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Journal of Biomedicine and Biotechnology
Volume 2010 (2010), Article ID 485468, 11 pages
Research Article

Cytokines and Growth Factors Stimulate Hyaluronan Production: Role of Hyaluronan in Epithelial to Mesenchymal-Like Transition in Non-Small Cell Lung Cancer

1Lung Cancer Biology Laboratory, Department of Biochemistry, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA
2Lung Cancer Biology Laboratory, Department of Internal Medicine, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA

Received 31 July 2009; Revised 23 March 2010; Accepted 5 May 2010

Academic Editor: Anne Hamburger

Copyright © 2010 Geraldine Chow et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


In this study, we investigated the role of hyaluronan (HA) in non-small cell lung cancer (NSCLC) since close association between HA level and malignancy has been reported. HA is an abundant extracellular matrix component and its synthesis is regulated by growth factors and cytokines that include epidermal growth factor (EGF) and interleukin-1β (IL-1β). We showed that treatment with recombinant EGF and IL-1β, alone or in combination with TGF-β, was able to stimulate HA production in lung adenocarcinoma cell line A549. TGF-β/IL-1β treatment induced epithelial to mesenchymal-like phenotype transition (EMT), changing cell morphology and expression of vimentin and E-cadherin. We also overexpressed hyaluronan synthase-3 (HAS3) in epithelial lung adenocarcinoma cell line H358, resulting in induced HA expression, EMT phenotype, enhanced MMP9 and MMP2 activities and increased invasion. Furthermore, adding exogenous HA to A549 cells and inducing HA H358 cells resulted in increased resistance to epidermal growth factor receptor (EGFR) inhibitor, Iressa. Together, these results suggest that elevated HA production is able to induce EMT and increase resistance to Iressa in NSCLC. Therefore, regulation of HA level in NSCLC may be a new target for therapeutic intervention.