Cytokines and growth factors stimulate hyaluronan production: role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer.
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-1beta (IL-1beta). We showed that treatment with recombinant EGF and IL-1beta, alone or in combination with TGF-beta, was able to stimulate HA production in lung adenocarcinoma cell line A549. TGF-beta/IL-1beta 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.
Chow
Geraldine
G
Lung Cancer Biology Laboratory, Department of Biochemistry, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA.
Tauler
Jordi
J
Mulshine
James L
JL
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C105458:HAS3 protein, human; D000076002:Hyaluronan Synthases; D066246:ErbB Receptors; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9