title: Sphingosine-1-phosphate receptor-3 signaling up-regulates epidermal             growth factor receptor and enhances epidermal growth factor receptor-mediated             carcinogenic activities in cultured lung adenocarcinoma cells.
abstract: Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions. However, the role of S1P signaling in tumorigenesis remains to be elucidated. In this study, we show that S1P receptor subtype 3 (S1P₃) is markedly up-regulated in a subset of lung adenocarcinoma cells compared to normal lung epithelial cells. Specific knockdown of S1P₃ receptors inhibits proliferation and anchorage-independent growth of lung adenocarcinoma cells. Mechanistically, we demonstrate that S1P₃ signaling increases epidermal growth factor receptor (EGFR) expression via the Rho kinase (ROCK) pathway in lung adenocarcinoma cells. Nuclear run-off analysis indicates that S1P/S1P₃ signaling transcriptionally increases EGFR expression. Knockdown of S1P₃ receptors diminishes the S1P-stimulated EGFR expression in lung adenocarcinoma cells. Moreover, S1P treatment greatly enhances EGF-stimulated colony formation, proliferation and invasion of lung adenocarcinoma cells. Together, these results suggest that the enhanced S1P₃-EGFR signaling axis may contribute to the tumorigenesis or progression of lung adenocarcinomas.
authors.affiliation: Bioactive Lipid Research Program, Department of Pathology, Wayne                     State University School of Medicine, 423 Chemistry Building, Detroit,                     MI 48202, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hsu
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.forename: Jen-Fu
authors.initials: JF
authors.lastname: Lee
authors.forename: Jin
authors.initials: J
authors.lastname: An
authors.forename: Prasanna
authors.initials: P
authors.lastname: Ekambaram
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Honn
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
authors.forename: Menq-Jer
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D054460:rho-Associated Kinases; D013110:Sphingosine