Matrix metalloproteinase-2: A key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling

Das, Kaushik; Prasad, Ramesh; Ansari, Shabbir A.; Roy, Abhishek; Mukherjee, Ashis K.; Sen, Prosenjit

doi:10.1016/j.biopha.2018.05.155

Cited by 36 publications

(30 citation statements)

References 31 publications

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“…Moreover, an NF‐κB inhibitor suppressed the HAI‐1 loss‐mediated enhancement of tumorigenicity in Apc Min/+ mice . Protease‐activated receptor‐2 is known to activate NF‐κB signaling in various human cancers, including colon cancer, and HAI‐1 regulates PAR‐2‐activating TTSPs . Thus, the activation of NF‐κB in HAI‐1‐deficient intestine might result from the excessive activation of PAR‐2.…”

Section: Resultsmentioning

confidence: 99%

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

et al. 2020

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Hepatocyte growth factor activator inhibitor‐1 (HAI‐1), encoded by the SPINT1 gene, is a membrane‐bound protease inhibitor expressed on the surface of epithelial cells. Hepatocyte growth factor activator inhibitor‐1 regulates type II transmembrane serine proteases that activate protease‐activated receptor‐2 (PAR‐2). We previously reported that deletion of Spint1 in ApcMin/+ mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor‐κB signaling. In this study, we examined the role of PAR‐2 in accelerating tumor formation in the ApcMin/+ model in the presence or absence of Spint1. We observed that knockout of the F2rl1 gene, encoding PAR‐2, not only eliminated the enhanced formation of intestinal tumors caused by Spint1 deletion, but also reduced tumor formation in the presence of Spint1. Exacerbation of anemia and weight loss associated with HAI‐1 deficiency was also normalized by compound deficiency of PAR‐2. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA/p65, vascular endothelial growth factor expression, and vascular density in ApcMin/+‐induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR‐2, and that HAI‐1 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR‐2 activating proteases.

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Section: Resultsmentioning

confidence: 99%

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

et al. 2020

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“…1A. Our previous results depict that PAR2 activation in TNBC promotes enhanced cell migration and invasion (18,19), which are hallmarks of EMT (29,30), leading us to investigate whether incorporation of PAR2-activated MDAMB231-derived MV into MCF7 induces EMT in MCF7. To examine this, the above mentioned MV were incubated with MCF7 and the expression of EMT markers was analyzed.…”

Section: MV Generated From Mdamb231 Induce Emt In Mcf7 Via Akt/nf-b mentioning

confidence: 96%

“…As AKT and NF-B play pivotal roles in promoting EMT (31,32) and we observed activation of PAR2 either by FVIIa or trypsin signals through this AKT/NF-B axis (19) to guide us to examine whether the same pathway also triggers the induction of EMT in MCF7 by MV. MCF7 cells were pre-treated with either AKT siRNAs (Fig.…”

Section: MV Generated From Mdamb231 Induce Emt In Mcf7 Via Akt/nf-b mentioning

confidence: 98%

“…TF-FVIIamediated PAR2 cleavage activates AKT/glycogen synthase kinase 3␤ axis followed by ␤-catenin accumulation to induce metastasis of human TNBC cells (18). PAR2-driven AKT/ NF-B activation also promotes human TNBC cell migration and invasion via matrix metalloprotease-2 (MMP-2) induction (19). Previously, we have explored that PAR2 induction not only promotes human TNBC progression but also induces the release of MV with metastatic potential from human TNBC cells (10,11).…”

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confidence: 99%

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Triple-negative breast cancer-derived microvesicles transfer microRNA221 to the recipient cells and thereby promote epithelial-to-mesenchymal transition

Das

Paul

Singh

et al. 2019

Journal of Biological Chemistry

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Edited by Alex Toker The triple-negative phenotype is the most prevalent form of human breast cancer worldwide and is characterized by poor survival, high aggressiveness, and recurrence. Microvesicles (MV) are shredded plasma membrane components and critically mediate cell-cell communication, but can also induce cancer proliferation and metastasis. Previous studies have revealed that protease-activated receptor 2 (PAR2) contributes significantly to human triple-negative breast cancer (TNBC) progression by releasing nano-size MV and promoting cell proliferation, migration, and invasion. MV isolated from highly aggressive human TNBC cells impart metastatic potential to nonmetastatic cells. Over-expression of microRNA221 (miR221) has also been reported to enhance the metastatic potential of human TNBC, but miR221's relationship to PAR2-induced MV is unclear. Here, using isolated MV, immunoblotting, quantitative RT-PCR, FACS analysis, and enzymatic assays, we show that miR221 is translocated via human TNBC-derived MV, which upon fusion with recipient cells, enhance their proliferation, survival, and metastasis both in vitro and in vivo by inducing the epithelial-to-mesenchymal transition (EMT). Administration of anti-miR221 significantly impaired MV-induced expression of the mesenchymal markers Snail, Slug, N-cadherin, and vimentin in the recipient cells, whereas restoring expression of the epithelial marker E-cadherin. We also demonstrate that MV-associated miR221 targets phosphatase and tensin homolog (PTEN) in the recipient cells, followed by AKT Ser/Thr kinase (AKT)/NF-B activation, which promotes EMT. Moreover, elevated miR221 levels in MV derived from human TNBC patients' blood could induce cell proliferation and metastasis in recipient cells. In summary, miR221 transfer from TNBC cells via PAR2-derived MV induces EMT and enhances the malignant potential of recipient cells. This work was supported in part by Department of Science and Technology, Government of India DST SR/SO/BB-0125/2012 for project grants and a fellowship from the Council of Scientific and Industrial Research, India. The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1-S14 and Tables S1-S3.

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“…22,23 Both TF and PAR2 are over-expressed in invasive cancer. 24,25 Previous reports document the direct involvement of PAR2 in cancer cell proliferation, metastasis, and angiogenesis [26][27][28] and in particular, PAR2 is highly associated with human breast cancer. [29][30][31][32] PAR2 is also found to be essential for FVIIa and Xa-induced signaling relating to migration and invasion of breast cancer cells.…”

Section: Introductionmentioning

confidence: 98%

Protease‐activated receptor 2 promotes actomyosin dependent transforming microvesicles generation from human breast cancer

Das

Prasad

Singh

et al. 2018

Molecular Carcinogenesis

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Apart from blood coagulation, coagulation proteases are involved inextricably in cancer progression/propagation via intra/inter-cellular signaling, mediated predominantly by protease-activated receptors (PARs). Microvesicles (MVs), a plasma membrane shredded component, has recently been identified as an important contributor to human breast cancer metastasis. However, the role of PAR2 in promoting MVs generation from breast cancer cells remains largely unexplored. The objective of this study is to investigate whether coagulation protease-mediated human breast cancer propagation commences via MVs and also to decipher the underlying signaling mechanism. Here, we elicited that coagulation factor-FVIIa and Trypsin activates PAR2, which governs MVs shedding from MDAMB231 cells by altering actomyosin dynamics. Treatment of cells with PAR2 activators facilitate MVs generation by activating three independent (MAPK, P38, and Rho) signaling cascades. MAPK, signals through activating MLCK followed by MLC phosphorylation to alter myosin organization whereas, P38 reorganizes actin dynamics by the sequential activation of MK2 and HSP27. RhoA-dependent ROCK-II activation again contributes to remodeling myosin II activity. Further, both our in vitro and in vivo analyses showed that these MVs potentiate invasive and migratory property to the recipient cells. Breast cancer patients blood show an elevation of TF-bearing, pro-metastatic MVs than normal. These findings give an insight into the detailed signaling mechanism involved in the production of MVs with transforming ability from PAR2-activated human breast cancer cells. Understanding these mechanistic details will certainly help to identify crucial targets for therapeutic interventions in MVs-associated human breast cancer metastasis.

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Matrix metalloproteinase-2: A key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling

Cited by 36 publications

References 31 publications

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

Triple-negative breast cancer-derived microvesicles transfer microRNA221 to the recipient cells and thereby promote epithelial-to-mesenchymal transition

Protease‐activated receptor 2 promotes actomyosin dependent transforming microvesicles generation from human breast cancer

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Matrix metalloproteinase-2: A key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling

Cited by 36 publications

References 31 publications

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in ApcMin/+ mice

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in ApcMin/+ mice

Triple-negative breast cancer-derived microvesicles transfer microRNA221 to the recipient cells and thereby promote epithelial-to-mesenchymal transition

Protease‐activated receptor 2 promotes actomyosin dependent transforming microvesicles generation from human breast cancer

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Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc^Min/+ mice