S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9

Abstract

We previously showed that the calcium-binding protein S100A4 is overexpressed during the progression of prostate cancer (CaP) in humans and in the TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse model. We tested a hypothesis that the S100A4 gene plays a role in the invasiveness of human CaP and may be associated with its metastatic spread. We observed that siRNAmediated suppression of the S100A4 gene significantly reduced the proliferative and invasive capability of the highly invasive CaP cells PC-3. We evaluated the mechanism through which the S100A4 gene controls invasiveness of cells by using a macroarray containing 96 well characterized metastatic genes. We found that matrix metalloproteinase 9 (MMP-9) and its tissue inhibitor (TIMP-1) were highly responsive to S100A4 gene suppression. Furthermore, S100A4 suppression significantly reduced the expression and proteolytic activity of MMP-9. By employing an MMP-9-promoter reporter, we observed a significant reduction in the transcriptional activation of the MMP-9 gene in S100A4-siRNA-transfected cells. Cells overexpressing the S100A4 gene (when transfected with pcDNA3.1-S100A4 plasmid) also significantly expressed MMP-9 and TIMP-1 genes with increased proteolytic activity of MMP-9 concomitant to increased transcriptional activation of the MMP-9 gene. S100A4-siRNA-transfected cells exhibited a reduced rate of tumor growth under in vivo conditions. Our data demonstrate that the S100A4 gene controls the invasive potential of human CaP cells through regulation of MMP-9 and that this association may contribute to metastasis of CaP cells. We suggest that S100A4 could be used as a biomarker for CaP progression and a novel therapeutic or chemopreventive target for human CaP treatment. extracellular matrix ͉ metastasis ͉ biomarker A pproximately 27,350 prostate cancer (CaP)-related deaths are predicted during this year alone in the United States, and despite recent improvements in diagnostic and therapeutic techniques, the survival rate of CaP patients is poor because of the posttreatment recurrence of disease (1, 2). The lack of effective therapies for advanced CaP is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Thus, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of CaP. S100A4 (also known as mts1), a calcium-binding protein associated with invasion and metastasis of cancer cells, has been reported to be frequently overexpressed in metastatic tumors, normal cells with uninhibited movement (such as macrophages), and transformed cells, and in various cancer types such as breast, ovary, thyroid, lung, esophageal squamous cell carcinoma, gastric, and colon (4-6). Studies have shown that breast cancers expressing high levels of S100A4 have a sign...

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