摘要
膜型基质金属蛋白酶(MT1-MMP,MMP-14)与肿瘤的侵袭和转移相关,可导致患者预后较差。MT1-MMP介导了癌细胞的入侵,通过基底膜和细胞外基质的降解以及细胞迁移的诱导。然而,在癌间质中MT1-MMP的表达可以带动体内癌细胞浸润,提示了MT1-MMP也可以通过paracrinemediated机制促进肿瘤侵袭。在癌细胞转移的重要一步是上皮-间质转化(EMT),在癌细胞中从静止的上皮表型进化到一个更能动的间质表型。我们在这里发现,EMT是引发MT1 MMP介导TGF-β的信号通路,包括持续诱导CUTL1,Wnt5a表达内源性MT1-MMP。恢复上皮表型MT1-MMP与Smad4,CUTL1癌细胞间质,或Wnt5a表达或TGF-β的活性受到抑制。在MT1 MMP表达Wnt5a抑制了LNCaP细胞的下降,以及迁移和软琼脂生长。而MT1-MMP的表达不影响总TGF-β水平,MT1-MMP的催化活性增加了TGF-β的主动性,使MT1-MMP的表达细胞激活了EMT周围的细胞。MT1-MMP表达细胞共培养了non-mt1-mmp-expressing细胞的TGF-依赖过程。这些结果强调了,肿瘤的侵袭性可能扩大通过MT1 MMP介导TGF-β信号,使自分泌和旁分泌介导EMT的通路
关键词: MT1-MMP;EMT;TGF-ββ;CUTL1;前列腺癌。
Current Cancer Drug Targets
Title:MT1-MMP Activation of TGF-β Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer
Volume: 16 Issue: 7
Author(s): Hoang-Lan Nguyen, Pournima Kadam, Alex Helkin, Kevin Cao, Song Wu, Ghassan J. Samara, Qian Zhang, Stanley Zucker, Jian Cao
Affiliation:
关键词: MT1-MMP;EMT;TGF-ββ;CUTL1;前列腺癌。
摘要: Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) is associated with cancer invasion and metastasis leading to poor patient prognosis. MT1-MMP mediates cancer cell invasion via degradation of basement membrane and extracellular matrix, and induction of cell migration. However, MT1-MMP expression in the cancer stroma can drive invasion of carcinoma cells in vivo, suggesting MT1-MMP may also promote cancer invasiveness via paracrinemediated mechanisms. A major step in cancer cell metastasis is thought to be an epithelial-mesenchymal transition (EMT), in which carcinoma cells evolve from a stationary epithelial phenotype to a more motile mesenchymal phenotype. We demonstrate here that EMT is triggered by MT1-MMP-mediated activation of TGF-β signaling, involving induction of CUTL1 and subsequently, of Wnt5a. Mesenchymal-like cancer cells expressing endogenous MT1-MMP reverted to an epithelial phenotype when MT1-MMP, SMAD4, CUTL1, or Wnt5a expression or TGF-β activity was inhibited. Wnt5a knockdown in MT1- MMP expressing LNCaP cells caused decreased cell migration and cell growth in soft agar. While MT1-MMP expression did not affect total TGF-β level, MT1-MMP catalytic activity increased the availability of active TGF-β, enabling MT1-MMP-expressing cells to activate the EMT in nearby cells. MT1-MMP-expressing cells induced co-cultured non-MT1-MMP-expressing cells to undergo EMT by a TGF-β-dependent process. These results highlight a pathway by which tumor invasiveness may be expanded via MT1-MMP-mediated activation of TGF-β signaling, enabling autocrine and paracrine-mediated induction of EMT.
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Cite this article as:
Hoang-Lan Nguyen, Pournima Kadam, Alex Helkin, Kevin Cao, Song Wu, Ghassan J. Samara, Qian Zhang, Stanley Zucker, Jian Cao , MT1-MMP Activation of TGF-β Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer, Current Cancer Drug Targets 2016; 16 (7) . https://dx.doi.org/10.2174/1568009616666160216125634
DOI https://dx.doi.org/10.2174/1568009616666160216125634 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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