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- Title
Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by PI3-kinase and NF-κB.
- Authors
Han, S. W.; Roman, J.
- Abstract
The extracellular matrix glycoprotein, fibronectin, influences a variety of cellular functions including adhesion, migration, survival, differentiation, and growth. Fibronectin has also been shown to increase the migration and proliferation of human lung carcinoma cells. However, the role of fibronectin in controlling lung airway epithelial cell phenotype remains unknown. Here, we demonstrate that fibronectin stimulates the proliferation of human bronchial epithelial cells (BEAS-2B and 16-HBE). Of note, fibronectin induced the mRNA and protein expression of c-Myc and cyclin D1, while it decreased the expressions of cyclin-dependent kinase inhibitor p21 WAF-1/CIP1/MDA-6 (p21) and the tumor suppressor gene phosphatase and tensin homolog deleted on chromosome ten (PTEN). Fibronectin also stimulated the phosphorylation of the phosphatidylinositol 3 kinase (PI3-K) downstream signal Akt. The inhibitor of PI3-K, Wortmannin, and anti-α5β1 integrin antibodies abrogated the effect of fibronectin on c-Myc, cyclin D1, p21, and PTEN expression. The stimulatory effect of fibronectin was mediated by nuclear factor kappaB (NF-κB) since fibronectin induced the expression of the p65 component of NF-κB and enhanced NF-κB DNA binding. Furthermore, we found that p65 small interfering RNA inhibited the effect of fibronectin on c-Myc, cyclin D1, p21, PTEN expression, and on fibronectin-induced cell proliferation. Finally, we found that fibronectin inhibits apoptosis by reducing DNA fragmentation and inhibiting the activities of caspases 3/7. Taken together, our findings demonstrate that fibronectin stimulates human bronchial epithelial cell growth and inhibits apoptosis through activation of NF-κB, which, in turn, increases the expression of c-Myc and cyclin D1 and decreases p21 and PTEN via α5β1 integrin-dependent signals that include PI3-K/Akt. Therefore, alternations in the extracellular matrix composition of the lung, with increased fibronectin, might promote epithelial cell growth and thereby contribute to oncogenesis in certain settings.Oncogene (2006) 25, 4341–4349. doi:10.1038/sj.onc.1209460; published online 6 March 2006
- Subjects
FIBRONECTINS; CELL proliferation; EPITHELIAL cells; GLYCOPROTEINS; MESSENGER RNA; PHOSPHATASES
- Publication
Oncogene, 2006, Vol 25, Issue 31, p4341
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1209460