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 siRNA-mediated 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.

• Authors: Mohammad Saleem, Mee-Hyang Kweon, Jeremy James Johnson, Vaqar Mustafa Adhami, Irina Elcheva, Naghma Khan, Bilal Bin Hafeez, Kumar M R Bhat, Sami Sarfaraz, Shannon Reagan-Shaw, Vladimir S Spiegelman, Vijayasaradhi Setaluri, Hasan Mukhtar
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 40 Pg. 14825-30 (Oct 03 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16990429 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• RNA, Messenger
• RNA, Small Interfering
• S100 Calcium-Binding Protein A4
• S100 Proteins
• Tissue Inhibitor of Metalloproteinase-1
• S100A4 protein, human
• Matrix Metalloproteinase 9

Topics

• Animals
• Gene Expression Regulation, Neoplastic
• Genes, Neoplasm (genetics)
• Humans
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplastic Stem Cells
• Prostatic Neoplasms (genetics, pathology)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• S100 Calcium-Binding Protein A4
• S100 Proteins (genetics, metabolism)
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Transcription, Genetic
• Transcriptional Activation (genetics)
• Transfection
• Transplantation, Heterologous
• Tumor Cells, Cultured