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

• Published in: BioMed research international 2010-01, Vol.2010 (2010), p.1-11
• Main Authors: Chow, Geraldine, Tauler, Jordi, Mulshine, James L.
• Format: Article
• Language: English
• Subjects: Acquisitions & mergers; Apoptosis; Biological and medical sciences; Biomedical research; Biotechnology; Breast cancer; Cancer; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell adhesion & migration; Cell Line, Tumor; Cytokines; Cytokines - pharmacology; Drug resistance; Epithelium - drug effects; Epithelium - pathology; Gene Expression Regulation, Neoplastic - drug effects; Genotype & phenotype; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Growth factors; Head & neck cancer; Humans; Hyaluronan; Hyaluronan Synthases; Hyaluronic Acid - biosynthesis; Hyaluronic Acid - pharmacology; Hydroxyapatite; Inhibitors; Intercellular Signaling Peptides and Proteins - pharmacology; Interleukin-1beta - pharmacology; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lungs; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mesoderm - drug effects; Mesoderm - pathology; Molecular weight; Neoplasm Invasiveness; Phenotype; Pneumology; Protein Kinase Inhibitors - pharmacology; Proteins; Receptor, Epidermal Growth Factor - metabolism; Studies; Transforming Growth Factor beta1 - pharmacology; Tumors of the respiratory system and mediastinum
• ISSN: 1110-7243; 2314-6133; 1110-7251; 2314-6141
• DOI: 10.1155/2010/485468

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.