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 beta-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 GSKbeta3 proteins. TSPAN12 ablation also altered expression of several genes regulated by beta-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 beta-catenin expression and function.
Knoblich, K., Wang, H-X., Sharma, C., Fletcher, A. L., Turley, S. J., & Hemler, M. E. (2014). Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits beta-catenin degradation. Cellular and Molecular Life Sciences, 71(7), 1305 - 1314. https://doi.org/10.1007/s00018-013-1444-8