转谷氨酰胺酶 2 通过 MEK/ERK 信号通路调节结直肠癌细胞中基质金属蛋白酶 7 的表达，从而促进上皮细胞向间质细胞的转变。
Transglutaminase 2 promotes epithelial-to-mesenchymal transition by regulating the expression of matrix metalloproteinase 7 in colorectal cancer cells via the MEK/ERK signaling pathway.
发表日期：2024 Oct 08
作者：
Roman A Blaheta, Jiaoyan Han, Elsie Oppermann, Wolf Otto Bechstein, Katrin Burkhard, Axel Haferkamp, Michael A Rieger, Patrizia Malkomes
来源：
Bba-Mol Basis Dis
摘要：
组织转谷氨酰胺酶 2 (TGM2) 和基质金属蛋白酶 7 (MMP7) 被认为参与癌症的发生和进展，然而，它们在结肠癌中的具体作用仍然难以捉摸。本研究调查了 TGM2 和 MMP7 是否影响结肠癌细胞的上皮间质转化 (EMT) 过程。 TGM2 在 SW480 和 HCT-116 细胞中过表达或被敲低，并分析了 MMP7 的表达和活性。相反，MMP7 被沉默，并检查其与 TGM2 表达和活性的相关性。免疫共沉淀用于评估 TGM2-MMP7 相互作用。 TGM2 和 MMP7 表达与侵袭、迁移、EMT 标志物表达（E-钙粘蛋白、N-钙粘蛋白、Slug、Snail）和 ERK/MEK 信号传导相关。 TGM2过表达增强MMP7表达和活性，促进细胞侵袭、迁移和EMT，其特征是N-钙粘蛋白和Snail/Slug表达增加。 TGM2 敲低导致相反的效果。敲除 MMP7 与 TGM2 蛋白表达、细胞侵袭和迁移减少有关。 MMP7 的下调会减弱 ERK/MEK 信号传导，而上调则激活该通路。 ERK 抑制剂 GDC-0994 阻断 MEK/ERK 磷酸化并抑制 TGM2 和 MMP7。 TGM2 与结肠癌细胞中的 MMP7 通讯，通过 MEK/ERK 信号通路迫使细胞迁移和侵袭，并触发 EMT。因此，抑制 TGM2 可以为结肠癌患者的治疗提供新的治疗选择，特别是预防转移进展。版权所有 © 2024。由 Elsevier B.V. 出版。
Tissue transglutaminase 2 (TGM2) and matrix metalloproteinase 7 (MMP7) are suggested to be involved in cancer development and progression, however, their specific role in colon cancer remains elusive. The present study investigated whether TGM2 and MMP7 influence epithelial-mesenchymal-transition (EMT) processes of colon cancer cells. TGM2 was either overexpressed or knocked down in SW480 and HCT-116 cells, and MMP7 expression and activity analyzed. Conversely, MMP7 was silenced and its correlation with TGM2 expression and activity examined. Co-immunoprecipitation served to evaluate TGM2-MMP7-interaction. TGM2 and MMP7 expression were correlated with invasion, migration, EMT marker expression (E-cadherin, N-cadherin, Slug, Snail), and ERK/MEK signaling. TGM2 overexpression enhanced MMP7 expression and activity, promoted cell invasion, migration and EMT, characterized by increased N-cadherin and Snail/Slug expression. TGM2 knockdown resulted in the opposite effects. Knocking down MMP7 was associated with reduced TGM2 protein expression, cell invasion and migration. Down-regulation of MMP7 diminished ERK/MEK signaling, whereas its up-regulation activated this pathway. The ERK-inhibitor GDC-0994 blocked phosphorylation of MEK/ERK and suppressed TGM2 and MMP7. TGM2 communicates with MMP7 in colon cancer cells forces cell migration and invasion by the MEK/ERK signaling pathway and triggers EMT. Inhibiting TGM2 could thus offer new therapeutic options to treat patients with colon cancer, particularly to prevent metastatic progression.Copyright © 2024. Published by Elsevier B.V.