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- Title
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas.
- Authors
Sizhi Paul Gao; Mark, Kevin G.; Leslie, Kenneth; Pao, William; Motoi, Noriko; Gerald, William L.; Travis, William D.; Bornmann, William; Veach, Darren; Clarkson, Bayard; Bromberg, Jacqueline F.
- Abstract
Persistently activated or tyrosine-phosphorylated STAT3 (pSTAT3) is found in 50% of lung adenocarcinomas. pSTAT3 is found in primary adenocarcinomas and cell lines harboring somatic-activating mutations in the tyrosine kinase domain of EGFR. Treatment of cell lines with either an EGFR inhibitor or an src kinase inhibitor had no effect on pSTAT3 levels, whereas a pan-JAK inhibitor (P6) blocked activation of STAT3 and inhibited tumorigenesis. Cell lines expressing these persistently activated mutant EGFRs also produced high IL-6 levels, and blockade of the IL-6/gp130/JAK pathway led to a decrease in pSTAT3 levels. In addition, reduction of IL-6 levels by RNA interference led to a decrease in tumorigenesis. Introduction of persistently activated EGFR into immortalized breast epithelial cells led to tumorigenesis, IL-6 expression, and STAT3 activation, all of which could be inhibited with P6 or gp130 blockade. Furthermore, inhibition of EGFR activity in multiple cell lines partially blocked transcription of IL-6 and concurrently decreased production and release of IL-6. Finally, immunohistochemical analysis revealed a positive correlation between pSTAT3 and IL-6 positivity in primary lung adenocarcinomas. Therefore, mutant EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment.
- Subjects
GENETIC mutation; LUNGS; CANCER; PROTEIN-tyrosine phosphatase; CELL lines; SOMATIC cells; CARCINOGENESIS
- Publication
Journal of Clinical Investigation, 2007, Vol 117, Issue 12, p3846
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI31871