Lung carcinoma often occurs in patients with chronic lung disease such as tobacco-related emphysema and asbestos-related pulmonary fibrosis. These diseases are characterized by dramatic alterations in the content and composition of the lung extracellular matrix including increased fibronectin deposition. We speculate that this ‘altered’ matrix promotes lung carcinoma cell proliferation. Consistent with this, we found that fibronectin stimulates lung carcinoma cell proliferation through upregulation of the expression of the pro-oncogene COX-2. Fibronectin appears to serve as an autocrine growth factor for lung cancer cells since both human small cell lung carcinoma and non-small cell lung carcinoma cell lines express high levels of fibronectin mRNA and protein. Treatment of the cells with the natural and synthetic proxisome proliferator-activated receptor gamma (PPARγ) ligands 15d-PGJ2, rosiglitazone (BRL 49653), and troglizatone (Trog) significantly reduced fibronectin gene expression and fibronectin-induced lung carcinoma cell growth. The effects of BRL 49653 and Trog, but not 15d-PGJ2, were blocked by the specific PPARγ antagonist GW9662 suggesting that PPARγ-dependent and -independent signaling was involved in regulation of fibronectin expression. Transient transfection experiments revealed that 15d-PGJ2, BRL 49653, and Trog inhibited fibronectin gene transcription. Studies with deletion mutants showed that a CRE binding site in the fibronectin promoter region (between -420 to -165 bp) plays a major role in this inhibition. Another region (from -165 to -41 bp) was also considered important and appeared to be a binding site for Sp1. Gel mobility shift assays showed that both 15d-PGJ2 and Trog inhibited CREB and Sp1, but not NF-κB binding activities in the fibronectin promoter. PPARγ ligands also inhibited SP-1 protein expression, but failed to stimulate phosphorylation of CREB. Taken together, these results indicate that PPARγ ligands inhibit fibronectin gene expression through a reduction in CREB and Sp1 nuclear protein binding activities in the fibronectin gene promoter via PPARγ-dependent and -independent signals.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]