Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas.
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.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Sizhi Paul
SP
Gao
Kevin G
KG
Mark
Kenneth
K
Leslie
William
W
Pao
Noriko
N
Motoi
William L
WL
Gerald
William D
WD
Travis
William
W
Bornmann
Darren
D
Veach
Bayard
B
Clarkson
Jacqueline F
JF
Bromberg
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D053612:Janus Kinases; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
D050822:Cytokine Receptor gp130; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D015850:Interleukin-6; D053612:Janus Kinases; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C494199:IL6ST protein, human; C494086:STAT3 protein, human; C512478:EGFR protein, human