Abstract
Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells significantly decreased primary tumor xenograft growth, while increasing tumor apoptosis. Furthermore, TSPAN12 removal markedly enhanced tumor-endothelial interactions and increased metastasis to mouse lungs. TSPAN12 removal from human MDA-MB-231 cells also caused diminished association between FZD4 (a key canonical Wnt pathway receptor) and its co-receptor LRP5. The result likely explains substantially enhanced proteosomal degradation of β-catenin, a key effecter of canonical Wnt signaling. Consistent with disrupted canonical Wnt signaling, TSPAN12 ablation altered expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1, and GSKβ3 proteins. TSPAN12 ablation also altered expression of several genes regulated by β-catenin (e.g. CCNA1, CCNE2, WISP1, ID4, SFN, ME1) that may help to explain altered tumor growth and metastasis. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4-LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced β-catenin expression and function.
Original language | English |
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Pages (from-to) | 1305-14 |
Number of pages | 10 |
Journal | Cellular and Molecular Life Sciences |
Volume | 71 |
Issue number | 7 |
DOIs | |
Publication status | Published - Apr 2014 |
Keywords
- Animals
- Apoptosis
- Breast Neoplasms
- Female
- Frizzled Receptors
- Gene Expression Regulation
- Gene Silencing
- Human Umbilical Vein Endothelial Cells
- Humans
- Low Density Lipoprotein Receptor-Related Protein-5
- Mice
- Mice, SCID
- Neoplasm Metastasis
- Tetraspanins
- Wnt Proteins
- Wnt Signaling Pathway
- beta Catenin