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MT1-MMP Activation of TGF-β Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer

[ Vol. 16 , Issue. 7 ]

Author(s):

Hoang-Lan Nguyen, Pournima Kadam, Alex Helkin, Kevin Cao, Song Wu, Ghassan J. Samara, Qian Zhang, Stanley Zucker and Jian CaoPages 618-630 (13)

Abstract:


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.

Keywords:

MT1-MMP, EMT, TGF-β, CUTL1, prostate cancer.

Affiliation:

Department of Medicine, Stony Brook University, Stony Brook, NY 11794.



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