Journal article
TGF-β/SMAD3 Pathway Stimulates Sphingosine-1 Phosphate Receptor 3 Expression IMPLICATION OF SPHINGOSINE-1 PHOSPHATE RECEPTOR 3 IN LUNG ADENOCARCINOMA PROGRESSION
The Journal of biological chemistry, v 291(53), pp 27343-27353
Dec 2016
PMID: 27856637
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- TGF-β/SMAD3 Pathway Stimulates Sphingosine-1 Phosphate Receptor 3 Expression IMPLICATION OF SPHINGOSINE-1 PHOSPHATE RECEPTOR 3 IN LUNG ADENOCARCINOMA PROGRESSION
- Creators
- Jiawei Zhao - From the Departments of Pathology andJingjing Liu - From the Departments of Pathology andJen-Fu Lee - From the Departments of Pathology andWenliang Zhang - From the Departments of Pathology andMustapha Kandouz - From the Departments of Pathology andGarrett C. VanHecke - Wayne State UniversityShiyou Chen - University of GeorgiaYoung-Hoon Ahn - ChemistryFulvio Lonardo - From the Departments of Pathology andMenq-Jer Lee - Wayne State University
- Publication Details
- The Journal of biological chemistry, v 291(53), pp 27343-27353
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Web of Science ID
- WOS:000391576300031
- Scopus ID
- 2-s2.0-85007579343
- Other Identifier
- 991020099026904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology