Molecular cancer, 2013-10-10, Vol.12 (1), p.120-120
Overexpression of Decoy Receptor 3 (DcR3), a soluble member of the tumor necrosis factor receptor superfamily, is a common event in several types of cancer. In renal cell carcinoma (RCC), DcR3 overexpression is associated with lymph node and distant metastasis as well as a poor prognosis. However, the functional role and regulation of DcR3 expression in RCC is so far unknown.
Modulation of DcR3 expression by siRNA and ectopic gene expression, respectively, was performed in ACHN and 769-P RCC cell lines. Functional effects of a modulated DcR3 expression were analyzed with regard to migration, invasion, adhesion, clonogenicity, and proliferation. Furthermore, quantitative RT-PCR and immunoblot analyses were performed to evaluate the expression of downstream mediators of DcR3. In further experiments, luciferase assays, quantitative RT-PCR and immunoblot analyses were applied to study the regulation of DcR3 expression in RCC. Additionally, an ex vivo tissue slice culture technique combined with immunohistochemistry was used to study the regulation of DcR3 expression in human RCC specimens.
Here, we show that DcR3 promotes adhesion, migration and invasiveness of RCC cells. The DcR3-dependent increase in cellular invasiveness is accompanied with an up-regulation of integrin alpha 4, matrixmetalloproteinase 7 and urokinase plasminogen activator (uPA). Further, we identified a signaling pathway regulating DcR3 expression in RCC. Using in vitro experiments as well as an ex vivo RCC tissue slice culture model, we demonstrate that expression of DcR3 is regulated in a PI3K/AKT-dependent manner involving the transcription factor nuclear factor of activated T-cells (NFAT).
Taken together, our results identify DcR3 as a key driver of tumor cell dissemination and suggest DcR3 as a promising target for rational therapy of RCC.
RNA, Small Interfering - genetics ; Signal Transduction ; Carcinoma, Renal Cell - pathology ; Neoplasm Invasiveness ; Receptors, Tumor Necrosis Factor, Member 6b - metabolism ; Humans ; NFATC Transcription Factors - metabolism ; Gene Expression Regulation, Neoplastic ; Morpholines - pharmacology ; Kidney Neoplasms - metabolism ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Cell Adhesion ; Fibronectins - metabolism ; Gene Knockdown Techniques ; Carcinoma, Renal Cell - metabolism ; HEK293 Cells ; Cell Line, Tumor ; Phosphatidylinositol 3-Kinases - physiology ; Kidney Neoplasms - pathology ; Transcription, Genetic ; Chromones - pharmacology ; Proto-Oncogene Proteins c-akt - metabolism ; Receptors, Tumor Necrosis Factor, Member 6b - genetics ; Cell Movement ; Immunohistochemistry ; Tumor necrosis factor ; Genes ; Development and progression ; Carcinoma, Renal cell ; Metastasis ; T cells ; Gene expression ; Integrins ; Index Medicus ; DcR3 ; AKT ; Research ; Renal cell carcinoma ; NFAT
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