Early role of Fsp1 in epithelial-mesenchymal transformation

Abstract

A seamless plasticity exists among cells shifting between epithelial and mesenchymal phenotypes during early development and again later, in adult tissues, following wound repair or organ remodeling in response to injury. Fsp1, a gene encoding a fibroblast-specific protein associated with mesenchymal cell morphology and motility, is expressed during epithelial-mesenchymal transformations (EMT) in vivo. In the current study, we identified several cytokines that induce Fsp1 in cultured epithelial cells. A combination of these factors, however, was most efficacious at completing the process of EMT. The optimal combination identified were two of the cytokines classically associated with fibrosis, i.e., transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF). To confirm that it was the induction of Fsp1 by these cytokines mediating EMT, we used antisense oligomers to block Fsp1 production and subsequently measured cell motility and markers of EMT phenotype. The antisense oligomers suppressed Fsp1 expression and epithelial transformation; therefore, we conclude that the appearance of Fsp1 is an important early event in the pathway toward EMT.

Systemic administration of naked plasmid encoding hepatocyte growth factor ameliorates chronic renal fibrosis in mice

“…35 Although these myofibroblasts are generally presumed to derive from local activation of residential fibroblasts under diseased conditions, evidence suggests that these cells may also derive from tubular epithelial cells via a process known as epithelial to mesenchymal transition. 36,37 Consistent with this view, our preliminary results show that TGF-␤1 can induce ␣SMA expression in both cultured renal interstitial fibroblasts and tubular epithelial cells in vitro (unpublished data). Regardless of the mechanisms, the fact that exogenous HGF inhibits myofibroblast activation in the obstructed kidneys underscores that exogenous HGF precisely targets a key event, the activation of principal matrix-producing cells, during renal fibrogenesis.…”

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

“…For example, in both cultured epithelial cells and a transgenic mouse model of metastatic breast cancer, S100A4 expression was activated during EMT; antisense oligonucleotides suppressed S100A4 expression and epithelial transformation. 39,40 Furthermore, recently it was shown that for colon carcinoma cell lines S100A4 was a direct target of the Wnt/b-catenin pathway. Specific knockdown of S100A4 in this system significantly reduced the migratory ability of these cells in vitro.…”

Endothelial–mesenchymal transition in human atrial fibrillation

“…S100A4 [19], also known as fibroblast-specific protein 1 (FSP1) [20,21], is a member of the S100 superfamily of EF-hand calcium-binding proteins. P4HD is an essential enzyme for the biosynthesis of procollagen [22] and HSP47 is an ER-resident stress protein that is believed to function as a molecular chaperone specific to the biosynthesis of procollagen [23,24].…”