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MMP proteolytic activity regulates cancer invasiveness by modulating integrins.

ABSTRACT: Cancer invasion through dense extracellular matrices (ECMs) is mediated by matrix metalloproteinases (MMPs) which degrade the ECM thereby creating paths for migration. However, how this degradation influences the phenotype of cancer cells is not fully clear. Here we address this question by probing the function of MMPs in regulating biophysical properties of cancer cells relevant to invasion. We show that MMP catalytic activity regulates cell spreading, motility, contractility and cortical stiffness by stabilizing integrins at the membrane and activating focal adhesion kinase. Interestingly, cell rounding and cell softening on stiff gels induced by MMP inhibition is attenuated on MMP pre-conditioned surfaces. Together, our results suggest that MMP catalytic activity regulates invasiveness of cancer cells by modulating integrins.

SUBMITTER: Das A

PROVIDER: S-EPMC5660204 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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MMP proteolytic activity regulates cancer invasiveness by modulating integrins.

Das Alakesh A Monteiro Melissa M Barai Amlan A Kumar Sandeep S Sen Shamik S

Scientific reports 20171027 1

Cancer invasion through dense extracellular matrices (ECMs) is mediated by matrix metalloproteinases (MMPs) which degrade the ECM thereby creating paths for migration. However, how this degradation influences the phenotype of cancer cells is not fully clear. Here we address this question by probing the function of MMPs in regulating biophysical properties of cancer cells relevant to invasion. We show that MMP catalytic activity regulates cell spreading, motility, contractility and cortical stiff ...[more]

PMID: 29079818

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Project description:BackgroundGolgin-97 is a tethering factor in the trans-Golgi network (TGN) and is crucial for vesicular trafficking and maintaining cell polarity. However, the significance of golgin-97 in human diseases such as cancer remains unclear.MethodsWe searched for a potential role of golgin-97 in cancers using Kaplan-Meier Plotter ( http://kmplot.com ) and Oncomine ( www.oncomine.org ) datasets. Specific functions of golgin-97 in migration and invasion were examined in golgin-97-knockdown and golgin-97-overexpressing cells. cDNA microarray, pathway analysis and qPCR were used to identify gene profiles regulated by golgin-97. The role of golgin-97 in NF-?B signaling pathway was examined by using subcellular fractionation, luciferase reporter assay, western blot analysis and immunofluorescence assay (IFA).ResultsWe found that low expression of golgin-97 correlated with poor overall survival of cancer patients and was associated with invasiveness in breast cancer cells. Golgin-97 knockdown promoted cell migration and invasion, whereas re-expression of golgin-97 restored the above phenotypes in breast cancer cells. Microarray and pathway analyses revealed that golgin-97 knockdown induced the expression of several invasion-promoting genes that were transcriptionally regulated by NF-?B p65. Mechanistically, golgin-97 knockdown significantly reduced I?B? protein levels and activated NF-?B, whereas neither I?B? levels nor NF-?B activity was changed in TGN46- or GCC185-knockdown cells. Conversely, golgin-97 overexpression suppressed NF-?B activity and restored the levels of I?B? in golgin-97-knockdown cells. Interestingly, the results of Golgi-disturbing agent treatment revealed that the loss of Golgi integrity was not involved in the NF-?B activation induced by golgin-97 knockdown. Moreover, both TGN-bound and cytosolic golgin-97 inhibited NF-?B activation, indicating that golgin-97 functions as an NF-?B suppressor regardless of its subcellular localization.ConclusionOur results collectively demonstrate a novel and suppressive role of golgin-97 in cancer invasiveness. We also provide a new avenue for exploring the relationship between the TGN, golgin-97 and NF-?B signaling in tumor progression.

Project description:Metastasis is the main cause of death in patients with colorectal cancer (CRC). Apart from platelets, platelet-derived microparticles (PMPs) are also considered important factors that can modify the activity of cancer cells. PMPs are incorporated by cancer cells and can also serve as intracellular signalling vesicles. PMPs are believed to affect cancer cells by upregulating their invasiveness. To date, there is no evidence that such a mechanism occurs in colorectal cancer. It has been shown that platelets can stimulate metalloproteases (MMPs) expression and activity via the p38MAPK pathway in CRC cells, leading to their elevated migratory potential. This study aimed to investigate the impact of PMPs on the invasive potential of CRC cells of various phenotypes via the MMP-2, MMP-9 and p38MAPK axis. We used various CRC cell lines, including the epithelial-like HT29 and the mesenchymal-like SW480 and SW620. Confocal imaging was applied to study PMP incorporation into CRC cells. The presence of surface receptors on CRC cells after PMP uptake was evaluated by flow cytometry. Transwell and scratch wound-healing assays were used to evaluate cell migration. The level of C-X-C chemokine receptor type 4 (CXCR4), MMP-2, and MMP-9 and the phosphorylation of ERK1/2 and p38MAPK were measured by western blot. MMP activity was determined using gelatine-degradation assays, while MMP release was evaluated by ELISA. We found that CRC cells could incorporate PMPs in a time-dependent manner. Moreover, PMPs could transfer platelet-specific integrins and stimulate the expression of integrins already present on tested cell lines. While mesenchymal-like cells expressed less CXCR4 than epithelial-like CRC cells, PMP uptake did not increase its intensity. No significant changes in CXCR4 level either on the surface or inside CRC cells were noticed. Levels of cellular and released MMP-2 and MMP-9 were elevated in all tested CRC cell lines after PMP uptake. PMPs increased the phosphorylation of p38MAPK but not that of ERK1/2. Inhibition of p38MAPK phosphorylation reduced the PMP-induced elevated level and release of MMP-2 and MMP-9 as well as MMP-dependent cell migration in all cell lines. We conclude that PMPs can fuse into both epithelial-like and mesenchymal-like CRC cells and increase their invasive potential by inducing the expression and release of MMP-2 and MMP-9 via the p38MAPK pathway, whereas CXCR4-related cell motility or the ERK1/2 pathway appears to not be affected by PMPs. Video Abstract.

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MMP proteolytic activity regulates cancer invasiveness by modulating integrins.

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MMP proteolytic activity regulates cancer invasiveness by modulating integrins.

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