Protease-activated receptor 2 modulates proliferation and invasion of oral squamous cell carcinoma cells

Al‐Eryani, Kamal; Cheng, Jun; Abé, Tatsuya; Maruyama, Satoshi; Yamazaki, Manabu; Babkair, Hamzah; Essa, Ahmed; Saku, Takashi

doi:10.1016/j.humpath.2015.03.003

Cited by 7 publications

(10 citation statements)

References 35 publications

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“…Sun et al found that PAR-2 might promote the migration and invasion of renal cell cancer cells through activating the PI3K/AKT signaling pathway [18]. And Al-Eryani reported that PAR-2 could regulate the proliferation and invasion of OSCC cells in vitro [19]. However, molecular mechanisms underlying PAR-2 affecting OSCC progression are rarely reported.…”

Section: Introductionmentioning

confidence: 99%

PAR-2 promotes cell proliferation, migration, and invasion through activating PI3K/AKT signaling pathway in oral squamous cell carcinoma

Tang

Han-Ying

et al. 2019

Bioscience Reports

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Objective: This research aimed to explore the function of protease activated receptor 2 (PAR-2) in oral squamous cell carcinoma (OSCC) development and progression, as well as underlying molecular mechanism. Methods: Tissue samples were collected from 115 OSCC patients. Quantitative real-time PCR (qRT-PCR) was performed to measure the expression of PAR-2 mRNA in OSCC tissues and cells. MTT and Transwell assays were used to detect the proliferation, migration, and invasion of OSCC cells, respectively. Western blot was performed to determine protein expression. Results: The expression of PAR-2 mRNA was up-regulated in OSCC tissue and cells (P<0.01), and its mRNA level was obviously correlated to tumor differentiation and TNM stage in OSCC (P<0.05 for both). The activation of PAR-2 with PAR-2AP (PAR-2 agonist) significantly promoted the proliferation, migration, and invasion of OSCC cells, while its knockout could inhibit malignant behaviors of OSCC cells (P<0.05). Excessive activation of PAR-2 enhanced phosphorylation level of PI3K, AKT, and mTOR revealing the activation of PI3K/AKT pathway. Moreover, LY294002, the inhibitor of PI3K/AKT pathway, could reverse oncogenic action caused by PAR-2 activation. Conclusion: PAR-2 can promote OSCC growth and progression via activating PI3K/AKT signaling pathway.

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Section: Introductionmentioning

confidence: 99%

PAR-2 promotes cell proliferation, migration, and invasion through activating PI3K/AKT signaling pathway in oral squamous cell carcinoma

Tang

Han-Ying

et al. 2019

Bioscience Reports

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“…However, OSCC cells themselves frequently expressed PAR‐2, which has been reported to stimulate their proliferation and invasion . Trypsin‐like serine proteases other than matriptase present in cancer tissues may also contribute to PAR‐2 activation, and the in vitro analysis in this study cannot exclude the possibility that a trypsin‐like protease activated by matriptase activated fibroblast PAR‐2.…”

Section: Discussionmentioning

confidence: 76%

“…The role of PAR‐2 in cancer has been considered mostly in the tumor cells themselves . Although PAR‐2 expression has also been observed in proliferating SMA‐positive fibroblasts surrounding the carcinoma cells, experiments performed in PAR‐2 deficient mice ( F2rl1 −/− ) so far do not provide a clear picture of the role of PAR‐2 signaling in the shaping of the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Deregulated matriptase activity in oral squamous cell carcinoma promotes the infiltration of cancer‐associated fibroblasts by paracrine activation of protease‐activated receptor 2

Kanemaru

Yamamoto

Kawaguchi

et al. 2016

Intl Journal of Cancer

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Cancer-associated fibroblasts (CAFs) are known to contribute to cancer progression. We have reported that cell surface expression of hepatocyte growth factor activator inhibitor 1 (HAI-1) is decreased in invasive oral squamous cell carcinoma (OSCC) cells. This study examined if HAI-1-insufficiency contributes to CAF recruitment in OSCC. Serum-free conditioned medium (SFCM) from a human OSCC line (SAS) stimulated the migration of 3 human fibroblast cell lines, NB1RGB, MRC5 and KD. SFCM from HAI-1-knockdown SAS showed an additive effect on the migration of NB1RGB and MRC5, but not KD. SAS SFCM induced protease-activated receptor-2 (PAR-2) expression in NB1RGB and MRC5, but not in KD, and a PAR-2 antagonist blocked the stimulatory effect of HAI-1 knockdown on migration of the PAR-2 expressing cell lines. Moreover, HAI-1-deficient SFCM showed additive stimulatory effects on the migration of wild-type but not PAR-2-deficient mouse fibroblasts. Therefore, the enhanced migration induced by HAI-1-insufficiency was mediated by PAR-2 activation in fibroblasts. This activation resulted from the deregulation of the activity of matriptase, a PAR-2 agonist protease. HAI-1 may thus prevent CAF recruitment to OSCC by controlling matriptase activity. When HAI-1 expression is reduced on OSCC, matriptase may contribute to CAF accumulation by paracrine activation of fibroblast PAR-2. Immunohistochemical analysis of resected OSCC revealed increased PAR2-positive CAFs in 35% (33/95) of the cases studied. The increased PAR-2 positive CAFs tended to correlate with infiltrative histology of the invasion front and shorter disease-free survival of the patients.

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“…The concentration of trypsin is increased in patients with gastric, colon, pancreatic, and ovarian cancer [ 54 , 155 , 192 ]. Increased expression of PAR-2 and its influence on cancer cell proliferation was defined in gastric, esophageal, colorectal, pancreatic, oral squamous, liver, cholangiocarcinoma, lung, breast, and ovarian cancers, as well as in melanoma and brain tumors (Table 3 ) [ 53 , 54 , 56 , 57 , 60 , 61 , 64 , 65 , 71 , 155 , 193 – 195 ]. PAR-2 may be highly expressed in stroma-rich tumor regions also.…”

Section: Pars and Proteases—cooperation In Cancer Progressionmentioning

confidence: 99%

“…In vitro studies with epithelial cancers have shown that PAR-2, like PAR-1, exerts mitogenic activity [ 46 , 53 , 54 , 56 – 61 , 64 , 71 , 155 , 193 – 195 ]. Trypsin and PAR-2 activating peptide, SLIGKV, significantly increased gelatinolytic activity of MMP-2, as well as ERK/AP-1, MEK1/2, and MAPK signaling to promote cancer cell proliferation, migration, and metastasis [ 53 , 57 , 58 , 60 – 62 , 195 ].…”

Section: Pars and Proteases—cooperation In Cancer Progressionmentioning

confidence: 99%

Protease-activated receptors (PARs)—biology and role in cancer invasion and metastasis

Wojtukiewicz

Hempel

Sierko

et al. 2015

Cancer Metastasis Rev

120

124

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Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.

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Protease-activated receptor 2 modulates proliferation and invasion of oral squamous cell carcinoma cells

Cited by 7 publications

References 35 publications

PAR-2 promotes cell proliferation, migration, and invasion through activating PI3K/AKT signaling pathway in oral squamous cell carcinoma

PAR-2 promotes cell proliferation, migration, and invasion through activating PI3K/AKT signaling pathway in oral squamous cell carcinoma

Deregulated matriptase activity in oral squamous cell carcinoma promotes the infiltration of cancer‐associated fibroblasts by paracrine activation of protease‐activated receptor 2

Protease-activated receptors (PARs)—biology and role in cancer invasion and metastasis

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