Olmeda David, Moreno-Bueno Gema, Flores Juana M, Fabra Angels, Portillo Francisco, Cano Amparo
Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Madrid, Spain.
Cancer Res. 2007 Dec 15;67(24):11721-31. doi: 10.1158/0008-5472.CAN-07-2318.
The transcription factor, SNAI1 (Snail), has recently been proposed as an important mediator of tumor invasion because of its role in E-cadherin down-regulation and induction of epithelial-mesenchymal transition. In human breast cancer, the expression of SNAI1 and/or the homologous SNAI2 (Slug) has been associated with E-cadherin repression, local or distant metastasis, tumor recurrence, or poor prognosis in different tumor series. However, the specific contribution of either factor to breast tumor progression is still unclear. We have analyzed the role of SNAI1 in human breast cancer by loss of function studies and provide evidence of a major role for SNAI1 in both primary tumor growth and metastasis of human breast carcinoma MDA-MB-231 cells. Specific silencing of SNAI1 by short hairpin RNA induces a decrease in mesenchymal and proinvasive markers (MMP9, ID1, SPARC) in MDA-MB-231 cells, concomitant with reduced in vitro invasive behavior. More importantly, stable SNAI1 silencing in MDA-MB-231 cells leads to a dramatic reduction of in vivo tumor incidence and growth rate. Tumors induced by MDA-MB-231-SNAI1-silenced cells show extensive necrotic regions and a significant decrease in invasive and angiogenic markers. Moreover, SNAI1 silencing increases the sensitivity of MDA-MB-231 cells to chemotherapeutics relevant in breast cancer treatments, gemcitabine and docetaxel. Remarkably, analysis of cell lines derived from lymph node metastasis indicates that SNAI1 expression is required for metastatic dissemination.
转录因子SNAI1（蜗牛蛋白）最近被认为是肿瘤侵袭的重要介导因子，因为它在E-钙黏蛋白下调和上皮-间质转化诱导中发挥作用。在人类乳腺癌中，SNAI1和/或同源的SNAI2（蛞蝓蛋白）的表达与不同肿瘤系列中的E-钙黏蛋白抑制、局部或远处转移、肿瘤复发或预后不良相关。然而，这两种因子对乳腺肿瘤进展的具体贡献仍不清楚。我们通过功能丧失研究分析了SNAI1在人类乳腺癌中的作用，并提供证据表明SNAI1在人乳腺癌MDA-MB-231细胞的原发性肿瘤生长和转移中均起主要作用。通过短发夹RNA特异性沉默SNAI1可导致MDA-MB-231细胞中间质和促侵袭标志物（MMP9、ID1、SPARC）减少，同时体外侵袭行为降低。更重要的是，在MDA-MB-231细胞中稳定沉默SNAI1会导致体内肿瘤发生率和生长速率显著降低。由MDA-MB-231-SNAI1沉默细胞诱导的肿瘤显示出广泛的坏死区域，侵袭和血管生成标志物显著减少。此外，SNAI1沉默增加了MDA-MB-231细胞对乳腺癌治疗相关化疗药物吉西他滨和多西他赛的敏感性。值得注意的是，对源自淋巴结转移的细胞系分析表明，转移扩散需要SNAI1表达。
