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

Sales, Katiuchia Uzzun; Friis, Stine; Konkel, Joanne E.; Godiksen, Sine; Hatakeyama, Márcia; Hansen, Karina K.; Rogatto, Sílvia Regina; Szabo, Roman; Vogel, Lotte K.; Chen, W; Gutkind, J. Silvio; Bugge, Thomas H.

doi:10.1038/onc.2013.563

Cited by 57 publications

(87 citation statements)

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“…Many studies have associated proteinase-activated receptor-2 (PAR-2) with both inflammation and tumor progression (11)(12)(13)(14)(15); however, the expression of PAR-2 in OSCC has not been evaluated. PAR-2 is a G protein-coupled receptor that is activated by trypsin-like serine proteinases.…”

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confidence: 99%

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Johnson

Miller

Jiang

et al. 2016

Journal of Biological Chemistry

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Oral cancer is the sixth most common cause of death from cancer with an estimated 400,000 deaths worldwide and a low (50%) 5-year survival rate. The most common form of oral cancer is oral squamous cell carcinoma (OSCC). OSCC is highly inflammatory and invasive, and the degree of inflammation correlates with tumor aggressiveness. The G protein-coupled receptor protease-activated receptor-2 (PAR-2) plays a key role in inflammation. PAR-2 is activated via proteolytic cleavage by trypsin-like serine proteases, including kallikrein-5 (KLK5), or by treatment with activating peptides. PAR-2 activation induces G protein-␣-mediated signaling, mobilizing intracellular calcium and Nf-B signaling, leading to the increased expression of pro-inflammatory mRNAs. Little is known, however, about PAR-2 regulation of inflammation-related microRNAs. Here, we assess PAR-2 expression and function in OSCC cell lines and tissues. Stimulation of PAR-2 activates Nf-B signaling, resulting in RelA nuclear translocation and enhanced expression of pro-inflammatory mRNAs. Concomitantly, suppression of the anti-inflammatory tumor suppressor microRNAs let-7d, miR-23b, and miR-200c was observed following PAR-2 stimulation. Analysis of orthotopic oral tumors generated by cells with reduced KLK5 expression showed smaller, less aggressive lesions with reduced inflammatory infiltrate relative to tumors generated by KLK5-expressing control cells. Together, these 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. Squamous cell carcinoma of the oral cavity (OSCC)2 is a highly inflammatory disease that ranks as the 6th most frequently diagnosed cancer worldwide, with a poor 5-year survival rate of about 50% (1). Early diagnosis of OSCC is challenging, predominantly because early oral cancers and premalignant lesions are often subtle and asymptomatic. Although many patients present for diagnosis with stage III or IV disease, premalignant lesions in the oral mucosa often precede invasive OSCC (2). Furthermore, unlike most solid tumors that are monoclonal in origin, multiple distinct foci of dysplastic cells may be present in the oral mucosa. These epithelial dysplasia are categorized as mild, moderate, severe, or carcinoma in situ based on the histologic abnormalities present in the oral epithelium (3). Studies show that ϳ12-36% of epithelial dysplasia progress to carcinoma (4, 5); however, current approaches do not enable accurate identification of premalignant lesions likely to undergo malignant transformation.The link between inflammation and cancer is now well established, and inflammatory mediators are present in the microenvironment of virtually all solid tumors (6 -10). Many studies have associated proteinase-activated receptor-2 (PAR-2) with both inflammation and tumor progression (11-15); however, the expression of PAR-2 in OSCC has not been evaluated. PAR-2 is a G protein-coupled receptor that is activated by trypsin-...

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confidence: 99%

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Johnson

Miller

Jiang

et al. 2016

Journal of Biological Chemistry

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“…40 Recent studies have suggested that PAR-2 is crucially involved in these protease-mediated skin abnormalities. 27,30,31 PAR-2 is expressed by keratinocytes and plays an important physiological role in the epidermis. Abnormal expression or activity of PAR-2 has been associated with several inflammatory skin disorders involving barrier abnormalities, such as atopic dermatitis, Netherton syndrome, psoriasis, and peeling skin syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…***P < 0.001. ajp.amjpathol.org -The American Journal of Pathology phenotypes observed in prostasin and matriptase transgenic/ mutant mice were completely abrogated when the F2rl1 gene encoding PAR-2 was deleted concomitantly. 30,31 Therefore, regulation of PAR-2 signaling is critically important for epidermal homeostasis. PAR-2 is activated by serine proteases, such as trypsin, factor Xa, KLKs 4, 5, 6, and 14, and tryptase, as well as membrane-anchored trypsin-like serine proteases, such as matriptase, prostasin, TMPRSS2, hepsin, and human airway trypsin-like protease.…”

Section: Discussionmentioning

confidence: 99%

“…17,27,30 The evidence suggested that the most important cognate protease of HAI-1 in keratinocytes is matriptase. 24 Therefore, we hypothesized that the activity of matriptase was enhanced because of insufficient HAI-1, which eventually led to PAR-2 activation in HAI KD HaCaT cells.…”

Section: Trypsin-like Protease Activity Increases In Hai-1 Kd Hacat Cmentioning

confidence: 99%

“…For example, matriptase-driven premalignant progression is prevented by genetic elimination of PAR-2, and a prostasin-induced ichthyosis-like skin phenotype is rescued by concomitant deletion of PAR-2. 30,31 Therefore, it is reasonable to speculate that HAI-1 regulates PAR-2 function through regulation of PAR-2eactivating serine proteases in keratinocytes, a relationship that may have significant impact on epidermal integrity.…”

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confidence: 99%

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Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Kawaguchi

Kanemaru

Sawaguchi

et al. 2015

The American Journal of Pathology

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Hepatocyte growth factor activator inhibitor type 1 (HAI-1; official symbol SPINT1) is a membraneassociated serine proteinase inhibitor abundantly expressed in epithelial tissues. Genetically engineered mouse models demonstrated that HAI-1 is critical for epidermal function, possibly through direct and indirect regulation of cell surface proteases, such as matriptase and prostasin. To obtain a better understanding of the role of HAI-1 in maintaining epidermal integrity, we performed ultrastructural analysis of Spint1-deleted mouse epidermis and organotypic culture of an HAI-1 knockdown (KD) human keratinocyte cell line, HaCaT. We found that the aggregation of tonofilaments to desmosomes was significantly reduced in HAI-1edeficient mouse epidermis with decreased desmosome number. Similar findings were observed in HAI-1 KD HaCaT organotypic cultures. Immunoblot and immunohistochemical analyses revealed that p38 mitogen-activated protein kinase was activated in response to HAI-1 insufficiency. Treatment of HAI-1 KD HaCaT cells with a p38 inhibitor abrogated the above-observed ultrastructural abnormalities. The activation of p38 induced by the loss of HAI-1 likely resulted from enhanced signaling of protease-activated receptor-2 (PAR-2), because its silencing abrogated the enhanced activation of p38. Consequently, treatment of HAI-1 KD HaCaT cells with a serine protease inhibitor, aprotinin, or PAR-2 antagonist alleviated the abnormal ultrastructural phenotype in organotypic culture. These results suggest that HAI-1 may have a critical role in maintaining normal keratinocyte morphology through regulation of PAR-2edependent p38 mitogen-activated protein kinase signaling. Human skin protects the body from both water loss and mechanical damage. This barrier function is primarily accomplished by the epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes. 1 To achieve the barrier functions, keratinocytes form dynamic and strong cell-cell junctions in which desmosomes and the network of keratin intermediate filaments (KIFs) are essential to maintain junctional integrity. 2 KIFs are anchored to the cytoplasm and interact with desmosomal cell-cell contacts at the plasma membrane. These are important for mechanical stability of cell-cell contacts between keratinocytes. 3 Disturbance of the integrity of the KIF network leads to skin-blistering diseases, such as epidermolysis bullosa simplex. 4 Although it is not known how KIF disassembly is regulated, recent studies suggested that p38 mitogen-activated protein kinase (MAPK) signaling is involved in these processes. 4e6 The p38 is a member of the MAPK family. It is present in epithelial cells, responds rapidly to various types of stresses,

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Physiological Functions and Role of Matriptase in Cancer

Varela

Hyland

List

2018

Extracellular Targeting of Cell Signaling in Cancer

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

Cited by 57 publications

References 48 publications

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Physiological Functions and Role of Matriptase in Cancer

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