoma(OSCC) cell lines had the 1.7 Mb commonly amplified region al chr. 22 q11.2.-12, where ERK2 is mapped. Overexpression of ERK mRNA was detected in the 2 cell lines. Interestingly, there was no overlapping in ERK overexpression , ras mutation and EGFR amplification in 15 but one cell line, being consistent with that these proteins work in the same pathway from EGF to ERK.(2) The aberrant growth signal transduction from EGF to ERK or from EGF to AKT was found in 2/10(20%) or 3/5(60%), respectively, cell lines, suggesting the frequent abnormal signal transduction.(3) 5 Genes for proteins which were first shown to interact with ERK2 were isolated, including one new gene. One of the known protein, Naf1(HIV Nef associated factor) was found to be localized in the cytoplasm, phosphorylated by ERK, and suppressed the translocation of ERK to the nuclei. Further Naf1 phosphorylation was important in binding to HIV Nef.(4) in colorectal cancer tissues overexpression of ERK or H-ras was.closely related to cases with distant metastasis. Further coordinate activation of signal proteins from EGFR to ERK were observed in cancer tissues but not in the adjacent normal tissue, suggesting the importance of this pathway in vivo.(5) an MEK inhibitor (U0126) suppressed the growth of high ERK-expressor more efficiently than high EGFR-expressor.

本研究旨在发现ERK2信号转导通路在口腔癌中的异常，并阐明其在口腔癌发生中的作用。结果表明：(1)CGH分析发现，3株口腔鳞状细胞癌(OSCC)细胞系均有1.7Mb共同扩增区al-Chr。22 q11.2.-12，其中定位了ERK2。ERK基因在两种细胞系中均有高表达。有趣的是，在15个细胞株中，ERK的过度表达、ras突变和EGFR扩增没有重叠，这与这些蛋白从EGF到ERK的作用途径是一致的。(2)分别有2/10(20%)和3/5(60%)的细胞株发现EGF到ERK和EGF到AKT的异常生长信号转导，表明信号转导频繁。(3)首次发现与ERK2相互作用的蛋白的5个基因，其中包括1个新基因。已知的蛋白之一，Naf1(HIV Nef相关因子)被发现定位于细胞质中，被ERK磷酸化，并抑制ERK到细胞核的转位。在结直肠癌组织中，ERK或H-ras的过度表达与远处转移密切相关。在癌组织中观察到从EGFR到ERK的信号蛋白的进一步协同激活，而在邻近的正常组织中则没有，这表明这一途径在体内的重要性。(5)MEK抑制剂(U0126)比EGFR高表达基因更有效地抑制ERK高表达基因的生长。