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

  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},
  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
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
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*
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
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.
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
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
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
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.
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*
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.


c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase
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.
Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation.
It is shown that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1, and the data implicate dysregulated matript enzyme expression in malignant epithelial transformation.
Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency–Associated Developmental Defects by Preventing Matriptase Activation
A genetic epistasis analysis was performed to identify additional components of this pathway by generating mice with combined deficiency in eitherHAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development.
Membrane-type serine protease-1/matriptase induces interleukin-6 and -8 in endothelial cells by activation of protease-activated receptor-2: potential implications in atherosclerosis.
  • I. SeitzS. Hess I. Ott
  • Biology, Medicine
    Arteriosclerosis, thrombosis, and vascular biology
  • 2007
Interaction of monocytic MT-SP1/matriptase with endothelial PAR-2 may contribute to atherosclerosis and is investigated to investigate the effects of MT- SP1/Matriptase on endothelial cytokine expression.
Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer.
High-level expression of Met, matriptase, and HAI-I were associated with poor patient outcome, and antibodies against the intracellular but not the extracellular domain of Met were prognostic, suggesting that overexpression of the cytoplasmic-tail of Met may play an important role in breast cancer progression.
Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor clinicopathological parameters.
Advanced-stage ovarian tumors that express matriptase are more likely to do so in the absence of its inhibitor, HAI-1, indicating that an imbalance in theMatriptase:HAI- 1 ratio could be important in the development of advanced disease.
The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals
The results show that dysregulation of the matriptase/HAI-1 mRNA ratio occurs early during carcinogenesis, and future studies are required to clarify whether the dysregulated matriptases/HAi-1 ratio was causing the malignant progression or is a consequence of the same.
Delineation of matriptase protein expression by enzymatic gene trapping suggests diverging roles in barrier function, hair formation, and squamous cell carcinogenesis.
Combined with previous studies, data suggest that matriptase has diverging functions in the genesis of stratified keratinized epithelium, hair follicles, and squamous cell carcinoma.
Imaging a functional tumorigenic biomarker in the transformed epithelium
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.