| Co-Investigator(Kenkyū-buntansha) |
DOBASHI Yoh Jichi Medical University, Omiya Medical Center, Associate professor, 大宮医療センター, 助教授 (90231456)
西川 圭一 山梨大学, 大学院・医学工学総合研究部, 講師 (90252048)
飯野 弥 山梨大学, 医学部付属病院, 講師 (00252031)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
The correlations among <I>EGFR</I> amplification, mutation, and activation of EGFR, Stat-3, Akt and Erk1/2 were investigated in 28 cases of human lung carcinomas. In 5 cases with <I>EGFR</I> amplification, EGFR expression and phosphorylation levels were higher, and Stat-3 was activated. Point mutations were detected in 5 cases, in which EGFR expression and phosphorylation were enhanced, and Akt was activated in 4 cases. In the remaining 19 cases, EGFR protein expression was upregulated and phosphorylated in 4 cases, but neither EGFR expression nor activation correlated with activation of particular downstream molecules. However, either Stat-3 or Akt, but not both, was activated reciprocally and complementarily. These results suggest that Stat-3 activation is a critical event downstream of overexpressed EGFR by gene amplifica tion. In contrast, tumor cells with <I>EGFR</I> mutation may persistently activate Akt-cascade. Finally, in the majority of cases without <I>EGFR</I> aberration, i
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ts downstream molecules function in reciprocal and complementary manner. The current data could provide novel insights into potential chemotherapeutic regimens for lung carcinomas, including inhibitors of Stat-3, Akt Correlations among EGFR aberrations and activation of proteins were investigated in 29 cases of bone/soft tissue tumors (BSTTs). By immunohistochemistry, EGFR overexpression was found in 22.6% of sarcomas. By immunoblotting, among sarcoma cases showing upregulation of EGFR, 47.4% showed EGFR activation. In 2 cases of MFH, with high level of EGFR copies, EGFR expression and phosphorylation levels were significantly higher, and Stat-3 was activated. Missense mutations were detected in 3 cases, and activation of EGFR and Stat-3 were found in 2 cases. In other cases, upregulation of the EGFR was found in both sarcomas and benign lesions, but activation was found only in sarcomas. Among the 3 downstream cascades, Akt pathway was most frequently activated than those of Stat-3 or Erkl/2,. and Stat-3 was activated in tumors exhibiting epithelial nature. These results suggest that Stat-3 activation may be a critical event downstream of overexpressed EGFR by high level EGFR copies. In contrast, EGFR mutation may not necessarily activate specific downstream cascades. These results suggest that EGFR-mediated cascades are candidates for molecular targeting therapy in defined subsets of BSTTs. Less
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