Epithelial-to-Mesenchymal Transition and Ovarian Tumor Progression Induced by Tissue Transglutaminase
Epithelial-to-Mesenchymal Transition and Ovarian Tumor Progression Induced by Tissue Transglutaminase
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DOI：
10.1158/0008-5472.can-09-1257
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Matei, Daniela
中科院分区：
文献类型：
--
作者：
Shao, Minghai;Cao, Liyun;Matei, Daniela
组织转氨酶（TG 2）是一种催化钙离子依赖性蛋白质聚集和聚合的酶，在卵巢癌细胞和肿瘤中过表达。我们先前报道了使用腹腔内异种移植模型，TG 2促进肿瘤扩散。在这里，我们表明，TG 2调节上皮间质转化（EMT），有助于增加卵巢癌细胞的侵袭力和肿瘤转移。通过在上皮性卵巢癌细胞中使用稳定的敲除和过表达，我们表明TG 2诱导间充质表型，其特征在于在基质胶基质中的钙粘蛋白开关和侵袭行为。这是通过改变包括Zeb 1在内的几种转录抑制因子的表达水平和功能在转录水平介导的。TG 2诱导Zeb 1的一种机制是通过激活核因子-κ B复合物。TG 2对卵巢癌细胞表型和侵袭性的影响转化为体内肿瘤形成和转移的增加，如通过原位卵巢异种移植模型所评估的。TG 2在卵巢肿瘤中高度表达，通过激活致癌信号促进EMT并增强卵巢肿瘤转移。[Cancer Res 2009;69（24）：9192-201]
Tissue transglutaminase (TG2), an enzyme that catalyzes Ca2+-dependent aggregation and polymerization of proteins, is overexpressed in ovarian cancer cells and tumors. We previously reported that TG2 facilitates tumor dissemination using an i.p. xenograft model. Here we show that TG2 modulates epithelial-to-mesenchymal transition (EMT), contributing to increased ovarian cancer cell invasiveness and tumor metastasis. By using stable knockdown and overexpression in epithelial ovarian cancer cells, we show that TG2 induces a mesenchymal phenotype, characterized by cadherin switch and invasive behavior in a Matrigel matrix. This is mediated at the transcriptional level by altering the expression levels and function of several transcriptional repressors, including Zeb1. One mechanism through which TG2 induces Zeb1 is by activating the nuclear factor-kappa B complex. The effects of TG2 on ovarian cancer cell phenotype and invasiveness translate into increased tumor formation and metastasis in vivo, as assessed by an orthotopic ovarian xenograft model. Highly expressed in ovarian tumors, TG2 promotes EMT and enhances ovarian tumor metastasis by activating oncogenic signaling. [Cancer Res 2009;69(24):9192-201]