Less is more: low expression of MT1-MMP is optimal to promote migration and tumourigenesis of breast cancer cells

Cepeda, Mario; Pelling, Jacob J. H.; Evered, Caitlin L.; Williams, Karla C.; Freedman, Zoey; Stan, Ioana; Willson, Jessica A.; Leong, Hon S.; Damjanovski, Sashko

doi:10.1186/s12943-016-0547-x

Cited by 33 publications

(51 citation statements)

References 75 publications

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“…When tested for their ability to inhibit the gelatinolytic activity of MMP9, our MMP9-selective N-TIMP2 variants showed selective inhibition of MMP9 stably expressed by MCF-7-MMP9 cells. The same effect was observed in a different experimental system in which cell migration/mobility, previously shown to be dependent on the expression of MMP9 and MMP14, of MCF-7 cells stably expressing MMP9 was measured [ 77 , 79 ]. Inhibited mobility was caused by N-TIMP2 WT and the specific MMP9-inhibiting N-TIMP2 protein variants at 100 nM concentrations, whereas no inhibition was observed with any of the MMP14-specific N-TIMP2 variants.…”

Section: Discussionsupporting

confidence: 69%

“…Many cancer cell lines express both MMP14 and MMP9 [ 74 , 75 ]. To assess the specific effects of our selective inhibitors on each MMP, we utilized the MCF-7 breast cancer cell line that is naturally MMP14- and MMP9-deficient [ 76 , 77 ]. First, we stably transfected the cells with a full-length MMP9 construct to generate MCF-7-MMP9 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Wild type MCF-7 cells lack migratory abilities [ 78 ] due to a lack of MMP14 expression [ 77 ]. At the same time, stable expression of MMP14 in these cells induced migration and invasion [ 77 ]. Previous works also showed that induction of MMP9 expression increased the invasiveness of MCF-7 cells [ 79 ].…”

Section: Resultsmentioning

confidence: 99%

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Combinatorial engineering of N-TIMP2 variants that selectively inhibit MMP9 and MMP14 function in the cell

2018

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Developing selective inhibitors for proteolytic enzymes that share high sequence homology and structural similarity is important for achieving high target affinity and functional specificity. Here, we used a combination of yeast surface display and dual-color selective library screening to obtain selective inhibitors for each of the matrix metalloproteinases (MMPs) MMP14 and MMP9 by modifying the non-specific N-terminal domain of the tissue inhibitor of metalloproteinase-2 (N-TIMP2). We generated inhibitor variants with 30- to 1175-fold improved specificity to each of the proteases, respectively, relative to wild type N-TIMP2. These biochemical results accurately predicted the selectivity and specificity obtained in cell-based assays. In U87MG cells, the activation of MMP2 by MMP14 was inhibited by MMP14-selective blockers but not MMP9-specific inhibitors. Target specificity was also demonstrated in MCF-7 cells stably expressing either MMP14 or MMP9, with only the MMP14-specific inhibitors preventing the mobility of MMP14-expressing cells. Similarly, the mobility of MMP9-expressing cells was inhibited by the MMP9-specific inhibitors, yet was not altered by the MMP14-specific inhibitors. The strategy developed in this study for improving the specificity of an otherwise broad-spectrum inhibitor will likely enhance our understanding of the basis for target specificity of inhibitors to proteolytic enzymes, in general, and to MMPs, in particular. We, moreover, envision that this study could serve as a platform for the development of next-generation, target-specific therapeutic agents. Finally, our methodology can be extended to other classes of proteolytic enzymes and other important target proteins.

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Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

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Combinatorial engineering of N-TIMP2 variants that selectively inhibit MMP9 and MMP14 function in the cell

2018

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“…24 Recent studies demonstrated that MMPs play fundamental roles in the migration and proliferation of tumor cells. 25 Additionally, high levels of MMP expression are associated with NPC development. Yang et al 26 reported that MMP2 and MMP9 promote NPC metastasis, and Hsu et al 27 showed that MMP9 enhances human NPC cell invasion.…”

Section: Discussionmentioning

confidence: 99%

The long noncoding RNA FOXCUT promotes proliferation and migration by targetingFOXC1in nasopharyngeal carcinoma

Chen

Zhao

et al. 2017

Tumour Biol.

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Long noncoding RNAs play an important role in various biological processes, including tumorigenesis. FOXC1 (Forkhead box C1) is a member of the Forkhead box family of transcription factors and plays a crucial role in nasopharyngeal carcinoma. In this study, a novel long noncoding RNA (FOXCUT) located upstream of FOXC1 was investigated in 42 nasopharyngeal carcinoma patients. Our analysis revealed that the expression levels of FOXCUT and FOXC1 in nasopharyngeal carcinoma tissues were significantly higher than those observed in chronic nasopharyngitis tissues and that FOXCUT expression was positively correlated with FOXC1 expression. Additionally, knockdown of FOXCUT significantly inhibited proliferation and migration of nasopharyngeal carcinoma cell lines and resulted in downregulated expression of the matrix metalloproteinase 7 and matrix metalloproteinase 9, as well as vascular endothelial growth factor A and β-catenin. Our findings suggested that FOXCUT expression contributed to the development and progression of nasopharyngeal carcinoma by targeting FOXC1 and that FOXCUT might be useful as a potential nasopharyngeal carcinoma biomarker and therapeutic target.

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“…Of these, MT1-MMP (membrane type-1 matrix metalloproteinase, MMP14) is a key protease that activates pro-MMPs such as MMP2 and MMP9 and is associated with ECM degradation and cell migration during cancer metastasis [33, 34]. Cepeda et al reported that optimal levels of active MT1-MMP required the elevated pERK levels in breast cancer [35]. Lin et al also showed that MT1-MMP mediated breast cancer invasion possibly through activating MAPK/ERK pathway [36].…”

Section: Discussionmentioning

confidence: 99%

DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

Liu

Wen

Zhou

et al. 2019

BioMed Research International

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Background. Doublecortin-like kinase 1 (DCLK1) has been universally identified as a cancer stem cell (CSC) marker and is found to be overexpressed in many types of cancers including breast cancer. However, there is little data regarding the functional role of DCLK1 in breast cancer metastasis. In the present study, we sought to investigate whether and how DCLK1 plays a metastatic-promoting role in human breast cancer cells. Methods. We used Crispr/Cas9 technology to knock out DCLK1 in breast cancer cell line BT474, which basically possesses DCLK1 at a higher level, and stably overexpressed DCLK1 in another breast cancer cell line, T47D, that basically expresses DCLK1 at a lower level. We further analyzed the alterations of metastatic characteristics and the underlying mechanisms in these cells. Results. It was shown that, compared with the corresponding control cells, DCLK1 overexpression led to an increase in metastatic behaviors including enhanced migration and invasion of T47D cells. By contrast, forced depletion of DCLK1 drastically inhibited these metastatic characteristics in BT474 cells. Mechanistically, the epithelial-mesenchymal transition (EMT) program, which is critical for cancer metastasis, was prominently activated in DCLK1-overexpressing cancer cells, evidenced by a decrease in an epithelial marker ZO-1 and an enhancement in several mesenchymal markers including ZEB1 and Vimentin. In addition, DCLK1 overexpression induced the ERK MAPK pathway, which resultantly enhanced the expression of MT1-MMP that is also involved in cancer metastasis. Knockout of DCLK1 could reverse these events, further supporting a metastatic-promoting role for DCLK1. Conclusions. Collectively, our data suggested that DCLK1 overexpression may be responsible for the increased metastatic features in breast cancer cells. Targeting DCLK1 may become a therapeutic option for breast cancer metastasis.

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Less is more: low expression of MT1-MMP is optimal to promote migration and tumourigenesis of breast cancer cells

Cited by 33 publications

References 75 publications

Combinatorial engineering of N-TIMP2 variants that selectively inhibit MMP9 and MMP14 function in the cell

Combinatorial engineering of N-TIMP2 variants that selectively inhibit MMP9 and MMP14 function in the cell

The long noncoding RNA FOXCUT promotes proliferation and migration by targetingFOXC1in nasopharyngeal carcinoma

DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells

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