title: A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in non-small cell lung cancer pathogenesis.
abstract: Definition of the molecular pathogenesis of lung cancer allows investigators an enhanced understanding of the natural history of the disease, thus fostering development of new prevention strategies. In addition to regulating epithelial-to-mesenchymal transition (EMT), the transcription factor Snail exerts global effects on gene expression. Our recent studies reveal that Snail is upregulated in non-small cell lung cancer (NSCLC), is associated with poor prognosis, and promotes tumor progression in vivo. Herein, we demonstrate that overexpression of Snail leads to the upregulation of secreted protein, acidic and rich in cysteine (SPARC) in models of premalignancy and established disease, as well as in lung carcinoma tissues in situ. Snail overexpression leads to increased SPARC-dependent invasion in vitro, indicating that SPARC may play a role in lung cancer progression. Bioinformatic analysis implicates transforming growth factor beta (TGF-β), extracellular signal-regulated kinase (ERK)1/2, and miR-29b as potential intermediaries in Snail-mediated upregulation of SPARC. Both the TGF-β1 ligand and TGF-β receptor 2 (TGF-βR2) are upregulated following Snail overexpression. Treatment of human bronchial epithelial cell (HBEC) lines with TGF-β1 and inhibition of TGF-β1 mRNA expression modulates SPARC expression. Inhibition of MAP-ERK kinase (MEK) phosphorylation downregulates SPARC. MiR-29b is downregulated in Snail-overexpressing cell lines, whereas overexpression of miR-29b inhibits SPARC expression. In addition, miR-29b is upregulated following ERK inhibition, suggesting a Snail-dependent pathway by which Snail activation of TGF-β and ERK signaling results in downregulation of miR-29b and subsequent upregulation of SPARC. Our discovery of pathways responsible for Snail-induced SPARC expression contributes to the definition of NSCLC pathogenesis.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, 37-131 Center for Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095. sdubinett@mednet.ucla.edu.
authors.forename: Jeanette L
authors.initials: JL
authors.lastname: Grant
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Hong
authors.forename: Kostyantyn
authors.initials: K
authors.lastname: Krysan
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Walser
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
mesh_terms: D001980:Bronchi / Q000166:cytology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015676:Osteonectin / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D008024:Ligands; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D015676:Osteonectin; D018125:Receptors, Transforming Growth Factor beta; C577241:SPARC protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II