Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2-Mediated Proliferation of Colon Cancer Cell

Nishibori, Masahiro; Mori, Shuji; Takahashi, Hideo

doi:10.1254/jphs.fmj04005x5

Cited by 28 publications

(24 citation statements)

References 29 publications

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“…However, based on current literature it is fair to say that PAR-2 might be as important in tumor biology as is PAR-1. For instance, PAR-2 plays an important role in the invasion and growth of malignant neoplasms of the gastric [50,91,92] , colon [64,[93][94][95][96] , pancreas [97][98][99][100][101] , breast [102] and cervix [103] . Moreover, TF-dependent PAR-2 activation also contributes to experimental tumor metastasis in murine models [104] and PAR-2 blocking attenuates breast tumor growth [105] .…”

Section: Protease-activated Receptors Tumor Growth and Apoptosismentioning

confidence: 99%

Protease-Activated Receptors, Apoptosis and Tumor Growth

Borensztajn

Spek

2007

Pathophysiol Haemos Thromb

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Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. Besides the important role of blood coagulation factors in preventing bleeding after vascular injury, these serine proteinases actively engage target cells thereby fulfilling critical functions in cell biology. Cellular responses triggered by coagulation factor-induced PAR activation suggest that PARs play an important role in proliferation, survival and/or malignant transformation of tumor cells. Indeed, PAR expression correlates with cancer malignancy and clinical studies show that anticoagulant treatment is beneficial in cancer patients. In this review, we provide an overview on the PAR family, their mode of activation and mechanisms by which PAR signaling is terminated. In addition, we discuss the relationship between blood coagulation and cancer biology focusing on the potential role of PAR-induced modulation of cell survival, apoptosis and tumor growth.

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Section: Protease-activated Receptors Tumor Growth and Apoptosismentioning

confidence: 99%

Protease-Activated Receptors, Apoptosis and Tumor Growth

Borensztajn

Spek

2007

Pathophysiol Haemos Thromb

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“…It has been reported that PAR 2 activation not only promotes cell proliferation (7, 9 -12) but also contributes to hypoxia-induced angiogenesis as well (13). Interestingly, PAR 2 and its activating proteinases are also expressed at the leading edge of cancer invasion (10,14), and its expression levels are tightly correlated with lymphatic metastasis in breast cancer and colorectal carcinoma (15,16). All these observations suggest that activation of PAR 2 promotes cell motility and facilitates tumor cell invasion.…”

mentioning

confidence: 96%

Proteinase-activated Receptor 2 Promotes Cancer Cell Migration through RNA Methylation-mediated Repression of miR-125b

Yang

Han

et al. 2015

Journal of Biological Chemistry

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Background: Proteinase-activated receptor 2 (PAR 2 ) correlated with cancer metastasis. Results: Down-regulation of miR-125b, which targets Gab2, mediates PAR 2 -induced cancer cell migration. Conclusion: PAR 2 promotes cancer cell migration through RNA methylation-mediated repression of miR-125b. Significance: This study suggests a novel epigenetic mechanism by which miRNA expression is altered to regulate cancer cell migration.

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“…PAR 2 , one of the four members of this receptor family, can be activated by trypsin (3), tryptase (4), and the tumor-derived proteinase matriptase (5) to stimulate processes ranging from inflammation and pain perception to tumorigenesis (3,(7)(8)(9). Tumor cells, especially those of epithelial origin, express a high level of PAR 2 (10,11). Trypsin and matriptase are commonly overexpressed in tumor cells and in their microenvironment at concentrations compatible with PAR 2 activation (12,13).…”

mentioning

confidence: 99%

Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through β-Catenin and Cyclic AMP-response Element-binding Protein

Wang

Wen

Bunnett

et al. 2008

Journal of Biological Chemistry

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Chronic inflammation of mucosae is associated with an increased cancer risk. Tumorigenesis in these tissues is associated with the activity of some proteinases, cyclooxygenase-2 (COX-2), and ␤-catenin. Serine proteinases participate in both inflammation and tumorigenesis through the activation of proteinase-activated receptor-2 (PAR 2 ), which up-regulates COX-2 by an unknown mechanism. We sought to determine whether ␤-catenin participated in PAR 2 -induced COX-2 expression and through what cellular mechanism. In A549 epithelial cells, we showed that PAR 2 activation increased COX-2 expression through the ␤-catenin/T cell factor transcription pathway. This effect was dependent upon ERK1/2 MAPK, which inhibited the ␤-catenin-regulating protein, glycogen synthase kinase-3␤, and induced the activity of the cAMP-response element-binding protein (CREB). Knockdown of CREB by small interfering RNA revealed that PAR 2 -induced ␤-catenin transcriptional activity and COX-2 expression were CREB-dependent. A co-immunoprecipitation assay revealed a physical interaction between CREB and ␤-catenin. Thus, PAR 2 up-regulated COX-2 expression via an ERK1/2-mediated activation of the ␤-catenin/Tcf-4 and CREB pathways. These findings reveal new cellular mechanisms by which serine proteinases may participate in tumor development and are particularly relevant to cancers associated with chronic mucosal inflammation, where serine proteinases are abundant and COX-2 overexpression is a common feature.Patients with chronic inflammatory diseases of mucosae, including those of the airway and intestine, have an increased risk for the development of cancer. Serine proteinases have been implicated as key factors in mucosal inflammation and the formation and metastasis of tumors. These proteinases trigger specific cellular responses through proteinase-activated receptors (PARs), 3 G-protein-coupled receptors that are activated by proteolytic cleavage of the extracellular N terminus at a specific amino acid sequence, revealing a new N-terminal "tethered ligand" that binds to and activates the receptor (1, 2). PAR 2 , one of the four members of this receptor family, can be activated by trypsin (3), tryptase (4), and the tumor-derived proteinase matriptase (5) to stimulate processes ranging from inflammation and pain perception to tumorigenesis (3, 7-9). Tumor cells, especially those of epithelial origin, express a high level of PAR 2 (10, 11). Trypsin and matriptase are commonly overexpressed in tumor cells and in their microenvironment at concentrations compatible with PAR 2 activation (12, 13).We have shown previously that the activation of PAR 2 stimulates COX-2 expression (14). COX-2 is expressed early in carcinogenesis and very likely plays a role in the development of cancer (15-17), as it correlates with tumor invasion and poor clinical outcome (18). The mechanisms by which PAR 2 activation induces the expression of COX-2 are still unclear. However, it is known that the cox2 gene can be induced by the transcriptional activity of ␤-catenin....

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Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2-Mediated Proliferation of Colon Cancer Cell

Cited by 28 publications

References 29 publications

Protease-Activated Receptors, Apoptosis and Tumor Growth

Protease-Activated Receptors, Apoptosis and Tumor Growth

Proteinase-activated Receptor 2 Promotes Cancer Cell Migration through RNA Methylation-mediated Repression of miR-125b

Proteinase-activated Receptor-2 Induces Cyclooxygenase-2 Expression through β-Catenin and Cyclic AMP-response Element-binding Protein

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