Sprouty-4 inhibits transformed cell growth, migration and invasion, and EMT and is regulated by Wnt7A through PPARγ in non-small cell lung cancer
| Autor: | Tennis, MA, Van Scoyk, MM, Freeman, SV, Vandervest, KM, Nemenoff, RA, Winn, RA |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Lung Neoplasms
Tumor Suppressor Proteins Intracellular Signaling Peptides and Proteins Epithelial Cells Nerve Tissue Proteins Article Frizzled Receptors Growth Inhibitors Cell Line Receptors G-Protein-Coupled Mesoderm PPAR gamma Wnt Proteins Cell Transformation Neoplastic Cell Movement Carcinoma Non-Small-Cell Lung Cell Line Tumor Cell Migration Inhibition Humans Neoplasm Invasiveness Cell Proliferation Signal Transduction |
| Popis: | Sprouty proteins are potent receptor tyrosine kinase inhibitors that antagonize growth factor signaling and are involved in lung development. However, little is known about the regulation or targets of Sprouty-4 (Spry4) in lung cancer. Our study aimed to determine the role of Spry4 in non-small cell lung cancer (NSCLC). We found that Spry4 mRNA expression was decreased in NSCLC cell lines and in dysplastic lung cell lines compared with a nontransformed cell line, suggesting that Spry4 has tumor-suppressing activity. When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. Changes in epithelial and mesenchymal markers indicated that Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a nontransformed lung epithelial cell line with short hairpin RNA to Spry4 led to the decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor. We showed that the activity of the Spry4 promoter is increased by Wnt7A/Fzd9 signaling through peroxisome proliferator-activated receptor gamma. These data present previously undescribed targets of Spry4 and suggest that Spry4 is a downstream target of Wnt7A/Fzd 9 signaling. Spry4 may have efficacy in the treatment of NSCLC. |
| Databáze: | OpenAIRE |
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