Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
Mol Cancer. 2011 Jul 21;10:87. doi: 10.1186/1476-4598-10-87.
Cancer progression is closely linked to the epithelial-mesenchymal transition (EMT) process. Studies have shown that there is increased expression of tissue tranglutaminase (TG2) in advanced invasive cancer cells. TG2 catalyzes the covalent cross-linking of proteins, exhibits G protein activity, and has been implicated in the modulation of cell adhesion, migration, invasion and cancer metastasis. This study explores the molecular mechanisms associated with TG2's involvement in the acquisition of the mesenchymal phenotype using the highly invasive A431-III subline and its parental A431-P cells.
The A431-III tumor subline displays increased expression of TG2. This is accompanied by enhanced expression of the mesenchymal phenotype, and this expression is reversed by knockdown of endogenous TG2. Consistent with this, overexpression of TG2 in A431-P cells advanced the EMT process. Furthermore, TG2 induced the PI3K/Akt activation and GSK3β inactivation in A431 tumor cells and this increased Snail and MMP-9 expression resulting in higher cell motility. TG2 also upregulated NF-κB activity, which also enhanced Snail and MMP-9 expression resulting in greater cell motility; interestingly, this was associated with the formation of a TG2/NF-κB complex. TG2 facilitated acquisition of a mesenchymal phenotype, which was reversed by inhibitors of PI3K, GSK3 and NF-κB.
This study reveals that TG2 acts, at least in part, through activation of the PI3K/Akt and NF-κB signaling systems, which then induce the key mediators Snail and MMP-9 that facilitate the attainment of a mesenchymal phenotype. These findings support the possibility that TG2 is a promising target for cancer therapy.
癌症的进展与上皮-间质转化（EMT）过程密切相关。研究表明，在晚期浸润性癌细胞中组织转谷氨酰胺酶（TG2）的表达增加。TG2 催化蛋白质的共价交联，表现出 G 蛋白活性，并与细胞黏附、迁移、侵袭和癌症转移的调节有关。本研究使用高侵袭性 A431-III 亚系及其亲本 A431-P 细胞，探讨 TG2 参与获得间充质表型的分子机制。
A431-III 肿瘤亚系显示 TG2 表达增加。这伴随着间充质表型的增强表达，并且这种表达通过内源性 TG2 的敲低而逆转。与此一致的是，在 A431-P 细胞中过表达 TG2 加速了 EMT 过程。此外，TG2 在 A431 肿瘤细胞中诱导 PI3K/Akt 激活和 GSK3β失活，从而增加 Snail 和 MMP-9 的表达，导致更高的细胞迁移性。TG2 还上调 NF-κB 活性，这也增强了 Snail 和 MMP-9 的表达，从而提高了细胞迁移性；有趣的是，这与 TG2/NF-κB 复合物的形成有关。TG2 促进获得间充质表型，这可以通过 PI3K、GSK3 和 NF-κB 的抑制剂逆转。
本研究表明，TG2 至少部分通过激活 PI3K/Akt 和 NF-κB 信号通路发挥作用，然后诱导关键介质 Snail 和 MMP-9，从而促进获得间充质表型。这些发现支持 TG2 可能是癌症治疗的一个有前途的靶点。
