Increased Expression of Protease-Activated Receptor 4 and Trefoil Factor 2 in Human Colorectal Cancer

Yu, Guoyu; Jiang, Ping; Xiang, Yang; Zhang, Yong; Zhu, Zhu; Zhang, Chuanrao; Lee, Siman; Lee, Wenhui; Zhang, Yun
April 2015
PLoS ONE;Apr2015, Vol. 10 Issue 4, p1
Academic Journal
Protease-activated receptor 4 (PAR4), a member of G-protein coupled receptors family, was recently reported to exhibit decreased expression in gastric cancer and esophageal squamous cancer, yet increased expression during the progression of prostate cancer. Trefoil factor 2 (TFF2), a small peptide constitutively expressed in the gastric mucosa, plays a protective role in restitution of gastric mucosa. Altered TFF2 expression was also related to the development of gastrointestinal cancer. TFF2 has been verified to promote cell migration via PAR4, but the roles of PAR4 and TFF2 in the progress of colorectal cancer are still unknown. In this study, the expression level of PAR4 and TFF2 in colorectal cancer tissues was measured using real-time PCR (n = 38), western blotting (n=38) and tissue microarrays (n = 66). The mRNA and protein expression levels of PAR4 and TFF2 were remarkably increased in colorectal cancer compared with matched noncancerous tissues, especially in positive lymph node and poorly differentiated cancers. The colorectal carcinoma cell LoVo showed an increased response to TFF2 as assessed by cell invasion upon PAR4 expression. However, after intervention of PAR4 expression, PAR4 positive colorectal carcinoma cell HT-29 was less responsive to TFF2 in cell invasion. Genomic bisulfite sequencing showed the hypomethylation of PAR4 promoter in colorectal cancer tissues and the hypermethylation in the normal mucosa that suggested the low methylation of promoter was correlated to the increased PAR4 expression. Taken together, the results demonstrated that the up-regulated expression of PAR4 and TFF2 frequently occurs in colorectal cancer tissues, and that overexpression of PAR4 may be resulted from promoter hypomethylation. While TFF2 promotes invasion activity of LoVo cells overexpressing PAR4, and this effect was significantly decreased when PAR4 was knockdowned in HT-29 cells. Our findings will be helpful in further investigations into the functions and molecular mechanisms of Proteinase-activated receptors (PARs) and Trefoil factor factors (TFFs) during the progression of colorectal cancer.


Related Articles

  • P618 PAR2 expression differentially regulates immune response upon treatment with Poly(I:C) and LPS. Weithaeuser, A; Schultheiss, HP; Rauch, U // Cardiovascular Research;Jul2014, Vol. 103 Issue suppl_1, pS112 

    Introduction: The protease activated receptor 2 (PAR2) is a G-protein coupled receptor, that is activated by serine proteases such as trypsin, tryptase and the complex composed of tissue factor (TF)/ factor VII (FVII) and factor X (FX). PAR2 is also involved in modulating immune response after...

  • The Expression of the Thrombin Receptors PAR-3 and PAR-4 is Downregulated in Pancreatic Cancer Cell Lines. Rudroff, Claudia; Richard, Annette; Hilswicht, Sarah; Neugebauer, Edmund A. M. // Jurnalul de Chirurgie;2014, Vol. 10 Issue 1, p31 

    Background: Patients with pancreatic cancer frequently suffer from thrombosis as a consequence of excess thrombin generation. In addition to its role in the plasmatic coagulation cascade, thrombin induces numerous cellular effects by activating a unique group of G-protein-coupled receptors on...

  • PERSPECTIVE. Coughlin, Shaun // Cardiology Today;Jun2014, Vol. 17 Issue 6, p30 

    The author discusses the health benefits of protease activated receptor-1 (PAR-1).

  • Targeting A549 lung adenocarcinoma cell growth and invasion with protease-activated receptor-1 siRNA. ZHUO WU; YANYAN ZENG; MINGKANG ZHONG; BIN WANG // Molecular Medicine Reports;2014, Vol. 9 Issue 5, p1787 

    Lung cancer is the major cause of cancer-associated mortality worldwide and the invasive and metastatic characteristics of lung tumor cells are responsible for their high malignancy. Protease-activated receptor 1 (PARI) is a G-protein-coupled receptor (GPCR) which is activated by a unique...

  • Down-regulation of PAR1 activity with a pHLIP-based allosteric antagonist induces cancer cell death. Burns, Kelly E.; Thèvenin, Damien // Biochemical Journal;12/15/2015, Vol. 472 Issue 3, p287 

    Even though abnormal expression of G protein-coupled receptors (GPCRs) and of their ligands is observed in many cancer cells of various origins, only a few anti-cancer compounds directly act on their signalling. One promising approach to modulate their activity consists of targeting the receptor...

  • Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist. Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun; No, Kyoung; Pae, Ae // Journal of Computer-Aided Molecular Design;Aug2016, Vol. 30 Issue 8, p625 

    Protease-activated receptor 2 (PAR) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds...

  • Development and Evaluation of Small Peptidomimetic Ligands to Protease-Activated Receptor-2 (PAR2) through the Use of Lipid Tethering. Boitano, Scott; Hoffman, Justin; Tillu, Dipti V.; Asiedu, Marina N.; Zhang, Zhenyu; Sherwood, Cara L.; Wang, Yan; Dong, Xinzhong; Price, Theodore J.; Vagner, Josef // PLoS ONE;Jun2014, Vol. 9 Issue 6, p1 

    Protease-activated receptor-2 (PAR2) is a G-Protein Coupled Receptor (GPCR) activated by proteolytic cleavage to expose an attached, tethered ligand (SLIGRL). We evaluated the ability for lipid-tethered-peptidomimetics to activate PAR2 with in vitro physiological and Ca2+ signaling assays to...

  • Altered Protease–Activated Receptor-1 Expression and Signaling in a Malignant Pleural Mesothelioma Cell Line, NCI-H28, with Homozygous Deletion of the β-Catenin Gene. Fazzini, Alessandra; D’Antongiovanni, Vanessa; Giusti, Laura; Da Valle, Ylenia; Ciregia, Federica; Piano, Ilaria; Caputo, Antonella; D’Ursi, Anna Maria; Gargini, Claudia; Lucacchini, Antonio; Mazzoni, Maria Rosa // PLoS ONE;Nov2014, Vol. 9 Issue 11, p1 

    Protease activated receptors (PARs) are G-protein coupled receptors that are activated by an unique proteolytic mechanism. These receptors play crucial roles in hemostasis and thrombosis but also in inflammation and vascular development. PARs have also been implicated in tumor progression,...

  • Protease Activated Receptor-2 Contributes to Heart Failure. Antoniak, Silvio; Sparkenbaugh, Erica M.; Tencati, Michael; Rojas, Mauricio; Mackman, Nigel; Pawlinski, Rafal // PLoS ONE;Nov2013, Vol. 8 Issue 11, p1 

    Heart failure is a major clinical problem worldwide. Previous studies have demonstrated an important role for G protein-coupled receptors, including protease-activated receptors (PARs), in the pathology of heart hypertrophy and failure. Activation of PAR-2 on cardiomyocytes has been shown to...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics