title: Diversity of epidermal growth factor receptor-mediated activation of downstream molecules in human lung carcinomas.
abstract: The correlations among epidermal growth factor receptor (EGFR) gene amplification, gene mutation, overexpression/phosphorylation of EGFR protein and activation of its downstream molecules, signal transducers and activators of transcription 3 (Stat-3), Akt and extracellular signal-related protein kinase 1/2 (Erk1/2) were investigated in 28 cases of human lung carcinomas. In five cases of carcinomas with EGFR amplification, EGFR expression and phosphorylation levels were higher than other cases, and Stat-3 was activated in all five cases. Point mutations in the tyrosine kinase domain of EGFR were detected in five cases, one of which was also associated with gene amplification. In these five cases, both EGFR expression and phosphorylation were enhanced, and Akt was activated in four cases. In the remaining 19 cases, EGFR protein expression was upregulated in eight cases and phosphorylated in four cases, but neither EGFR nor phosphorylated-EGFR expression levels specifically correlated with activation of particular downstream molecules. In general, either Stat-3 or Akt, but not both, was activated reciprocally and complementarily to each other, as indicated by their phosphorylation. However, Erk1/2 was activated regardless of the status of Stat-3, Akt or EGFR proteins. The current data suggest that persistent Stat-3 activation may be a critical event downstream of EGFR that has been overexpressed by gene amplification. In contrast, tumor cells harboring the EGFR mutation may persistently activate a cascade via Akt. Finally, in the majority of cases that have no aberration of the EGFR, its downstream molecules function in reciprocal and/or complementary manner in the maintenance and/or progression of carcinomas. These overall results could provide novel insights into potential chemotherapeutic regimens for lung carcinomas, such as inhibitors of Stat-3, Akt and Erk1/2.
authors.affiliation: Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Shioto
authors.initials: S
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Igarashi
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Hanawa
authors.forename: Hirochika
authors.initials: H
authors.lastname: Matsubara
authors.forename: Akishi
authors.initials: A
authors.lastname: Ooi
authors.forename: Yoh
authors.initials: Y
authors.lastname: Dobashi
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3