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Appasamy P, Nag JK, Malka H, Bar-Shavit R. PAR 2 Serves an Indispensable Role in Controlling PAR 4 Oncogenicity: The β-Catenin-p53 Axis. Int J Mol Sci 2025; 26:2780. [PMID: 40141421 PMCID: PMC11942634 DOI: 10.3390/ijms26062780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/18/2025] [Accepted: 03/18/2025] [Indexed: 03/28/2025] Open
Abstract
Although the role of G-protein-coupled receptors (GPCRs) in cancer is acknowledged, GPCR-based cancer therapy is rare. Mammalian protease-activated receptors (PARs), a sub-group of GPCRs, comprise four family members, termed PAR1-4. Here, we demonstrate that PAR2 is dominant over PAR4 oncogene in cancer. We performed a knockdown of Par2/f2rl1 and expressed C-terminally truncated PAR2 (TrPAR2), incapable of inducing signaling, to assess the impact of PAR2 on PAR4 oncogenic function by β-catenin stabilization assessment, immunoprecipitation, and xenograft tumor generation in Nude/Nude mice. PAR2 and PAR4 act together to promote tumor generation. Knockdown Par2 and TrPAR2 inhibited the PAR2 and PAR4-induced β-catenin levels, nuclear dishevelled 1(DVL1), and TOPflash reporter activity. Likewise, PAR2 and PAR4-induced invasion and migration were inhibited when Par2 was knocked down or in the presence of TrPAR2. PAR cyclic (4-4) [Pc(4-4)], a PAR-based compound directed toward the PAR pleckstrin homology (PH)-binding site, effectively inhibited PAR2 oncogenic activity. Pc(4-4) inhibition is mediated via the increase in p53 level and the up-regulation of p21 as caspase-3 as well. Overall, we showed that in the absence of PAR2 signaling, the PAR4 pro-tumor functions are significantly inhibited. Pc(4-4) inhibits PAR2 acting via the modification of wt p53, thus offering a powerful drug measure for fighting cancer.
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Affiliation(s)
| | | | | | - Rachel Bar-Shavit
- Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; (P.A.)
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Rajala R, Griffin CT. Endothelial protease-activated receptor 4: impotent or important? Front Cardiovasc Med 2025; 12:1541879. [PMID: 39935714 PMCID: PMC11810968 DOI: 10.3389/fcvm.2025.1541879] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025] Open
Abstract
The protease thrombin, which increases its levels with various pathologies, can signal through the G protein-coupled receptors protease-activated receptors 1 and 4 (PAR1/PAR4). PAR1 is a high-affinity receptor for thrombin, whereas PAR4 is a low-affinity receptor. Finding functions for PAR4 in endothelial cells (ECs) has been an elusive goal over the last two decades. Several studies have demonstrated a lack of functionality for PAR4 in ECs, with many claiming that PAR4 function is confined mostly to platelets. A recent study from our lab identified low expressing but functional PAR4 in hepatic ECs in vivo. We also found that PAR4 likely has a higher signaling potency than PAR1. Given this potency, ECs seem to limit PAR4 signaling except for extreme cases. As a result, we claim PAR4 is not an impotent receptor because it is low expressing, but rather PAR4 is low expressing because it is a very potent receptor. Since we have finally shown PAR4 to be present and functional on ECs in vivo, it is important to outline why such controversy arose over the last two decades and, more importantly, why the receptor was undervalued on ECs. This timely review aims to inspire investigators in the field of vascular biology to study the regulatory aspect of endothelial PAR4 and its relationship with the more highly expressed PAR1.
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Affiliation(s)
- Rahul Rajala
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Courtney T. Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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3
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Chen PY, Wang PY, Liu B, Jia YP, Zhang ZX, Liu X, Wang DH, Yan YJ, Fu WH, Zhu F. RGS4 promotes the progression of gastric cancer through the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition. World J Gastroenterol 2025; 31:100898. [PMID: 39811500 PMCID: PMC11684191 DOI: 10.3748/wjg.v31.i2.100898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/28/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND Regulator of G protein signaling (RGS) proteins participate in tumor formation and metastasis by acting on the α-subunit of heterotrimeric G proteins. The specific effect of RGS, particularly RGS4, on the progression of gastric cancer (GC) is not yet clear. AIM To explore the role and underlying mechanisms of action of RGS4 in GC development. METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC. Function assays were employed to assess the carcinogenic impact of RGS4, and the mechanism of its possible influence was detected by western blot analysis. A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro. RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues. Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage, increased tumor grade as well as poorer overall survival in patients with GC. Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation, migration and invasion. Similarly, xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth. Moreover, RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase, phosphatidyl-inositol-3-kinase, and protein kinase B, decreased vimentin and N-cadherin, and elevated E-cadherin. CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker. RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.
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Affiliation(s)
- Peng-Yu Chen
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Pei-Yao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Bang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Yang-Pu Jia
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Zhao-Xiong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Dao-Han Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Yong-Jia Yan
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Wei-Hua Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
| | - Feng Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, China
- Department of General Surgery, Jincheng People’s Hospital, Jincheng 048000, Shanxi Province, China
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Tang M, Zhai L, Chen J, Wang F, Chen H, Wu W. The Antitumor Potential of λ-Carrageenan Oligosaccharides on Gastric Carcinoma by Immunomodulation. Nutrients 2023; 15:2044. [PMID: 37432179 DOI: 10.3390/nu15092044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/21/2023] [Accepted: 04/22/2023] [Indexed: 07/12/2023] Open
Abstract
Gastric carcinoma is a frequently detected malignancy worldwide, while its mainstream drugs usually result in some adverse reactions, including immunosuppression. λ-carrageenan oligosaccharides (COS) have attracted increasing attention as potential anticancer agents due to their ability to enhance immune function. Our current work assessed the antitumor mechanism of λ-COS using BGC-823 cells. Our findings indicated that λ-COS alone did not have a significant impact on BGC-823 cells in vitro; however, it was effective in inhibiting tumor growth in vivo. When THP-1 cells were pre-incubated with λ-COS and used to condition the medium, BGC-823 cells in vitro displayed a concentration-dependent induction of cell apoptosis, nuclear damage, and the collapse of mitochondrial transmembrane potential. These findings suggested that the antineoplastic effect of λ-COS was primarily due to its immunoenhancement property. Treatment with λ-COS was found to significantly enhance the phagocytic capability of macrophages, increase the secretion of TNF-α and IFN-γ, and improve the indexes of spleen and thymus in BALB/c mice. In addition, λ-COS was found to inhibit the growth of BGC-823-derived tumors in vitro by activating the Par-4 signaling pathway, which may be stimulated by the combination of TNF-α and IFN-γ. When used in combination with 5-FU, λ-COS demonstrated enhanced anti-gastric carcinoma activity and improved the immunosuppression induced by 5-FU alone. These findings suggested that λ-COS could be used as an immune-modulating agent for chemotherapy.
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Affiliation(s)
- Min Tang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo 315211, China
| | - Leilei Zhai
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo 315211, China
| | - Juanjuan Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo 315211, China
- Collaborative Innovation Center for Zhejiang Marine High-Efficiency and Healthy Aquaculture, Ningbo University, Ningbo 315211, China
| | - Feng Wang
- Department of Laboratory Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo 315040, China
| | - Haimin Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo 315211, China
- Collaborative Innovation Center for Zhejiang Marine High-Efficiency and Healthy Aquaculture, Ningbo University, Ningbo 315211, China
| | - Wei Wu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Ningbo University, Ningbo 315211, China
- Collaborative Innovation Center for Zhejiang Marine High-Efficiency and Healthy Aquaculture, Ningbo University, Ningbo 315211, China
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Bhardwaj A, Liyanage SI, Weaver DF. Cancer and Alzheimer's Inverse Correlation: an Immunogenetic Analysis. Mol Neurobiol 2023; 60:3086-3099. [PMID: 36797545 DOI: 10.1007/s12035-023-03260-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/05/2023] [Indexed: 02/18/2023]
Abstract
Numerous studies have demonstrated an inverse link between cancer and Alzheimer's disease (AD), with data suggesting that people with Alzheimer's have a decreased risk of cancer and vice versa. Although other studies have investigated mechanisms to explain this relationship, the connection between these two diseases remains largely unexplained. Processes seen in cancer, such as decreased apoptosis and increased cell proliferation, seem to be reversed in AD. Given the need for effective therapeutic strategies for AD, comparisons with cancer could yield valuable insights into the disease process and perhaps result in new treatments. Here, through a review of existing literature, we compared the expressions of genes involved in cell proliferation and apoptosis to establish a genetic basis for the reciprocal association between AD and cancer. We discuss an array of genes involved in the aforementioned processes, their relevance to both diseases, and how changes in those genes produce varying effects in either disease.
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Affiliation(s)
- Aditya Bhardwaj
- Krembil Discovery Tower, Krembil Brain Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, Toronto, ON, M5T 0S8, Canada
| | - S Imindu Liyanage
- Krembil Discovery Tower, Krembil Brain Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, Toronto, ON, M5T 0S8, Canada
| | - Donald F Weaver
- Krembil Discovery Tower, Krembil Brain Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, Toronto, ON, M5T 0S8, Canada.
- Departments of Medicine and Chemistry, University of Toronto, Toronto, Canada.
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6
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An Insight into GPCR and G-Proteins as Cancer Drivers. Cells 2021; 10:cells10123288. [PMID: 34943797 PMCID: PMC8699078 DOI: 10.3390/cells10123288] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 12/14/2022] Open
Abstract
G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including tumor growth and metastasis. Various molecules such as hormones, lipids, peptides, and neurotransmitters activate GPCRs that enable the coupling of these receptors to highly specialized transducer proteins, called G-proteins, and initiate multiple signaling pathways. Integration of these intricate networks of signaling cascades leads to numerous biochemical responses involved in diverse pathophysiological activities, including cancer development. While several studies indicate the role of GPCRs in controlling various aspects of cancer progression such as tumor growth, invasion, migration, survival, and metastasis through its aberrant overexpression, mutations, or increased release of agonists, the explicit mechanisms of the involvement of GPCRs in cancer progression is still puzzling. This review provides an insight into the various responses mediated by GPCRs in the development of cancers, the molecular mechanisms involved and the novel pharmacological approaches currently preferred for the treatment of cancer. Thus, these findings extend the knowledge of GPCRs in cancer cells and help in the identification of therapeutics for cancer patients.
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Kim Y, Ghil S. Regulators of G-protein signaling, RGS2 and RGS4, inhibit protease-activated receptor 4-mediated signaling by forming a complex with the receptor and Gα in live cells. Cell Commun Signal 2020; 18:86. [PMID: 32517689 PMCID: PMC7285472 DOI: 10.1186/s12964-020-00552-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Protease-activated receptor 4 (PAR4) is a seven transmembrane G-protein coupled receptor (GPCR) activated by endogenous proteases, such as thrombin. PAR4 is involved in various pathophysiologies including cancer, inflammation, pain, and thrombosis. Although regulators of G-protein signaling (RGS) are known to modulate GPCR/Gα-mediated pathways, their specific effects on PAR4 are not fully understood at present. We previously reported that RGS proteins attenuate PAR1- and PAR2-mediated signaling through interactions with these receptors in conjunction with distinct Gα subunits. METHODS We employed a bioluminescence resonance energy transfer technique and confocal microscopy to examine potential interactions among PAR4, RGS, and Gα subunits. The inhibitory effects of RGS proteins on PAR4-mediated downstream signaling and cancer progression were additionally investigated by using several assays including ERK phosphorylation, calcium mobilization, RhoA activity, cancer cell proliferation, and related gene expression. RESULTS In live cells, RGS2 interacts with PAR4 in the presence of Gαq while RGS4 binding to PAR4 occurs in the presence of Gαq and Gα12/13. Co-expression of PAR4 and Gαq induced a shift in the subcellular localization of RGS2 and RGS4 from the cytoplasm to plasma membrane. Combined PAR4 and Gα12/13 expression additionally promoted translocation of RGS4 from the cytoplasm to the membrane. Both RGS2 and RGS4 abolished PAR4-activated ERK phosphorylation, calcium mobilization and RhoA activity, as well as PAR4-mediated colon cancer cell proliferation and related gene expression. CONCLUSIONS RGS2 and RGS4 forms ternary complex with PAR4 in Gα-dependent manner and inhibits its downstream signaling. Our findings support a novel physiological function of RGS2 and RGS4 as inhibitors of PAR4-mediated signaling through selective PAR4/RGS/Gα coupling. Video Abstract.
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Affiliation(s)
- Yukeyoung Kim
- Department of Life Science, Kyonggi University, Suwon, 16227, South Korea
| | - Sungho Ghil
- Department of Life Science, Kyonggi University, Suwon, 16227, South Korea.
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8
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Verma M, Agarwal N, Verma M, Kumar V. Epigenetics and animal models: applications in cancer control and treatment. Anim Biotechnol 2020. [DOI: 10.1016/b978-0-12-811710-1.00004-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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9
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Activation of PAR4 Upregulates p16 through Inhibition of DNMT1 and HDAC2 Expression via MAPK Signals in Esophageal Squamous Cell Carcinoma Cells. J Immunol Res 2018; 2018:4735752. [PMID: 30363984 PMCID: PMC6186345 DOI: 10.1155/2018/4735752] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 07/30/2018] [Accepted: 08/14/2018] [Indexed: 12/13/2022] Open
Abstract
A previous study showed that a downexpression of protease-activated receptor 4 (PAR4) is associated with the development of esophageal squamous cell carcinoma (ESCC). In this study, we explored the relationship between PAR4 activation and the expression of p16, and elucidated the underlying mechanisms in PAR4 inducing the tumor suppressor role in ESCC. ESCC cell lines (EC109 and TE-1) were treated with PAR4-activating peptide (PAR4-AP). Immunohistochemistry for DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) was performed in 26 cases of ESCC tissues. We found that DNMT1 and HDAC2 immunoreactivities in ESCC were significantly higher than those in adjacent noncancerous tissues. PAR4 activation could suppress DNMT1 and HDAC2, as well as increase p16 expressions, whereas silencing PAR4 dramatically increased HDAC2 and DNMT1, as well as reduced p16 expressions. Importantly, the chromatin immunoprecipitation-PCR (ChIP-PCR) data indicated that treatment of ESCC cells with PAR4-AP remarkably suppressed DNMT1 and HDAC2 enrichments on the p16 promoter. Furthermore, we demonstrated that activation of PAR4 resulted in an increase of p38/ERK phosphorylation and activators for p38/ERK enhanced the effect of PAR4 activation on HDAC2, DNMT1, and p16 expressions, whereas p38/ERK inhibitors reversed these effects. Moreover, we found that activation of PAR4 in ESCC cells significantly inhibited cell proliferation and induced apoptosis. These findings suggest that PAR4 plays a potential tumor suppressor role in ESCC cells and represents a potential therapeutic target of this disease.
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10
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Zhang H, Jiang P, Zhang C, Lee S, Wang W, Zou H. PAR4 overexpression promotes colorectal cancer cell proliferation and migration. Oncol Lett 2018; 16:5745-5752. [PMID: 30333860 PMCID: PMC6176407 DOI: 10.3892/ol.2018.9407] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 08/02/2018] [Indexed: 12/12/2022] Open
Abstract
Protease-activated receptor 4 (PAR4), a member of the G-protein-coupled receptor family, was previously identified to be involved in the progression of cancer. Previous study revealed that the expression of PAR4 was increased in colorectal cancer tissues compared with the associated normal tissues, particularly in positive lymph node and poorly differentiated types of cancer. We hypothesized that PAR4 serves a function in the progression of colorectal cancer. In the present study, overexpression of PAR4 in colorectal cancer LoVo cells promoted proliferation, anchorage-independent growth and migration. In vivo, PAR4 increased LoVo cell tumorgenicity. In contrast, knockdown of PAR4 in HT-29 cells decreased proliferation, anchorage-independent growth and migration. Mechanistic studies revealed that PAR4 increased the phosphorylation of extracellular-signal-regulated kinase 1/2 in colorectal cancer cells, which is the potential molecular mechanism that promotes cellular proliferation and migration. Taken together, the results of the present study indicated that overexpression of PAR4 promoted colorectal cancer cell proliferation, survival and metastasis, indicating that PAR4 is a promising therapeutic target for preventing colon cancer progression.
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Affiliation(s)
- Hongshan Zhang
- Department of Cardiac Function, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Ping Jiang
- Department of Pathology and Pathophysiology, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Chuanrao Zhang
- Department of Functional Experimental Center, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Siman Lee
- Department of Biochemistry, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Wei Wang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Hao Zou
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
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11
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Jiang P, De Li S, Li ZG, Zhu YC, Yi XJ, Li SM. The expression of protease-activated receptors in esophageal carcinoma cells: the relationship between changes in gene expression and cell proliferation, apoptosis in vitro and growing ability in vivo. Cancer Cell Int 2018; 18:81. [PMID: 29977156 PMCID: PMC5992767 DOI: 10.1186/s12935-018-0577-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 05/31/2018] [Indexed: 12/25/2022] Open
Abstract
Background Protease-activated receptors (PARs) are a family of four G protein-coupled receptors expressed widely in many types of cells. PAR1, 2, and 4 have been shown to play an important role in many of the physiological activities of cells and many types of cancer cells. Esophageal carcinoma has become the fourth most common clinically diagnosed cancer and one of the top three leading causes of cancer-related deaths in China. The functions and expression patterns of PAR1, 2, and 4 in esophageal carcinoma have not published previously. Methods Here, we systematically studied the expression of PAR1, 2, and 4 in clinical esophageal carcinoma patients and determined their role in esophageal carcinoma in vivo and in vitro through the overexpression or knockdown of PAR1, 2, and 4. Results We found that the expression of PAR1 and 2 expressed higher in esophageal carcinoma than in the paracarcinoma tissues on clinical patients. PAR1 and 2 enhanced cell proliferation both in vivo and in vitro and reduced apoptosis to strengthen cancer cell vitality in TE-1 cells. In contrast, the expression of PAR4 expressed decreased in esophageal carcinoma, and its expression induced apoptosis in vivo and vitro. Conclusion In our previous studies and the present study, we noted that the expression of PAR1, 2, and 4 was almost absent in different stages of esophageal carcinoma. PAR1 and 2 might be potential molecular markers for esophageal carcinoma, and PAR4 might be an effective treatment target for esophageal carcinoma prevention and treatment.
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Affiliation(s)
- Ping Jiang
- 1Department of Pathology, Kunming Medical University, Kunming, 650500 Yunnan China
| | - Shu De Li
- 2Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming, 650500 Yunnan China
| | - Zhi Gang Li
- 2Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming, 650500 Yunnan China
| | - Yue Chun Zhu
- 2Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming, 650500 Yunnan China
| | - Xiao Jia Yi
- 3Department of Pathology, Second Affiliated Hospital of Kunming Medical University, Kunming, 650000 China
| | - Si Man Li
- 2Department of Biochemistry and Molecular Biology, Kunming Medical University, Kunming, 650500 Yunnan China
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Wang M, An S, Wang D, Ji H, Geng M, Guo X, Wang Z. Quantitative Proteomics Identify the Possible Tumor Suppressive Role of Protease-Activated Receptor-4 in Esophageal Squamous Cell Carcinoma Cells. Pathol Oncol Res 2018; 25:937-943. [PMID: 29502225 DOI: 10.1007/s12253-018-0395-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 02/21/2018] [Indexed: 12/21/2022]
Abstract
Exposure to carcinogens of tobacco smoke may result in methylation of protease-activated receptors-4 (PAR4) gene and further induces the loss of PAR4 expression, which is considered to be involved in carcinogenesis of esophageal squamous cell carcinoma (ESCC). Here we employed a TMT-based quantitative proteomic approach to identify PAR4-regulated changes of proteomic profiles in ESCC cells and to identify potentially therapeutic value. A total of 33 proteins were found significantly changed with 15 up-regulated and 18 down-regulated in PAR4-activating peptide (PAR4-AP) treated ESCC cells compared with controls. Bioinformatics analysis showed that key higher expressed proteins included those associated with apoptosis and tumor suppressor (e.g. CASP9), and lower expressed proteins included those associated with anti-apoptosis, autophagy and promoting cell proliferation (e.g. CHMP1B, PURA, PARG and HIST1H2AH). Western blot verified changes in five representative proteins including CASP9, CHMP1B, PURA, PARG and HIST1H2AH. Immunohistochemistry analysis showed that CHMP1B, PURA, PARG and HIST1H2AH expression in ESCC tissues were significantly higher than those in adjacent nontumorous tissues. Our findings will be helpful in further investigations into the functions and molecular mechanisms of PAR4 in ESCC.
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Affiliation(s)
- Ming Wang
- Department of Human Anatomy, Taishan Medical University, 2 Ying Sheng Dong Lu, Tai'an, 271000, China
| | - Shuhong An
- Department of Human Anatomy, Taishan Medical University, 2 Ying Sheng Dong Lu, Tai'an, 271000, China
| | - Diyi Wang
- Department of Pathology, Affiliated Hospital of Taishan Medical University, Tai'an, 271000, China
| | - Haizhen Ji
- Department of Physiology, Taishan Medical University, Tai'an, China
| | - Min Geng
- Department of Human Anatomy, Taishan Medical University, 2 Ying Sheng Dong Lu, Tai'an, 271000, China
| | - Xingjing Guo
- Department of Physiology, Taishan Medical University, Tai'an, China
| | - Zhaojin Wang
- Department of Human Anatomy, Taishan Medical University, 2 Ying Sheng Dong Lu, Tai'an, 271000, China.
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Jhun MA, Smith JA, Ware EB, Kardia SLR, Mosley TH, Turner ST, Peyser PA, Park SK. Modeling the Causal Role of DNA Methylation in the Association Between Cigarette Smoking and Inflammation in African Americans: A 2-Step Epigenetic Mendelian Randomization Study. Am J Epidemiol 2017; 186:1149-1158. [PMID: 29149250 DOI: 10.1093/aje/kwx181] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 01/17/2017] [Indexed: 01/17/2023] Open
Abstract
The association between cigarette smoking and inflammation is well known. However, the biological mechanisms behind the association are not fully understood, particularly the role of DNA methylation, which is known to be affected by smoking. Using 2-step epigenetic Mendelian randomization, we investigated the role of DNA methylation in the association between cigarette smoking and inflammation. In 822 African Americans from the Genetic Epidemiology Network of Arteriopathy, phase 2 (Jackson, Mississippi; 2000-2005), study population, we examined the association of cigarette smoking with DNA methylation using single nucleotide polymorphisms identified in previous genome-wide association studies of cigarette smoking. We then investigated the association of DNA methylation with levels of inflammatory markers using cis-methylation quantitative trait loci single nucleotide polymorphisms. We found that current smoking status was associated with the DNA methylation levels (M values) of cg03636183 in the coagulation factor II (thrombin) receptor-like 3 gene (F2RL3) (M = -0.64, 95% confidence interval (CI): -0.84, -0.45) and of cg19859270 in the G protein-coupled receptor 15 gene (GPR15) (M = -0.21, 95% CI: -0.27, -0.15). The DNA methylation levels of cg03636183 in F2RL3 were associated with interleukin-18 concentration (-0.11 pg/mL, 95% CI: -0.19, -0.04). These combined negative effects suggest that cigarette smoking increases interleukin-18 levels through the decrease in DNA methylation levels of cg03636183 in F2RL3.
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Increased expression of protease-activated receptor 4 and Trefoil factor 2 in human colorectal cancer. PLoS One 2015; 10:e0122678. [PMID: 25876034 PMCID: PMC4395443 DOI: 10.1371/journal.pone.0122678] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 02/24/2015] [Indexed: 01/24/2023] Open
Abstract
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.
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Li SM, Jiang P, Xiang Y, Wang WW, Zhu YC, Feng WY, Li SD, Yu GY. Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma. DONG WU XUE YAN JIU = ZOOLOGICAL RESEARCH 2015; 35:420-5. [PMID: 25297082 DOI: 10.13918/j.issn.2095-8137.2014.5.420] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Here, we used reverse transcription-PCR (RT-PCR) and western blot to detect protease-activated receptor (PAR) 1, PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma, and investigated the co-relationship between PAR expression and clinic-pathological data for esophageal cancer. The methylation of PAR4 gene promoter involved in esophageal carcinoma was also analyzed. By comparing the mRNA expressions of normal esophageal tissue and human esophageal epithelial cells (HEEpiC), we found that among the 28 cases of esophageal squamous cell carcinoma, PAR1 (60%) and PAR2 (71%) were elevated in 17 and 20 cases, respectively, and PAR4 (68%) expression was lowered in 19 cases. Whereas, in human esophageal squamous cells (TE-1 and TE-10), PAR1 and PAR2 expression was increased but PAR4 was decreased. Combined with clinical data, the expression of PAR1 in poorly differentiated (P=0.016) and middle and lower parts of the esophagus (P=0.016) was higher; expression of PAR4 in poorly differentiated carcinoma was lower (P=0.049). Regarding TE-1 and TE-10 protein expression, we found that in randomized esophageal carcinoma, PAR1 (P=0.027) and PAR2 (P=0.039) expressions were increased, but lowered for PAR4 (P=0.0001). In HEEpiC, TE-1, TE-10, esophageal and normal esophagus tissue samples (case No. 7), the frequency of methylation at the 19 CpG loci of PAR4 was 35.4%, 95.2%, 83.8%, 62.6% and 48.2%, respectively. Our results indicate that the expression of PAR1 and PAR2 in esophageal squamous cell carcinoma is increased but PAR4 is decreased. Hypermethylation of the promoter of the PAR4 gene may contribute to reduced expression of PAR4 in esophageal squamous cell carcinoma.
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Affiliation(s)
- Si-Man Li
- Kunming Medical University, Kunming 650500, China
| | - Ping Jiang
- Kunming Medical University, Kunming 650500, China
| | - Yang Xiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China
| | - Wei-Wei Wang
- Third Affiliated Hospital of Kunming Medical University, Department of Thoracic Surgery, Kunming 650000, China
| | - Yue-Chun Zhu
- Kunming Medical University, Kunming 650500, China
| | | | - Shu-De Li
- Kunming Medical University, Kunming 650500, China
| | - Guo-Yu Yu
- Kunming Medical University, Kunming 650500, China.
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Sedda S, Marafini I, Caruso R, Pallone F, Monteleone G. Proteinase activated-receptors-associated signaling in the control of gastric cancer. World J Gastroenterol 2014; 20:11977-11984. [PMID: 25232234 PMCID: PMC4161785 DOI: 10.3748/wjg.v20.i34.11977] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Revised: 02/10/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common cancer in the world and the second cause of cancer-related death. Gastric carcinogenesis is a multifactorial process, in which environmental and genetic factors interact to activate multiple intracellular signals thus leading to uncontrolled growth and survival of GC cells. One such a pathway is regulated by proteinase activated-receptors (PARs), seven transmembrane-spanning domain G protein-coupled receptors, which comprise four receptors (i.e., PAR-1, PAR-2, PAR-3, and PAR-4) activated by various proteases. Both PAR-1 and PAR-2 are over-expressed on GC cells and their activation triggers and/or amplifies intracellular pathways, which sustain gastric carcinogenesis. There is also evidence that expression of either PAR-1 or PAR-2 correlates with depth of wall invasion and metastatic dissemination and inversely with the overall survival of patients. Consistently, data emerging from experimental models of GC suggest that both these receptors can be important targets for therapeutic interventions in GC patients. In contrast, PAR-4 levels are down-regulated in GC and correlate inversely with the aggressiveness of GC, thus suggesting a negative role of this receptor in the control of GC. In this article we review the available data on the expression and role of PARs in GC and discuss whether manipulation of PAR-driven signals may be useful for interfering with GC cell behavior.
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Jiang P, Yu GY, Zhang Y, Xiang Y, Hua HR, Bian L, Wang CY, Lee WH, Zhang Y. Down-regulation of protease-activated receptor 4 in lung adenocarcinoma is associated with a more aggressive phenotype. Asian Pac J Cancer Prev 2014; 14:3793-8. [PMID: 23886184 DOI: 10.7314/apjcp.2013.14.6.3793] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The role of protease-activated receptors (PARs) in lung tumors is controversial. Although PAR4 is preferentially expressed in human lung tissues, its possible significance in lung cancer has not been defined. The studies reported herein used a combination of clinical observations and molecular methods. Surgically resected lung adenocarcinomas and associated adjacent normal lung tissues were collected and BEAS-2B and NCI-H157 cell lines were grown in tissue culture. PAR4 expression was evaluated by RT-PCR, RT-qPCR, Western blotting and immunohistochemistry analysis. The results showed that PAR4 mRNA expression was generally decreased in lung adenocarcinoma tissues as compared with matched noncancerous tissues (67.7%) and was associated with poor differentiation (p=0.017) and metastasis (p=0.04). Western blotting and immunohistochemical analysis also showed that PAR4 protein levels were mostly decreased in lung adenocarcinoma tissues (61.3%), and were also associated with poor differentiation (p=0.035) and clinical stage (p=0.027). Moreover, PAR4 expression was decreased in NCI-H157 cells as compared with BEAS-2B cells. In conclusion, PAR4 expression is significantly decreased in lung adenocarcinoma, and down-regulation of PAR4 is associated with a more clinically aggressive phenotype. PAR4 may acts as a tumor suppressor in lung adenocarcinoma.
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Affiliation(s)
- Ping Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
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Zhang Y, Yang R, Burwinkel B, Breitling LP, Holleczek B, Schöttker B, Brenner H. F2RL3 methylation in blood DNA is a strong predictor of mortality. Int J Epidemiol 2014; 43:1215-25. [PMID: 24510982 DOI: 10.1093/ije/dyu006] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Smoking is a major cause of morbidity and mortality. Smoking-related epigenetic biomarkers may open new avenues to better quantify the adverse health effects of smoking, and to better understanding of the underlying mechanisms. We aimed to evaluate the clinical implications of F2RL3 methylation, a novel epigenetic biomarker of smoking exposure disclosed by recent genome-wide methylation studies. METHODS Blood DNA methylation at F2RL3 (also known as PAR-4) was quantified in baseline samples of 3588 participants aged 50-75 years in a large population-based prospective cohort study by MALDI-TOF mass spectrometry. Deaths were recorded during a median follow-up of 10.1 years. The associations of methylation intensity and of smoking with all-cause, cardiovascular, cancer and other mortality were assessed by Cox's proportional hazards regression, controlling for potential confounding factors. RESULTS Lower methylation intensity at F2RL3 was strongly associated with mortality. After adjustment for multiple covariates including smoking, hazard ratios [95% confidence interval (CI)] for death from any cause, cardiovascular disease, cancer or other causes were 2.60 (95% CI, 1.81-3.74), 2.45 (95% CI, 1.28-4.68), 2.94 (95% CI, 1.68-5.14) and 2.39 (95% CI, 1.11-5.16), respectively, in subjects in the lowest quartile of methylation intensity compared with subjects in the highest quartile. The associations with mortality outcomes were much stronger among men than among women. In addition, strong positive associations of smoking with each of the outcomes were substantially weakened, and almost disappeared when controlling for F2RL3 methylation intensity. CONCLUSIONS F2RL3 methylation is a strong predictor of mortality, including all-cause, cardiovascular, cancer and other mortality. Systemic adverse effects of smoking may be mediated by pathways associated with F2RL3 methylation.
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Affiliation(s)
- Yan Zhang
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, Germany
| | - Rongxi Yang
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, GermanyDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, Germany
| | - Barbara Burwinkel
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, GermanyDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, Germany
| | - Lutz P Breitling
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, Germany
| | - Bernd Holleczek
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany, Division of Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany, Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany and Saarland Cancer Registry, Saarbrücken, Germany
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Du TY, Luo HM, Qin HC, Wang F, Wang Q, Xiang Y, Zhang Y. Circulating serum trefoil factor 3 (TFF3) is dramatically increased in chronic kidney disease. PLoS One 2013; 8:e80271. [PMID: 24282531 PMCID: PMC3840008 DOI: 10.1371/journal.pone.0080271] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 10/11/2013] [Indexed: 01/10/2023] Open
Abstract
Objectives Trefoil factor 3 (TFF3) is a small peptide that plays an important role in mucosal protection, cell proliferation, and cell migration. The aberrant expression of TFF3 is correlated with gastrointestinal inflammation, solid tumors, and other clinical diseases. The objective of this study was to identify the distribution characteristics of serum TFF3 in common clinical diseases. Materials and Methods A large prospective randomized study of 1,072 Chinese patients was performed using an enzyme-linked immunosorbent assay (ELISA) to examine the serum TFF3 concentrations in patients with different diseases. A matched case-control study was conducted on patients with chronic kidney disease (CKD) stages 1–5. Immunohistochemistry (IHC) was performed using renal tissues to determine the relationship between the severity of CKD and the serum and urine concentrations of TFF3 peptides. Results The mean serum concentrations of TFF3 in patients with CKD, metastatic and secondary carcinoma (MC) and acute gastroenteritis (AG) (200.9 ng/ml, 95.7 ng/ml and 71.7 ng/ml, respectively) were significantly higher than those in patients with other common clinical diseases. A positive correlation tendency was observed between the serum TFF3 concentrations and the severity of CKD. The mean serum TFF3 values for CKD stages 1–5 were 23.6 ng/ml, 29.9 ng/ml, 54.9 ng/ml, 85.0 ng/ml and 176.6 ng/ml, respectively. The same trend was observed in the urine TFF3 concentrations and the CKD stages. The creatinine(Cr)-corrected concentrations of TFF3 in urine were 367.1 ng/mg·Cr, 910.6 ng/mg·Cr, 1,149.0 ng/mg·Cr, 1,610.0 ng/mg·Cr and 3,475.0 ng/mg·Cr for CKD stages 1–5, respectively. IHC revealed that TFF3 expression was concentrated in tubular epithelial cells. Conclusions The influence of kidney injuries must be fully considered when performing clinical TFF3 research. Further studies on TFF3 in CKD will contribute to our understanding of its pathological roles and mechanisms in other diseases.
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Affiliation(s)
- Ting-yi Du
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, Yunnan Province, China
- University of the Chinese Academy of Sciences, Beijing, China
- Department of Clinical Laboratory Medicine, the First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Hui-ming Luo
- Department of Nephrology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Hai-chun Qin
- Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Fang Wang
- Department of Clinical Laboratory Medicine, the First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Qing Wang
- Department of Gynecology, The First People’s Hospital of Yunnan Province,Kunming, Yunnan Province, China
| | - Yang Xiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, Yunnan Province, China
| | - Yun Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, Yunnan Province, China
- * E-mail:
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