Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Oncogene. 2012 May 17;31(20):2521-34. doi: 10.1038/onc.2011.429. Epub 2011 Oct 3.
Tissue transglutaminase (TG2), an enzyme involved in cell proliferation, differentiation and apoptosis is overexpressed in ovarian carcinomas, where it modulates epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Its regulation in ovarian cancer (OC) remains unexplored. Here, we show that transforming growth factor (TGF)-β, a cytokine involved in tumor dissemination is abundantly secreted in the OC microenvironment and induces TG2 expression and enzymatic activity. This is mediated at transcriptional level by SMADs and by TGF-β-activated kinase 1-mediated activation of the nuclear factor-κB complex. TGF-β-stimulated OC cells aggregate as spheroids, which enable peritoneal dissemination. We show that TGF-β-induced TG2 regulates EMT, formation of spheroids and OC metastasis. TG2 knock-down in OC cells decreases the number of cells harboring a cancer stem cell phenotype (CD44+/CD117+). Furthermore, CD44+/CD117+ cells isolated from human ovarian tumors express high levels of TG2. In summary, TGF-β-induced TG2 enhances ovarian tumor metastasis by inducing EMT and a cancer stem cell phenotype.
组织转谷氨酰胺酶（TG2）是一种参与细胞增殖、分化和凋亡的酶，在卵巢癌中过度表达，它调节上皮间质转化（EMT）并促进转移。其在卵巢癌（OC）中的调节尚不清楚。在这里，我们表明，转化生长因子（TGF）-β，一种参与肿瘤扩散的细胞因子，在 OC 微环境中大量分泌，并诱导 TG2 的表达和酶活性。这是通过 SMADs 在转录水平上介导的，以及通过 TGF-β激活激酶 1 介导的核因子-κB 复合物的激活。TGF-β 刺激的 OC 细胞聚集形成球体，从而实现腹膜扩散。我们表明，TGF-β 诱导的 TG2 调节 EMT、球体形成和 OC 转移。OC 细胞中的 TG2 敲低会减少具有癌症干细胞表型（CD44+/CD117+）的细胞数量。此外，从人卵巢肿瘤中分离的 CD44+/CD117+细胞表达高水平的 TG2。总之，TGF-β 诱导的 TG2 通过诱导 EMT 和癌症干细胞表型增强卵巢肿瘤转移。
