Abstract
Emerging evidence suggests that the SAM pointed domain containing ETS transcription factor (SPDEF) plays a significant role in tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there are no in vivo studies with respect to the role of SPDEF in tumor metastasis. The present study examined the effects of SPDEF on tumor cell metastasis using prostate tumor cells as a model. Utilizing two experimental metastasis models, we demonstrate that SPDEF inhibits cell migration and invasion in vitro and acts a tumor metastasis suppressor in vivo. Using stable expression of SPDEF in PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we demonstrate for the first time that SPDEF diminished the ability of disseminated tumors cells to survive at secondary sites and establish micrometastases. These effects on tumor metastasis were not a result of the effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth in vitro or subcutaneous tumor xenograft-growth in vivo. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression. These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo.
Highlights
Role of SAM pointed domain containing ETS transcription factor (SPDEF) in tumor biology remains hotly debated
MMP9 and MMP13 mRNA Levels Are Differentially Regulated by SPDEF—Because SPDEF has been shown to regulate several genes in various cell lines, many of which are involved in epithelial-to-mesenchymal transition, and to begin to dissect a mechanism of SPDEF-mediated modulation of tumor metastasis, we evaluated the expression of genes involved in cell motility, invasion, and metastasis among those genes previously described to be regulated by SPDEF [6]
Results presented here demonstrate that forced SPDEF expression in cells that have decreased or no detectible SPDEF expression (PC3-Luc) impairs the ability of these cells to establish successful metastasis in vivo, whereas SPDEF knockdown in cells that have abundant SPDEF expression (LNCaP-Luc) enhances the ability of these cells to establish successful metastasis by increasing tumor cell survival at metastatic sites
Summary
Role of SPDEF in tumor biology remains hotly debated. Results: SPDEF suppressed tumor metastasis in part by modulating MMP9 and MMP13. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo. Results presented demonstrate for the first time that stable expression of SPDEF in PC3-Luc cells decreased, whereas stable knockdown of SPDEF in LNCaP-Luc prostate tumor cells increased, the ability of these cells to survive at metastatic sites. To the best of our knowledge, this is the first study, in any model, demonstrating a tumor metastasis suppressor function of SPDEF in vivo
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