Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis

@article{Sales2014NonhematopoieticPI,
  title={Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis},
  author={Katiuchia Uzzun Sales and Stine Friis and Joanne E. Konkel and Sine Godiksen and Marcia Hatakeyama and Karina K. Hansen and S{\'i}lvia Regina Rogatto and Roman Szabo and Lotte K. Vogel and Wanjun Chen and J. Silvio Gutkind and Thomas H. Bugge},
  journal={Oncogene},
  year={2014},
  volume={34},
  pages={346 - 356}
}
The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of… 
Matriptase promotes inflammatory cell accumulation and progression of established epidermal tumors
TLDR
The data suggest that matriptase-dependent signaling may be a therapeutic target for both squamous cell carcinoma chemoprevention and for the treatment of established tumors.
Downregulation of matriptase suppresses the PAR-2/PLCγ2/PKC-mediated invasion and migration abilities of MCF-7 breast cancer cells
TLDR
Light is shed on the mechanism underlying the role of matriptase in MCF-7 cell invasion and migration ability, and it is suggested that matript enzyme modulation could be a promising therapeutic strategy for preventing breast cancer metastasis.
Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma*
TLDR
Data support a model wherein KLK5-mediated PAR-2 activation regulates the expression of inflammation-associated mRNAs and microRNAs, thereby modulating progression of oral tumors.
Inhibition of nuclear factor-κB signaling suppresses Spint1-deletion-induced tumor susceptibility in the ApcMin/+ model
TLDR
Investigation of the effect of dehydroxymethylepoxyquinomicin (DHMEQ), a synthetic inhibitor of NF-κB, on intestinal HAI-1-deficient ApcMin/+ mice found that treatment with DHMEQ reduced the formation of intestinal tumors compared with vehicle control.
PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells.
TLDR
PAR2/GSK3β is identified as a novel pathway that plays a critical role in the regulation of stem/progenitor cell survival and proliferation in normal colon crypts and colon cancer.
Deregulated matriptase activity in oral squamous cell carcinoma promotes the infiltration of cancer‐associated fibroblasts by paracrine activation of protease‐activated receptor 2
TLDR
The enhanced migration induced by HAI‐1‐insufficiency was mediated by PAR‐2 activation in fibroblasts, which resulted from the deregulation of the activity of matriptase, aPAR‐2 agonist protease, which may prevent CAF recruitment to OSCC by controlling matript enzyme activity.
Expression of protease activating receptor-2 (PAR-2) is positively correlated with the recurrence of non-muscle invasive bladder cancer: an immunohistochemical analysis
TLDR
Increased expression of PAR-2 was significantly correlated with worse recurrence rate in patients with NMIBC, and expression of matriptase indicated a tendency toward recurrence in high-grade UC, suggesting an important role ofMatriptase-inducedPAR-2 activation in N MIBC.
Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX
TLDR
It is demonstrated that zebrafish hai1a mutants show increased H2O2, NfκB signalling, and IP3R -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility, while inhibition of the Gq subunit in hai 1a mutants rescues both the inflammation and epithelial phenotypes.
Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis.
TLDR
These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model and suggest targeting matript enzyme, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF.
The Protease Inhibitor HAI-2, but Not HAI-1, Regulates Matriptase Activation and Shedding through Prostasin*
TLDR
Genetically engineered mice were used to determine the effect of ablation of endogenous HAI-1 and endogenousHAI-2 on endogenous matriptase expression, subcellular localization, and activation in polarized intestinal epithelial cells, and data indicate that HAi-2 has an essential role in regulating prostasin-dependent matriptases zymogen activation.
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TLDR
It is shown that the oncogenic protease matriptase is ubiquitously co-expressed with the c-Met in human squamous cell carcinomas and amplifies migratory and proliferative responses of primary epithelial cells to the cognate ligand for c- met, pro-hepatocyte growth factor/scatter factor (proHGF/SF), through c- Met and Gab1 signaling.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
The findings suggest, through a HAI-1–dependent mechanism, that emergent active matriptase is a functional biomarker of the transformed epithelium and that its proteolytic activity can be exploited to noninvasively evaluate tumorigenesis in vivo.
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