Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival.
Transglutaminase Is Required for Epidermal Squamous Cell Carcinoma Stem Cell Survival.
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DOI：
10.1158/1541-7786.mcr-14-0685-t
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Kerr C
中科院分区：
文献类型：
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作者：
Fisher ML;Keillor JW;Xu W;Eckert RL;Kerr C
癌症干细胞被认为是负责快速肿瘤生长，转移和增强肿瘤存活后的药物治疗。由于这个原因，主要强调鉴定可以靶向杀死癌症干细胞或控制其生长的蛋白质，并且II型转氨酶（TGM 2/TG 2）是表皮鳞状细胞癌中的这种靶点。TG 2最初被描述为细胞外基质（ECM）中的转酰胺酶，其通过催化ε-（γ-谷氨酰基）赖氨酸键来交联蛋白质。然而，随后的研究表明，TG 2是一种GTP结合蛋白，在细胞信号传导和存活中起着重要作用。在本研究中，TG 2显示出作为人类鳞状细胞癌中抗癌干细胞治疗靶点的希望。TG 2在表皮癌干细胞（ECS细胞）中被确定为高度升高，并且TG 2敲低或用抑制剂抑制TG 2功能减少了ECS细胞存活、球状体形成、基质胶侵袭和迁移。存活率的降低与细胞凋亡的激活有关。使用TG 2突变体的机制研究表明，GTP结合活性是维持ECS细胞生长和存活所必需的，并且TG 2在ECS细胞中的作用不是由NFκB信号传导介导的。该研究表明，TG 2在维持癌症干细胞存活、侵袭和转移行为中具有重要作用，并且是降低表皮鳞状细胞癌中癌症干细胞存活的重要治疗靶点。
Cancer stem cells are thought to be responsible for rapid tumor growth, metastasis and enhanced tumor survival following drug treatment. For this reason, there is a major emphasis on identifying proteins that can be targeted to kill cancer stem cells or control their growth and transglutaminase type II (TGM2/TG2) is such a target in epidermal squamous cell carcinoma. TG2 was originally described as a transamidase in the extracellular matrix (ECM) that crosslinks proteins by catalyzing ε-(γ-glutamyl)lysine bonds. However, subsequent studies have shown that TG2 is a GTP binding protein that plays an important role in cell signaling and survival. In the present study, TG2 shows promise as a target for anti-cancer stem cell therapy in human squamous cell carcinoma. TG2 was determined to be highly elevated in epidermal cancer stem cells (ECS cells) and TG2 knockdown or suppression of TG2 function with inhibitors reduced ECS cell survival, spheroid formation, matrigel invasion and migration. The reduction in survival is associated with activation of apoptosis. Mechanistic studies, using TG2 mutants revealed that the GTP-binding activity is required for maintenance of ECS cell growth and survival, and that the action of TG2 in ECS cells is not mediated by NFκB signaling. This study suggests that TG2 has an important role in maintaining cancer stem cell survival, invasive and metastatic behavior, and is an important therapeutic target to reduce survival of cancer stem cells in epidermal squamous cell carcinoma.