Systemic shRNA mediated knock-down of S100A4 in colorectal cancer xenografted mice reduces metastasis formation
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Mathias Dahlmann1, Ulrike Sack2, Pia Herrmann1, Margit Lemm2, Iduna Fichtner2, Peter M. Schlag1,3, Ulrike Stein1
1 Experimental and Clinical Research Center, a joint cooperation between the Charité, Medical Faculty and the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
2 Max-Delbrück-Center for Molecular Medicine, Germany
3 Charité Comprehensive Cancer Center, Germany
Ulrike Stein, email:
Keywords: colorectal, cancer, metastasis, S100A4, RNAi
Received: July 26, 2012, Accepted: August 04, 2012, Published: August 07, 2012
The metastasis-inducing protein S100A4 was found to be a prognostic indicator for the development of metachronous metastases. S100A4 expression levels correlate with the formation of human colorectal cancer metastases and shorter patients’ survival. Inhibition of S100A4 expression in patients might therefore result in decreased metastasis formation and prolonged survival. In the present study, we used shRNA expression plasmids to inhibit S100A4 expression in the colorectal cancer cell lines HCT116, SW620 and DLD-1. Cell lines with reduced S100A4 expression showed reduced cell migration and invasion in vitro. The knock-down of S100A4 expression also led to significantly diminished formation of liver metastases when intrasplenically transplanted in mice (P= 0.004). We then focused on the therapeutic potential of systemically applied shRNA expression plasmids acting on S100A4 via repeated hydrodynamics-based tail vein injection of plasmid DNA. Mice, intrasplenically transplanted with HCT116 cells and treated systemically with S100A4-shRNA plasmids, showed a decrease of S100A4 and MMP9 expression levels, resulting in significantly reduced liver metastases (P= 0.005). In summary, we show for the first time the intratumoral knock-down of S100A4 via systemic application of S100A4-shRNA plasmid DNA, which restricts metastasis formation in a xenografted mouse model of colorectal cancer.
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