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

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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.