Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer

Autor: Beach, Jessica A, Aspuria, Paul-Joseph P, Cheon, Dong-Joo, Lawrenson, Kate, Agadjanian, Hasmik, Walsh, Christine S, Karlan, Beth Y, Orsulic, Sandra
Rok vydání: 2016
Předmět:
sphingosine kinase 1
Knockout
cancer-associated fibroblast
Messenger
Oncology and Carcinogenesis
Cystadenocarcinoma
Fluorescent Antibody Technique
Apoptosis
Real-Time Polymerase Chain Reaction
transforming growth factor-beta 1
Immunoenzyme Techniques
Mice
Rare Diseases
Sphingosine
Transforming Growth Factor beta
Cell Movement
Receptors
Animals
Humans
2.1 Biological and endogenous factors
Aetiology
Phosphorylation
Myofibroblasts
Cell Proliferation
Cancer
Ovarian Neoplasms
Cultured
Blotting
Reverse Transcriptase Polymerase Chain Reaction
Phosphotransferases
Serous
Cell Differentiation
Fibroblasts
Prognosis
microenvironment
Tumor Cells
Ovarian Cancer
Survival Rate
Phosphotransferases (Alcohol Group Acceptor)
Lysosphingolipid
sphingosine-1-phosphate
RNA
Female
Lysophospholipids
Neoplasm Grading
Western
Signal Transduction
Zdroj: Oncotarget, vol 7, iss 4
Popis: Sphingosine kinase 1 (SPHK1), the enzyme that produces sphingosine 1 phosphate (S1P), is known to be highly expressed in many cancers. However, the role of SPHK1 in cells of the tumor stroma remains unclear. Here, we show that SPHK1 is highly expressed in the tumor stroma of high-grade serous ovarian cancer (HGSC), and is required for the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). Knockout or pharmacological inhibition of SPHK1 in ovarian fibroblasts attenuated TGF-β-induced expression of CAF markers, and reduced their ability to promote ovarian cancer cell migration and invasion in a coculture system. Mechanistically, we determined that SPHK1 mediates TGF-β signaling via the transactivation of S1P receptors (S1PR2 and S1PR3), leading to p38 MAPK phosphorylation. The importance of stromal SPHK1 in tumorigenesis was confirmed in vivo, by demonstrating a significant reduction of tumor growth and metastasis in SPHK1 knockout mice. Collectively, these findings demonstrate the potential of SPHK1 inhibition as a novel stroma-targeted therapy in HGSC.
Databáze: OpenAIRE
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