TGFβ-mediated suppression of CD248 in non-cancer cells via canonical Smad-dependent signaling pathways is uncoupled in cancer cells.
Suresh Babu, S
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BACKGROUND: CD248 is a cell surface glycoprotein, highly expressed by stromal cells and fibroblasts of tumors and inflammatory lesions, but virtually undetectable in healthy adult tissues. CD248 promotes tumorigenesis, while lack of CD248 in mice confers resistance to tumor growth. Mechanisms by which CD248 is downregulated are poorly understood, hindering the development of anti-cancer therapies. METHODS: We sought to characterize the molecular mechanisms by which CD248 is downregulated by surveying its expression in different cells in response to cytokines and growth factors. RESULTS: Only transforming growth factor (TGFβ) suppressed CD248 protein and mRNA levels in cultured fibroblasts and vascular smooth muscle cells in a concentration- and time-dependent manner. TGFβ transcriptionally downregulated CD248 by signaling through canonical Smad2/3-dependent pathways, but not via mitogen activated protein kinases p38 or ERK1/2. Notably, cancer associated fibroblasts (CAF) and cancer cells were resistant to TGFβ mediated suppression of CD248. CONCLUSIONS: The findings indicate that decoupling of CD248 regulation by TGFβ may contribute to its tumor-promoting properties, and underline the importance of exploring the TGFβ-CD248 signaling pathway as a potential therapeutic target for early prevention of cancer and proliferative disorders.
Version of record
Cell Line, Tumor
Disease Models, Animal
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
p38 Mitogen-Activated Protein Kinases
Transforming Growth Factor beta
Receptors, Transforming Growth Factor beta
Gene Expression Regulation, Neoplastic
Bone Morphogenetic Protein 2
License start date
BMC cancer, 2014, 14 pp. 113 - ?
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