Abstract
Recent studies have revealed that newly emerging transformed cells are often eliminated from epithelia via cell competition with the surrounding normal epithelial cells. However, it remains unknown whether and how soluble factors are involved in this cancer preventive phenomenon. By performing stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative mass spectrometric analyses, we have identified ADAM-like Decysin-1 (ADAMDEC1) as a soluble protein whose expression is upregulated in the mix culture of normal and RasV12-transformed epithelial cells. Expression of ADAMDEC1 is elevated in normal epithelial cells co-cultured with RasV12 cells. Knockdown of ADAMDEC1 in the surrounding normal cells substantially suppresses apical extrusion of RasV12 cells, suggesting that ADAMDEC1 secreted by normal cells positively regulate the elimination of the neighboring transformed cells. In addition, we show that the metalloproteinase activity of ADAMDEC1 is dispensable for the regulation of apical extrusion. Furthermore, ADAMDEC1 facilitates the accumulation of filamin, a crucial regulator of Epithelial Defense Against Cancer (EDAC), in normal cells at the interface with RasV12 cells. This is the first report demonstrating that an epithelial intrinsic soluble factor is involved in cell competition in mammals.
Highlights
Be involved in selection of developmentally optimal cells[19]
ADAMDEC1 is identified by SILAC-based analyses as a soluble protein enriched in the co-culture of normal and RasV12-transformed epithelial cells
We have demonstrated that when RasV12-transformed cells are surrounded by normal epithelial cells, the transformed cells are apically extruded from the epithelial monolayer[11]
Summary
Be involved in selection of developmentally optimal cells[19]. It still remains elusive whether and how soluble factors play a role in cell competition, especially in mammals. ADAM-like Decysin-1 (ADAMDEC1), a member of the ADAM family, is a secreted type of metalloprotease[20,21]. ADAMDEC1 contains a signal peptide, a prodomain, a catalytic domain, and an incomplete disintegrin domain, but lacks a typical transmembrane domain and a cytoplasmic tail[22]. ADAMDEC1 contains the ADAM consensus sequence for the proteolytic activity and exhibits a metalloproteinase activity for α2-macroglobulin (α2M) in vitro[20]. We demonstrate that normal epithelial cells secrete ADAMDEC1, upon interaction with RasV12-transformed cells, which facilitates apical extrusion of the transformed cells
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