Expression of protease-activated receptor-2 (PAR-2) is related to advanced clinical stage and adverse prognosis in ovarian clear cell carcinoma

Aman, Murasaki; Ohishi, Yoshihiro; Imamura, Hiroko; Shinozaki, Tomoko; Yasutake, Nobuko; Kato, Kanefusa; Oda, Yoshinao

doi:10.1016/j.humpath.2017.04.008

Cited by 15 publications

(16 citation statements)

References 32 publications

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“…Abnormal activation of PAR-2 may result in a series of pathophysiologic processes, such as inflammation, metabolism, pain processing, cardiovascular diseases, neurological disorders, and cancers [11,12]. In tumorigenesis, PAR-2 activation may enhance biological behaviors of tumor cells, including cell proliferation, growth, invasion, and metastasis [13–15]. Oncogenic function of PAR-2 has been reported in ovarian clear cell carcinoma [13], esophageal cancer [15], pancreatic cancer [16], hepatocellular carcinoma [17], etc.…”

Section: Introductionmentioning

confidence: 99%

“…In tumorigenesis, PAR-2 activation may enhance biological behaviors of tumor cells, including cell proliferation, growth, invasion, and metastasis [13–15]. Oncogenic function of PAR-2 has been reported in ovarian clear cell carcinoma [13], esophageal cancer [15], pancreatic cancer [16], hepatocellular carcinoma [17], etc. 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].…”

Section: Introductionmentioning

confidence: 99%

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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%

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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“…At this respect, endometriotic cysts fluid present with higher levels of free iron, lactate dehydrogenase, lipid peroxide, 8-OHdG and potential antioxidant in comparison to non-endometriotic cysts and OCCC. Also, higher levels of 8-OHdG are reportedly associated with OCCC, being almost negative in EOC [93]. In agreement with these results, Fujimoto and co-workers [94] found increased levels of 8-OHdG and heme-oxygenase 1 in cyst fluid from OMA when compared to EAOC (mainly OCCC).…”

Section: Endometriosis-associated Ovarian Cancersupporting

confidence: 53%

“…Amano and collaborators [114] observed that increased levels of SOD2 in EAOC specimens associated with worse prognosis (overall survival and progression-free survival). Additionally, protease-activated receptor-2 (PAR-2) expression, which is up-regulated by OS, correlated with shorter survival in OCCC specimens [93]. Further immunohistochemical analyses also revealed that higher 8-OHdG levels is associated with poor differentiation, higher stage, and non-optimal surgical outcomes in epithelial ovarian cancer, including HGSOC, EOC, and OCCC specimens [156].…”

Section: Potential Role Of Mirnas and Oxidative Stress In Diagnosimentioning

confidence: 99%

Interplay Between MicroRNAs and Oxidative Stress in Ovarian Conditions with a Focus on Ovarian Cancer and Endometriosis

Marí-Alexandre

Carcelén

Agababyan

et al. 2019

IJMS

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Ovarian cancer and endometriosis are two distinct gynaecological conditions that share many biological aspects incuding proliferation, invasion of surrounding tissue, inflammation, inhibition of apoptosis, deregulation of angiogenesis and the ability to spread at a distance. miRNAs are small non-coding RNAs (19-22 nt) that act as post-transcriptional modulators of gene expression and are involved in several of the aforementioned processes. In addition, a growing body of evidence supports the contribution of oxidative stress (OS) to these gynaecological diseases: increased peritoneal OS due to the decomposition of retrograde menstruation blood facilitates both endometriotic lesion development and fallopian tube malignant transformation leading to high-grade serous ovarian cancer (HGSOC). Furthermore, as HGSOC develops, increased OS levels are associated with chemoresistance. Finally, continued bleeding within ovarian endometrioma raises OS levels and contributes to the development of endometriosis-associated ovarian cancer (EAOC). Therefore, this review aims to address the need for a better understanding of the dialogue between miRNAs and oxidative stress in the pathophysiology of ovarian conditions: endometriosis, EAOC and HGSOC.

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“…A global transcriptome array analysis of PAR expression in over 1,000 ovarian cancer and normal tissue samples showed that human epithelial ovarian cancers predominantly overexpress PAR-2, followed closely by PAR-1, with minimal detection of PAR-3 and PAR-4 (32). Consistent with this, increased PAR-2 is associated with poor prognosis and decreased progression-free and overall survival in patients with ovarian, cervical, and hepatocellular carcinoma (30,(33)(34)(35). Increased PAR-2 expression and activation is also correlated with the degree of invasiveness exhibited by both primary and metastatic tumors (29,30,36).…”

Section: Par-2 Signaling and Cancermentioning

confidence: 84%

Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2–Mediated Signaling: Co-Conspirators in Cancer Progression

2019

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Pericellular proteolysis provides a significant advantage to developing tumors through the ability to remodel the extracellular matrix, promote cell invasion and migration, and facilitate angiogenesis. Recent advances demonstrate that pericellular proteases can also communicate directly to cells by activation of a unique group of transmembrane G-protein-coupled receptors (GPCR) known as proteaseactivated receptors (PAR). In this review, we discuss the specific roles of one of four mammalian PARs, namely PAR-2, which is overexpressed in advanced stage tumors and is activated by trypsin-like serine proteases that are highly expressed or otherwise dysregulated in many cancers. We highlight recent insights into the ability of different protease agonists to bias PAR-2 signaling and the newly emerging evidence for an interplay between PAR-2 and membrane-anchored serine proteases, which may co-conspire to promote tumor progression and metastasis. Interfering with these pathways might provide unique opportunities for the development of new mechanism-based strategies for the treatment of advanced and metastatic cancers.

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Expression of protease-activated receptor-2 (PAR-2) is related to advanced clinical stage and adverse prognosis in ovarian clear cell carcinoma

Cited by 15 publications

References 32 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

Interplay Between MicroRNAs and Oxidative Stress in Ovarian Conditions with a Focus on Ovarian Cancer and Endometriosis

Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2–Mediated Signaling: Co-Conspirators in Cancer Progression

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