Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas
Sizhi Paul Gao, … , Bayard Clarkson, Jacqueline F. Bromberg
Sizhi Paul Gao, … , Bayard Clarkson, Jacqueline F. Bromberg
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):3846-3856. https://doi.org/10.1172/JCI31871.
View: Text | PDF
Research Article

Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas

  • Text
  • PDF
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.

Authors

Sizhi Paul Gao, Kevin G. Mark, Kenneth Leslie, William Pao, Noriko Motoi, William L. Gerald, William D. Travis, William Bornmann, Darren Veach, Bayard Clarkson, Jacqueline F. Bromberg

×

Figure 9

pSTAT3 levels correlate positively with IL-6 expression in primary lung adenocarcinomas.

Options: View larger image (or click on image) Download as PowerPoint
pSTAT3 levels correlate positively with IL-6 expression in primary lung ...
Immunohistochemical analysis of TMAs of primary lung adenocarcinomas (92 tumor specimens) for IL-6 were scored as 0 (5/92), +1 (26/92), +2 (54/92), or +3 (7/92). Examples of selected tumor specimens from sequential sections of the same TMAs stained for IL-6 (top, left to right, 0, +1, +3, and +3) and pSTAT3 (bottom, left to right, 0, 0, +3, and +3) are shown. A positive correlation was observed in specimens that were pSTAT3 positive (+1, +2, or +3) and expressing moderate-to-high (+2 to +3) levels of IL-6 as determined by analysis with the Fisher exact test (P < 0.001).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts