Abstract
BackgroundOverexpression 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.MethodsModulation 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.ResultsHere, 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).ConclusionsTaken 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.
Highlights
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
We demonstrate that DcR3 promotes adhesion, migration and invasiveness of renal cell carcinoma (RCC) cells which is accompanied by an up-regulation of integrin alpha 4, matrixmetalloproteinase 7 and urokinase plasminogen activator
DcR3 promotes migration of RCC cells As our previous work demonstrates a clinical significance of DcR3 overexpression in RCC [19], we were interested in functionally characterizing DcR3 in RCC
Summary
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. Defects in the induction of apoptotic cell death, immune evasion mechanisms and a high metastatic potential are determinants of RCC In these processes, the members of the TNF (tumor necrosis factor) superfamily play an important role. DcR3 is capable to bind and neutralize CD95 ligand (CD95L, FasL, APO1L), TL1A (TNF-like molecule 1A) and LIGHT By binding to these ligands DcR3 can inhibit apoptosis, induce angiogenesis and modulate immune cell functions [9,10,11,12,13]. Our results identify DcR3 as a key driver of tumor cell dissemination and suggest DcR3 as a promising target for rational therapy of RCC
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