TGFβ-mediated suppression of CD248 in non-cancer cells via canonical Smad-dependent signaling pathways is uncoupled in cancer cells.
Abstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Mice, Knockout
Humans
Mice
Neoplasms
Disease Models, Animal
Activins
Protein-Serine-Threonine Kinases
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
p38 Mitogen-Activated Protein Kinases
Transforming Growth Factor beta
Receptors, Transforming Growth Factor beta
RNA, Messenger
Antigens, CD
Antigens, Neoplasm
Cytokines
Signal Transduction
Gene Expression Regulation, Neoplastic
RNA Stability
Smad Proteins
Bone Morphogenetic Protein 2
Receptor, Transforming Growth Factor-beta Type I
Research team
Tumour Microenvironment
Language
eng
Date accepted
2014-02-17
License start date
2014-02-20
Citation
BMC cancer, 2014, 14 pp. 113 - ?
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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