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

Geraldine Chow,James L Mulshine,Jordi Tauler

doi:10.1155/2010/485468

Geraldine Chow, James L Mulshine + Show 1 more

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https://doi.org/10.1155/2010/485468

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Abstract

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.

Highlights

Lung cancer is the leading cause of death, both in the United States as well as worldwide
When A549 cells were treated individually with epidermal growth factor (EGF) (50 ng/mL) or IL-1β (10 ng/mL), an increased in both mRNA for HAS2 and hyaluronan synthase-3 (HAS3) was observed at 24 hours for EGF (2-fold for HAS2, 1.4 fold for HAS3) and IL-1β (4.5-fold for HAS2, 2.9-fold for HAS3) (Figure 1(b))
We investigated the effect of EGF, IL1β and TGF-β1 in modulating HA synthesis in A549 cells, a lung adenocarcinoma cell line

Summary

Introduction

Lung cancer is the leading cause of death, both in the United States as well as worldwide. One potential target is HA as it has previously been reported that high HA expression in the tumor cells and stroma of patients with lung adenocarcinoma, a subtype of NSCLC, is associated poor tumor differentiation and high recurrence rate [2]. HAS2 is more catalytically active than HAS1 and it produces high molecular weight HA (2000 kDa) and is implicated in developmental processes involving tissue expansion and growth. The existence of these three different isoforms implies that HA functions are diversely regulated through the activities and expression of the HAS genes. Various growth factors and cytokines including TFG-β1 [8], EGF [9] and heregulin [10] have been shown to modulate HAS expressions and HA production in tumor cells

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