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1 National Defense Medical Center, Graduate Institute of Life Sciences, Taipei, Taiwan; Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan
2 Section of Thoracic Oncology, Chest Department, Taipei Veterans General Hospital and Department of Medicine, National Yang-Ming University, Taipei, Taiwan
3 Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan
4 Academia Sinica, Nankang, Institute of Molecular Biology, Taipei, Taiwan
5 National Defense Medical Center, Graduate Institute of Life Sciences, Taipei, Taiwan
* To whom correspondence should be addressed. E-mail: chiying{at}nhri.org.tw.
Interleukin-6 (IL-6) has been identified as an important growth regulator of lung cancer cells. Elevation of serum levels of IL-6 has been found in a subpopulation of lung cancer patients, but rarely in patients with benign lung diseases. Approximately 15% of non-small cell lung cancer (NSCLC) tumors exhibit neuroendocrine (NE) properties (NSCLC-NE), and have been suggested to have the biological characteristics similar to small cell lung cancer (SCLC) with early metastasis and initial responsiveness to chemotherapy. We recently showed that IL-6 promotes cell proliferation and down-regulates the expression of neuron specific enolase (NSE, one of the major NE markers) in NSCLC-NE cells. In this study, we show that IL-6 stimulates a transient increase of tyrosine phosphorylation of STAT3 in a dose-dependent fashion. Inhibition of STAT3 signaling pathway by either AG490 (JAK2 specific inhibitor) or overexpression of STAT3Y705F (a dominant negative STAT3) reverses NSE expression in IL-6 treated NSCLC-NE cells. In addition, IL-6 induces phosphorylation and activation of p38 MAPK. SB203580, a p38 MAPK-specific inhibitor, inhibits IL-6-induced p38 MAPK phosphorylating activity and suppresses IL-6-stimulated cell proliferation. Taken together, our results indicate that STAT3 signaling pathway is involved in IL-6-induced NE differentiation and the p38 MAPK is associated with IL-6-stimulated growth regulation in NSCLC-NE cells. These data suggest that both kinase pathways play critical roles in the pathogenesis of NSCLC-NE malignancies, providing new molecular targets for future therapeutic approaches.
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