| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
We constructed tissue microarray (TMA) that consisted of 5 cases of bronchiolo-alveolar carcinoma (BAC), 23 cases of mixed type adenocarcinoma with BAC component, and 20 cases of pure adenocarcinomas. Using this TMA, we investigated the expressions of (A) cell cycle regulators (p16, p21, p27, cyclin D1, and cyclin E), (B) tumor suppressors (p53, E-cadherin, PTEN, TSLC1, Smad3, and Smad4), and the results were compared between BAC, mixed adenocarcinoma, and pure adenocarcinomas. We found that (1) expressions of p16, p27, PTEN, E-cadherin, and TSLC1 were significantly decreased in pure adenocarcinomas compared to the other two groups, (2) expression of cyclin D1 was more frequently elevated in BAC and mixed adenocarcinomas than in pure adenocarcinomas, and (3) expression of Smad4 was maintained in BAC, but decreased in mixed and pure adenocarcinoms.
We microdissected cancer cells from peripheral and central areas of mixed adenocarcinomas (n=7 and 5, respectively), and performed comprehensive gene expression analysis. Normal lung tissues (n=3) were also analyzed for comparison. Gene enrichment analysis demonstrated that gene sets induced by epithelial-mesenchymal transition (EMT) and hypoxia were overexpressed in the central vs. peripheral areas of mixed adenocarcinomas.
To investigate the influence of hypoxia on cellular properties of cancer cells, we subjected lung adenocarcinoma cell line A549 to hypoxia, and gene expression profiles were analyzed by oligonuleotide arrays. The results showed that among the genes induced by hypoxia were those related to cell cycle, DNA repair, extracellular matrix synthesis, and angiogenesis. We also noted upregulation of EGFR and CXCR4, which may explain the motile phenotype that was induced by hypoxia. In fact, inhibition of EGFR completely abrogated the increase of motility caused by hypoxic treatment.
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