Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes
Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes
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DOI：
10.1074/jbc.m110.146019
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发表时间：
2010-09-03
影响因子：
4.8
通讯作者：
Munshi, Hidayatullah G.
中科院分区：
文献类型：
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作者：
Dangi-Garimella, Surabhi;Redig, Amanda J.;Munshi, Hidayatullah G.
膜型1-基质金属蛋白酶（MT 1-MMP，MMP 14）与鳞状细胞癌（SCC）中细胞外基质（ECM）的降解有关，促进肿瘤形成和上皮-间质转化。然而，在这份报告中，我们表明，MT 1-MMP，通过切割底层ECM，导致角质形成细胞和SCC细胞的细胞聚集。用MMP抑制剂处理废除了MT 1-MMP诱导的表型变化，但降低E-cadherin表达并不影响MT 1-MMP诱导的细胞聚集。由于ROCK 1/2可以调节细胞-细胞和细胞-ECM相互作用，我们研究了其在介导MT 1-MMP诱导的表型变化中的作用。阻断ROCK 1/2表达或活性可消除由MT 1-MMP表达引起的细胞聚集。此外，阻断Rho和非肌肉肌球蛋白减弱MT 1-MMP诱导的表型变化。此外，SCC细胞表达的催化活性的MT 1-MMP蛋白表现出增加的细胞聚集和增加肌球蛋白II的活性，在体内皮下注射到裸鼠。总之，这些结果表明，MT 1-MMP的表达可能是抗肿瘤的角质形成细胞通过促进细胞聚集。
Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP14), which is associated with extracellular matrix (ECM) breakdown in squamous cell carcinoma (SCC), promotes tumor formation and epithelial-mesenchymal transition. However, in this report we demonstrate that MT1-MMP, by cleaving the underlying ECM, causes cellular aggregation of keratinocytes and SCC cells. Treatment with an MMP inhibitor abrogated MT1-MMP-induced phenotypic changes, but decreasing E-cadherin expression did not affect MT1-MMP-induced cellular aggregation. As ROCK1/2 can regulate cell-cell and cell-ECM interaction, we examined its role in mediating MT1-MMP-induced phenotypic changes. Blocking ROCK1/2 expression or activity abrogated the cellular aggregation resulting from MT1-MMP expression. Additionally, blocking Rho and nonmuscle myosin attenuated MT1-MMP-induced phenotypic changes. Moreover, SCC cells expressing only the catalytically active MT1-MMP protein demonstrated increased cellular aggregation and increased myosin II activity in vivo when injected subcutaneously into nude mice. Together, these results demonstrate that expression of MT1-MMP may be anti-tumorigenic in keratinocytes by promoting cellular aggregation.