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

本研究的目的是发现ERK 2信号转导通路在口腔癌中的异常，并阐明这些信号在口腔癌发生中的作用。结果表明：（1）通过CGH分析，我们发现3个口腔鳞癌细胞系都有1.7Mb的共同扩增区域al chr.22q11.2。12，其中ERK 2被映射。2种细胞系均检测到ERK mRNA的过表达。有趣的是，在15个细胞系中，ERK过表达、ras突变和EGFR扩增没有重叠，而只有一个细胞系，这与这些蛋白质在从EGF到ERK的相同途径中起作用一致。(2)EGF向ERK或AKT的异常生长信号转导分别在2/10（20%）和3/5（60%）细胞系中发现，提示异常信号转导是常见的。(3)5分离了首次显示与ERK 2相互作用的蛋白质的基因，包括一个新基因。已知的蛋白质之一，Naf 1（HIV Nef associated factor）被发现定位于细胞质中，被ERK磷酸化，并抑制ERK向细胞核的移位。进一步的Naf 1磷酸化在与HIV Nef结合中是重要的。(4)大肠癌组织中ERK和H-ras的过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调激活，但在邻近的正常组织中没有观察到，这表明该途径在体内的重要性。(5)MEK抑制剂（U 0126）比EGFR高表达者更有效地抑制ERK高表达者的生长。

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.