Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1
Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1
复制标题
DOI：
10.1073/pnas.0910962106
复制
发表时间：
2009-12-01
影响因子：
11.1
通讯作者：
Weiss, Stephen J.
中科院分区：
文献类型：
--
作者：
Ota, Ichiro;Li, Xiao-Yan;Weiss, Stephen J.
在原发部位产生的癌细胞跨越基底膜（一种特殊形式的细胞外基质，覆盖所有上皮细胞）并进入宿主脉管系统的能力是恶性表型的核心特征。侵袭性表型的开始与锌指转录抑制因子的异常表达有关，如Snail1，其作用是通过调节大部分未定义的下游效应物触发上皮-间充质细胞样转化（emt样）。在此，我们发现Snail1通过基质金属蛋白酶（MMP）依赖性过程诱导癌细胞(i)降解并穿透基底膜屏障，（ii）启动血管生成，以及（iii）体内血管内网络。出乎意料的是，完整的Snail1入侵程序可以通过直接表达膜锚定金属蛋白酶MT1-MMP或MT2-MMP来重现。相对于所有其他金属蛋白酶家族成员，MT1-MMP和MT2-MMP的促侵袭、血管生成和转移活性是独一无二的，并且在体内不能被分泌的MMPs、MMP-1、MMP-2、MMP-3、MMP-7、MMP-9或MMP-13所模仿。此外，sirna特异性沉默MT1-MMP和MT2-MMP完全削弱了Snail1驱动癌细胞BM侵袭、诱导血管生成或触发体内浸润的能力。综上所述，这些数据表明MT1-MMP和MT2-MMP作为直接作用的促侵袭因子协同作用，赋予snail1触发的细胞与癌症发病率和死亡率最常见的关键活性。
The ability of carcinoma cells arising at primary sites to cross their underlying basement membrane (BM), a specialized form of extracellular matrix that subtends all epithelial cells, and to access the host vasculature are central features of the malignant phenotype. The initiation of the invasive phenotype has been linked to the aberrant expression of zinc-finger transcriptional repressors, like Snail1, which act by triggering an epithelial-mesenchymal cell-like transformation (EMT-like) via the regulation of largely undefined, downstream effectors. Herein, we find that Snail1 induces cancer cells to (i) degrade and perforate BM barriers, (ii) initiate angiogenesis, and (iii) and intravasate vascular networks in vivo via a matrix metalloproteinase (MMP)-dependent process. Unexpectedly, the complete Snail1 invasion program can be recapitulated by expressing directly either of the membrane-anchored metalloproteinases, MT1-MMP or MT2-MMP. The pro-invasive, angiogenic, and metastatic activities of MT1-MMP and MT2-MMP are unique relative to all other metalloproteinase family members and cannot be mimicked in vivo by the secreted MMPs, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, or MMP-13. Further, siRNA-specific silencing of MT1-MMP and MT2-MMP ablates completely the ability of Snail1 to drive cancer cell BM invasion, induce angiogenesis, or trigger intravasation. Taken together, these data demonstrate that MT1-MMP and MT2-MMP cooperatively function as direct-acting, pro-invasive factors that confer Snail1-triggered cells with the key activities most frequently linked to morbidity and mortality in cancer.