Study of mechanisms of the highly metastatic feature using human lung cancer sublines with highly metastatic property established

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A better understanding of the key factors of metastasis may be useful for designing new molecular targets of therapy. In order to identify these factors, we established two highly metastatic human lung adenocarcinoma cell lines in an experimental metastasis model by repeated inoculation in nude mice and compared the expression profiles of two subpopulations of an adenocarcinoma cell line with high metastatic potential, with the parent cell line, using cDNA arrays ; microarray and macroarray. The expression of 5 genes was found to be significantly enhanced or reduced in the highly metastatic subpopulations by microarray. The genomic structure of these genes will be detrmined. The expression of matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor-1 (PAI-1), carcinoembryonic antigen (CEA), Fas ligand and etc.were upregulated or downregulated in the highly metastatic subpopulations. The differential expression of these genes was confirmed by Northern blot analysis or reverse transcription-polymerase chain reaction (RT-PCR). Altered expression of these genes seems to promote the highly metastatic phenotype in these function. To determine whether the change in p16INK4 methylation status and the genomic status of hBUB1, hMAD2, Insulin-like growth factor 2 receptor genes occurs during metastasis of primary lung cancers, we also analyzed the primary and metastatic tumor tissues and normal lung samples from 30 cases of advanced lung cancer with distant metastasis. The results of this study indicate that tumor cells in which the p16INK4 gene has been inactivated by hypermethylation of the promoter region could have an advantage in metastasis in non-small cell lung cancers. The differential expression of the gene was not detected among subpopulations with high metastatic potential of the cell line and the parent line. The expression of the p16INK4 gene did not seem to be involved in the highly metastatic phenotype in this cell line.