Transglutaminase 2 (TG2) is an important cancer stem-like cell survival protein that is highly expressed in epidermal squamous cell carcinoma and drives an aggressive cancer phenotype. In the present study, we show that TG2 knockdown or inactivation results in a reduction in mammalian target of rapamycin (mTOR) level and activity in epidermal cancer stem-like cells which are associated with reduced spheroid formation, invasion, and migration, and reduced cancer stem cell and epithelial–mesenchymal transition (EMT) marker expression. Similar changes were observed in both cultured cells and tumors. mTOR knockdown or treatment with rapamycin phenocopies the reduction in spheroid formation, invasion, and migration, and cancer stem cell and EMT marker expression. Moreover, mTOR appears to be a necessary mediator of TG2 action, as a forced expression of constitutively active mTOR in TG2 knockdown cells partially restores the aggressive cancer phenotype and cancer stem cell and EMT marker expression. Tumor studies show that rapamycin reduces tumor growth and cancer stem cell marker expression and EMT. These studies suggest that TG2 stimulates mTOR activity to stimulate cancer cell stemness and EMT and drive aggressive tumor growth.

中文翻译：

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转谷氨酰胺酶 2 癌细胞存活因子维持 mTOR 活性以驱动侵袭性癌症表型


转谷氨酰胺酶 2 (TG2) 是一种重要的癌症干细胞样细胞存活蛋白，在表皮鳞状细胞癌中高表达并驱动侵袭性癌症表型。在本研究中，我们发现 TG2 敲低或失活会导致表皮癌干细胞中哺乳动物雷帕霉素靶点 (mTOR) 水平和活性的降低，这与球体形成、侵袭和迁移的减少以及癌症的减少有关干细胞和上皮间质转化（EMT）标记物的表达。在培养的细胞和肿瘤中也观察到类似的变化。 mTOR 敲除或雷帕霉素治疗可减少球体形成、侵袭和迁移，以及癌症干细胞和 EMT 标志物表达的减少。此外，mTOR 似乎是 TG2 作用的必要介质，因为 TG2 敲低细胞中组成型活性 mTOR 的强制表达可部分恢复侵袭性癌症表型以及癌症干细胞和 EMT 标志物的表达。肿瘤研究表明雷帕霉素可减少肿瘤生长、癌症干细胞标志物表达和 EMT。这些研究表明，TG2 刺激 mTOR 活性，从而刺激癌细胞干性和 EMT 并驱动肿瘤侵袭性生长。