title: TGF-β/SMAD3 Pathway Stimulates Sphingosine-1 Phosphate Receptor 3 Expression: IMPLICATION OF SPHINGOSINE-1 PHOSPHATE RECEPTOR 3 IN LUNG ADENOCARCINOMA PROGRESSION.
abstract: Previously, we showed that levels of sphingosine-1 phosphate receptor 3 (S1PR3) are increased in a panel of cultured human lung adenocarcinoma cell lines, and that S1PR3-mediated signaling pathways regulate proliferation, soft agar growth, and invasion of human lung adenocarcinoma cells in vitro In the present study, we examine S1PR3 levels in human lung adenocarcinoma specimens. cDNA array and tumor microarray analysis shows that mRNA and protein levels of S1PR3 are significantly increased in human lung adenocarcinomas when compared with normal lung epithelial cells. Promoter analysis shows 16 candidate SMAD3 binding sites in the promoter region of S1PR3. ChIP indicates that TGF-β treatment stimulates the binding of SMAD3 to the promoter region of S1PR3. Luciferase reporter assay demonstrates that SMAD3 transactivates S1PR3 promoter. TGF-β stimulation or ectopic expression of TGF-β up-regulates S1PR3 levels in vitro and ex vivo Pharmacologic inhibition of TGF-β receptor or SMAD3 abrogates the TGF-β-stimulated S1PR3 up-regulation. Moreover, S1PR3 knockdown dramatically inhibits tumor growth and lung metastasis, whereas ectopic expression of S1PR3 promotes the growth of human lung adenocarcinoma cells in animals. Pharmacological inhibition of S1PR3 profoundly inhibits the growth of lung carcinoma in mice. Our studies suggest that levels of S1PR3 are up-regulated in human lung adenocarcinomas, at least in part due to the TGF-β/SMAD3 signaling axis. Furthermore, S1PR3 activity promotes the progression of human lung adenocarcinomas. Therefore, S1PR3 may represent a novel therapeutic target for the treatment of deadly lung adenocarcinomas.
authors.affiliation: From the Departments of Pathology and.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zhao
authors.affiliation: From the Departments of Pathology and.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Departments of Pathology and.
authors.forename: Jen-Fu
authors.initials: JF
authors.lastname: Lee
authors.affiliation: From the Departments of Pathology and.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Departments of Pathology and.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Kandouz
authors.affiliation: Chemistry.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: VanHecke
authors.affiliation: the Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602.
authors.forename: Shiyou
authors.initials: S
authors.lastname: Chen
authors.affiliation: Chemistry.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: From the Departments of Pathology and.|Karmanos Cancer Institute, and.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Lonardo
authors.affiliation: From the Departments of Pathology and menqjer.lee@wayne.edu.|Karmanos Cancer Institute, and.|Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, Michigan 48201 and.
authors.forename: Menq-Jer
authors.identifier: 0000-0003-0857-5346
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D000081025:Sphingosine-1-Phosphate Receptors; D016212:Transforming Growth Factor beta; C577483:sphingosine-1-phosphate receptor-3, human
keywords: S1PR3; SMAD transcription factor; TGF-β; lung cancer; sphingolipid; sphingosine-1 phosphate (S1P); transforming growth factor β (TGF-B)