| 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. |
| Keywords: |
immunohistochemistry; signal transduction; protein expression; protein phosphorylation; gene mutation; mutation; adenocarcinoma; animals; mice; cell survival; cell cycle progression; stat3 protein; reverse transcription polymerase chain reaction; enzyme inhibition; cell growth; lung neoplasms; rna, small interfering; rna interference; genetic transcription; receptor, epidermal growth factor; transcription, genetic; cancer cell culture; enzyme activation; cell line, tumor; protein tyrosine kinase; phosphorylation; carcinogenesis; gene expression regulation, neoplastic; lung adenocarcinoma; immunoglobulin g; mice, nude; enzyme inhibitors; western blotting; interleukin 6; interleukin-6; cytokine receptor gp130; stat3 transcription factor; upregulation; neoplasm transplantation; tissue microarray; cytokine release; tubulin; epidermal growth factor receptor kinase; janus kinases
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