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

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-10-09 DOI:10.1016/j.bbadis.2024.167538

Roman A. Blaheta , Jiaoyan Han , Elsie Oppermann , Wolf Otto Bechstein , Katrin Burkhard , Axel Haferkamp , Michael A. Rieger , Patrizia Malkomes

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引用次数: 0

Abstract

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.

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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转化。

组织转谷氨酰胺酶 2（TGM2）和基质金属蛋白酶 7（MMP7）被认为参与了癌症的发生和发展，但它们在结肠癌中的具体作用仍不明确。本研究探讨了 TGM2 和 MMP7 是否会影响结肠癌细胞的上皮-间质转化（EMT）过程。在 SW480 和 HCT-116 细胞中过表达或敲除 TGM2，并分析 MMP7 的表达和活性。反之，则对 MMP7 进行沉默，并检测其与 TGM2 表达和活性的相关性。共免疫沉淀用于评估 TGM2 与 MMP7 的相互作用。TGM2和MMP7的表达与侵袭、迁移、EMT标记物（E-cadherin、N-cadherin、Slug、Snail）的表达以及ERK/MEK信号转导相关。TGM2的过表达增强了MMP7的表达和活性，促进了细胞的侵袭、迁移和EMT，其特征是N-adherin和Snail/Slug的表达增加。而敲除 TGM2 则会产生相反的效果。敲除 MMP7 与 TGM2 蛋白表达、细胞侵袭和迁移减少有关。下调 MMP7 会减少 ERK/MEK 信号传导，而上调则会激活这一途径。ERK抑制剂GDC-0994阻断了MEK/ERK的磷酸化，抑制了TGM2和MMP7。TGM2 与结肠癌细胞中的 MMP7 通过 MEK/ERK 信号通路进行交流，迫使细胞迁移和侵袭，并引发 EMT。因此，抑制 TGM2 可为治疗结肠癌患者提供新的治疗方案，尤其是防止转移进展。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.