Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation
Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits β-catenin degradation
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DOI：
10.1007/s00018-013-1444-8
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发表时间：
2014-04-01
影响因子：
8
通讯作者：
Hemler, Martin E.
中科院分区：
文献类型：
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作者：
Knoblich, Konstantin;Wang, Hong-Xing;Hemler, Martin E.
去除人MDA-MB-231细胞中的TSPAN12蛋白可显著减少原发肿瘤移植瘤的生长，同时增加肿瘤细胞的凋亡率。此外，去除TSPAN12显著增强了肿瘤-内皮细胞的相互作用，并增加了对小鼠肺的转移。从人MDA-MB-231细胞中去除TSPAN12还导致FZD4(一种关键的典型Wnt途径受体)与其辅助受体LRP5之间的联系减弱。这一结果可能解释了β-连环素蛋白酶体降解显著增强的原因，β-连环素是规范Wnt信号的关键效应因子。与被破坏的经典Wnt信号一致，TSPAN12消融改变了LRP5、Naked1和2、DVL2、DVL3、Axin 1和GSKβ3蛋白的表达。TSPAN12还改变了几个受β-连环素调控的基因(如CCNA1、CCNE2、WISP1、ID4、SFN、ME1)的表达，这可能有助于解释肿瘤生长和转移的改变。总之，这些结果为TSPAN12在支持原发肿瘤生长和抑制转移方面发挥作用提供了第一个证据。TSPAN12似乎通过稳定FZD4-LRP5的结合，支持规范的Wnt途径信号，导致β-连环素的表达和功能增强而发挥作用。
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 GSK beta 3 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.