Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
Cell Mol Life Sci. 2014 Apr;71(7):1305-14. doi: 10.1007/s00018-013-1444-8. Epub 2013 Aug 18.
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.
从人 MDA-MB-231 细胞中剔除四跨膜蛋白 TSPAN12 显著降低了原发性肿瘤异种移植物的生长，同时增加了肿瘤细胞凋亡。此外，TSPAN12 的去除显著增强了肿瘤-内皮细胞相互作用，并增加了向小鼠肺部的转移。从人 MDA-MB-231 细胞中剔除 TSPAN12 还导致 FZD4（关键的经典 Wnt 途径受体）与其共受体 LRP5 之间的关联减少。这一结果可能解释了经典 Wnt 信号通路的关键效应物β-连环蛋白（β-catenin）的蛋白体降解显著增强。与经典 Wnt 信号通路的破坏一致，TSPAN12 的剔除改变了 LRP5、Naked 1 和 2、DVL2、DVL3、Axin 1 和 GSKβ3 蛋白的表达。TSPAN12 的剔除还改变了受 β-catenin 调控的几个基因的表达（例如 CCNA1、CCNE2、WISP1、ID4、SFN、ME1），这可能有助于解释肿瘤生长和转移的改变。总之，这些结果首次提供了 TSPAN12 支持原发性肿瘤生长和抑制转移的证据。TSPAN12 似乎通过稳定 FZD4-LRP5 之间的相互作用来发挥作用，支持经典 Wnt 信号通路，从而导致 β-catenin 表达和功能增强。
