title: Systemic shRNA mediated knock down of S100A4 in colorectal cancer xenografted mice reduces metastasis formation.
abstract: 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.
authors.affiliation: Experimental and Clinical Research Center, joint cooperation between Charité, Medical Faculty and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Dahlmann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sack
authors.forename: Pia
authors.initials: P
authors.lastname: Herrmann
authors.forename: Margit
authors.initials: M
authors.lastname: Lemm
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schlag
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stein
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse