title: Sprouty-4 inhibits transformed cell growth, migration and invasion, and epithelial-mesenchymal transition, and is regulated by Wnt7A through PPARgamma in non-small cell lung cancer.
abstract: 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.
authors.affiliation: University of Colorado at Denver and Health Sciences Center, 12700 East 19th Avenue, Box C272, RC2 9th Floor, Aurora, CO 80045, USA. Meredith.tennis@ucdenver.edu
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Tennis
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Van Scoyk
authors.forename: Scott V
authors.initials: SV
authors.lastname: Freeman
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Vandervest
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.forename: Robert A
authors.initials: RA
authors.lastname: Winn
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D051157:Frizzled Receptors / Q000502:physiology; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C549560:FZD9 protein, human; D051157:Frizzled Receptors; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; C499038:SPRY4 protein, human; D025521:Tumor Suppressor Proteins; C092778:WNT7A protein, human; D051153:Wnt Proteins