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Kotnala S, Dhasmana A, Dhasmana S, Haque S, Yallapu MM, Tripathi MK, Jaggi M, Chauhan SC. A Systems Biology Approach Unveils a Critical Role of DPP4 in Upper Gastrointestinal Cancer Patient Outcomes. J Environ Pathol Toxicol Oncol 2024; 43:43-55. [PMID: 38505912 PMCID: PMC11419273 DOI: 10.1615/jenvironpatholtoxicoloncol.2023048056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024] Open
Abstract
Gastrointestinal (GI) cancers comprise of cancers that affect the digestive system and its accessory organs. The late detection and poor prognosis of GI cancer emphasizes the importance of identifying reliable and precise biomarkers for early diagnosis and prediction of prognosis. The membrane-bound glycoprotein dipeptidyl-peptidase 4 (DPP4), also known as CD26, is ubiquitously expressed and has a wide spectrum of biological roles. The role of DPP4/CD26 in tumor progression in different types of cancers remains elusive. However, the link between DPP4 and tumor-infiltrating cells, as well as its prognostic significance in malignancies, still require further investigation. This study was intended to elucidate the correlation of DPP4 expression and survival along with prognosis, followed by its associated enriched molecular pathways and immune cell marker levels in upper GI cancers. Results demonstrated a strong correlation between increased DPP4 expression and a worse prognosis in esophageal and gastric cancer and the co-expressed common genes with DPP4 were associated with crucial molecular pathways involved in tumorigenesis. Additionally, DPP4 was shown to be significantly linked to several immune infiltrating cell marker genes, including Macrophages (M1, M2 and Tumor Associated Macrophages), neutrophils, Treg, T-cell exhaustion, Th1 and Th2. Overall, our findings suggest that DPP4 may serve as a substantial prognostic biomarker, a possible therapeutic target, as well as it can play a critical role in the regulation of immune cell invasion in patients with gastroesophageal (esophageal, gastroesophageal junction and gastric) cancer. KEY WORDS: DPP4, integrated analysis, GI cancer, gastroesophageal cancer, gastroesophageal junction, prognosis.
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Affiliation(s)
- Sudhir Kotnala
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Swati Dhasmana
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Murali M. Yallapu
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Manish K. Tripathi
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Subhash C. Chauhan
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
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Zubaľ M, Výmolová B, Matrasová I, Výmola P, Vepřková J, Syrůček M, Tomáš R, Vaníčková Z, Křepela E, Konečná D, Bušek P, Šedo A. Fibroblast activation protein as a potential theranostic target in brain metastases of diverse solid tumours. Pathology 2023; 55:806-817. [PMID: 37419841 DOI: 10.1016/j.pathol.2023.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 03/30/2023] [Accepted: 05/30/2023] [Indexed: 07/09/2023]
Abstract
Brain metastases are a very common and serious complication of oncological diseases. Despite the vast progress in multimodality treatment, brain metastases significantly decrease the quality of life and prognosis of patients. Therefore, identifying new targets in the microenvironment of brain metastases is desirable. Fibroblast activation protein (FAP) is a transmembrane serine protease typically expressed in tumour-associated stromal cells. Due to its characteristic presence in the tumour microenvironment, FAP represents an attractive theranostic target in oncology. However, there is little information on FAP expression in brain metastases. In this study, we quantified FAP expression in samples of brain metastases of various primary origin and characterised FAP-expressing cells. We have shown that FAP expression is significantly higher in brain metastases in comparison to non-tumorous brain tissues, both at the protein and enzymatic activity levels. FAP immunopositivity was localised in regions rich in collagen and containing blood vessels. We have further shown that FAP is predominantly confined to stromal cells expressing markers typical of cancer-associated fibroblasts (CAFs). We have also observed FAP immunopositivity on tumour cells in a portion of brain metastases, mainly originating from melanoma, lung, breast, and renal cancer, and sarcoma. There were no significant differences in the quantity of FAP protein, enzymatic activity, and FAP+ stromal cells among brain metastasis samples of various origins, suggesting that there is no association of FAP expression and/or presence of FAP+ stromal cells with the histological type of brain metastases. In summary, we are the first to establish the expression of FAP and characterise FAP-expressing cells in the microenvironment of brain metastases. The frequent upregulation of FAP and its presence on both stromal and tumour cells support the use of FAP as a promising theranostic target in brain metastases.
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Affiliation(s)
- Michal Zubaľ
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Barbora Výmolová
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Ivana Matrasová
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Výmola
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jana Vepřková
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Martin Syrůček
- Department of Pathology, Na Homolce Hospital, Prague, Czech Republic
| | - Robert Tomáš
- Department of Neurosurgery, Na Homolce Hospital, Prague, Czech Republic
| | - Zdislava Vaníčková
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Evžen Křepela
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Dora Konečná
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic; Departments of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University and Military University Hospital, Prague, Czech Republic
| | - Petr Bušek
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Aleksi Šedo
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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Pillai U J, Ray A, Maan M, Dutta M. Repurposing drugs targeting metabolic diseases for cancer therapeutics. Drug Discov Today 2023; 28:103684. [PMID: 37379903 DOI: 10.1016/j.drudis.2023.103684] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 06/01/2023] [Accepted: 06/18/2023] [Indexed: 06/30/2023]
Abstract
Hurdles in the identification of new drugs for cancer treatment have made drug repurposing an increasingly appealing alternative. The approach involves the use of old drugs for new therapeutic purposes. It is cost-effective and facilitates rapid clinical translation. Given that cancer is also considered a metabolic disease, drugs for metabolic disorders are being actively repurposed for cancer therapeutics. In this review, we discuss the repurposing of such drugs approved for two major metabolic diseases, diabetes and cardiovascular disease (CVD), which have shown potential as anti-cancer treatment. We also highlight the current understanding of the cancer signaling pathways that these drugs target.
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Affiliation(s)
- Jisha Pillai U
- Department of Biotechnology, BITS Pilani, Dubai Campus, Academic City, Dubai, UAE
| | - Anindita Ray
- Department of Biotechnology, BITS Pilani, Dubai Campus, Academic City, Dubai, UAE
| | - Meenu Maan
- Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai, UAE; New York University-Abu Dhabi, Abu Dhabi, UAE.
| | - Mainak Dutta
- Department of Biotechnology, BITS Pilani, Dubai Campus, Academic City, Dubai, UAE.
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Gu Y, Lin X, Dong Y, Wood G, Seidah NG, Werstuck G, Major P, Bonert M, Kapoor A, Tang D. PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2023; 42:2. [PMID: 36588164 PMCID: PMC9806914 DOI: 10.1186/s13046-022-02584-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear. METHODS PCSK9's association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9-/- mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. RESULTS PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9-/- mice. CONCLUSIONS Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9's oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.
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Affiliation(s)
- Yan Gu
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Xiaozeng Lin
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Ying Dong
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Geoffrey Wood
- grid.34429.380000 0004 1936 8198Department of Pathology, University of Guelph, Guelph, ON N1G 2W1 Canada
| | - Nabil G. Seidah
- grid.511547.30000 0001 2106 1695Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, University of Montreal, Montreal, QC H2W 1R7 Canada
| | - Geoff Werstuck
- grid.25073.330000 0004 1936 8227Department of Medicine, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Pierre Major
- grid.25073.330000 0004 1936 8227Department of Oncology, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Michael Bonert
- grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Anil Kapoor
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Damu Tang
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
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Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease? Cancers (Basel) 2022; 14:cancers14092072. [PMID: 35565202 PMCID: PMC9103952 DOI: 10.3390/cancers14092072] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary There is growing interest in identifying the effects of antidiabetic agents on cancer risk, progression, and anti-cancer treatment due to the long-term use of these medications and the inherently increased risk of malignancies in diabetic patients. Tumor development and progression are affected by multiple mediators in the tumor microenvironment, several of which may be proteolytically modified by the multifunctional protease dipeptidyl peptidase-IV (DPP-IV, CD26). Currently, low-molecular-weight DPP-IV inhibitors (gliptins) are used in patients with type 2 diabetes based on the observation that DPP-IV inhibition enhances insulin secretion by increasing the bioavailability of incretins. However, the DPP-IV-mediated cleavage of other biopeptides and chemokines is also prevented by gliptins. The potential utility of gliptins in other areas of medicine, including cancer, is therefore being evaluated. Here, we critically review the existing evidence on the role of DPP-IV inhibitors in cancer pathogenesis, their potential to be used in anti-cancer treatment, and the possible perils associated with this approach. Abstract Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments.
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Zhao M, Jin X, Chen Z, Zhang H, Zhan C, Wang H, Wang Q. Weighted Correlation Network Analysis of Cancer Stem Cell-Related Prognostic Biomarkers in Esophageal Squamous Cell Carcinoma. Technol Cancer Res Treat 2022; 21:15330338221117003. [PMID: 35899307 PMCID: PMC9340319 DOI: 10.1177/15330338221117003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background: The role of cancer stem cells in esophageal squamous
cell carcinoma (ESCC) remains unclear. Methods: The mRNA stemness
index (mRNAsi) of 179 ESCC patients (GSE53625) was calculated using a machine
learning algorithm based on their mRNA expression. Stemness-related genes were
identified by weighted correlation network analysis (WGCNA) and LASSO
regression, whose associations with mutation status, immune cell infiltrations,
and potential compounds were also analyzed. The role of these genes in
proliferation and their expressions was assessed in ESCC cell lines and 112
samples from our center. Results: The ESCC samples had
significantly higher mRNAsi than the normal tissues. Patients with high mRNAsi
exhibited higher worse OS. Seven stemness-related genes were identified by WGCNA
and LASSO regression, based on which a risk-predicted score model was
constructed. Among them, CST1, CILP, PITX2, F2RL2, and RIOX1 were favorable for
OS, which were adverse for DPP4 and ZFHX4 in the GSE53625 dataset. However,
RIOX1 was unfavorable for OS in patients from our center. In vitro assays showed
that CST1, CILP, PITX2, F2RL2, and RIOX1 were pro-proliferated, which were
opposite for DDP4 and ZFHX4. In addition, SMARCA4, NOTCH3, DNAH5, and KALRN were
more mutated in the low-score group. The low-score group had significantly more
memory B cells, monocytes, activated NK cells, and Tregs and less macrophages
M2, resting mast cells, and resting dendritic cells. Conclusions:
Seven stemness-related genes are significantly related to the prognosis, gene
mutations, and immune cell infiltration of ESCC. Some potential anticancer
compounds may be favorable for OS.
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Affiliation(s)
- Mengnan Zhao
- Department of Thoracic Surgery, 92323Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xing Jin
- Department of Thoracic Surgery, 92323Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhencong Chen
- Department of Thoracic Surgery, 92323Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huan Zhang
- Department of Thoracic Surgery, 92323Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Zhan
- Department of Thoracic Surgery, 92323Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Wang
- Department of Thoracic Surgery, 92323Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qun Wang
- Department of Thoracic Surgery, 92323Zhongshan Hospital, Fudan University, Shanghai, China
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Abstract
Dipeptidyl peptidase 4 (DPP4), a serine protease expressed on luminal and apical cell membrane, is identical to the lymphocyte cell surface protein CD26. DPP4 rapidly deactivates hormones and cytokines by cleaving their NH2-terminal dipeptides. Its functions are based on membrane digestion and/or binding of bioactive peptides, signal molecules, and extracellular matrix components. The soluble form is also present in body fluids such as serum, urine, semen, and synovial fluid. The extremely broad distribution of CD26/DPP4 indicates its divergent roles depending on cell type and activated conditions. The cellular localization was earlier examined by enzyme histochemistry and subsequently by immunohistochemistry. Although immunohistochemical analyses are higher in specificity and easier to use at electron microscopic levels than enzyme histochemistry, the immunoreaction is considerably affected by the animal species, types of tissue sections, and specificity of antibodies. Understanding of the functional significance and advancement of its clinical use (diagnosis and treatment of diseases) require precise information on the cellular distribution including subcellular localization and pathological changes. This short review summarizes in particular immunohistochemical findings on CD26/DPP4.
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Affiliation(s)
- Toshihiko Iwanaga
- Laboratory of Histology and Cytology, Department of Anatomy, Hokkaido University Graduate School of Medicine
| | - Junko Nio-Kobayashi
- Laboratory of Histology and Cytology, Department of Anatomy, Hokkaido University Graduate School of Medicine
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Zhang T, Tong X, Zhang S, Wang D, Wang L, Wang Q, Fan H. The Roles of Dipeptidyl Peptidase 4 (DPP4) and DPP4 Inhibitors in Different Lung Diseases: New Evidence. Front Pharmacol 2021; 12:731453. [PMID: 34955820 PMCID: PMC8696080 DOI: 10.3389/fphar.2021.731453] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 11/25/2021] [Indexed: 02/05/2023] Open
Abstract
CD26/Dipeptidyl peptidase 4 (DPP4) is a type II transmembrane glycoprotein that is widely expressed in various organs and cells. It can also exist in body fluids in a soluble form. DPP4 participates in various physiological and pathological processes by regulating energy metabolism, inflammation, and immune function. DPP4 inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. More evidence has shown the role of DPP4 in the pathogenesis of lung diseases, since it is highly expressed in the lung parenchyma and the surface of the epithelium, vascular endothelium, and fibroblasts of human bronchi. It is a potential biomarker and therapeutic target for various lung diseases. During the coronavirus disease-19 (COVID-19) global pandemic, DPP4 was found to be an important marker that may play a significant role in disease progression. Some clinical trials on DPP4 inhibitors in COVID-19 are ongoing. DPP4 also affects other infectious respiratory diseases such as Middle East respiratory syndrome and non-infectious lung diseases such as pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), and asthma. This review aims to summarize the roles of DPP4 and its inhibitors in infectious lung diseases and non-infectious diseases to provide new insights for clinical physicians.
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Affiliation(s)
| | | | | | | | | | | | - Hong Fan
- Department of Respiratory and Critical Care Medicine, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China
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De Zutter A, Van Damme J, Struyf S. The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer. Cancers (Basel) 2021; 13:cancers13174247. [PMID: 34503058 PMCID: PMC8428238 DOI: 10.3390/cancers13174247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/04/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity is the NH2-terminal truncation by peptidases. CD26 is a dipeptidyl peptidase (DPPIV), which typically clips a NH2-terminal dipeptide from the chemokine. With a certain degree of selectivity in terms of chemokine substrate, CD26 only recognizes chemokines with a penultimate proline or alanine. Chemokines can be protected against CD26 recognition by specific amino acid residues within the chemokine structure, by oligomerization or by binding to cellular glycosaminoglycans (GAGs). Upon truncation, the binding affinity for receptors and GAGs is altered, which influences chemokine function. The consequences of CD26-mediated clipping vary, as unchanged, enhanced, and reduced activities are reported. In tumors, CD26 most likely has the most profound effect on CXCL12 and the interferon (IFN)-inducible CXCR3 ligands, which are converted into receptor antagonists upon truncation. Depending on the tumor type, expression of CD26 is upregulated or downregulated and often results in the preferential generation of the chemokine isoform most favorable for tumor progression. Considering the tight relationship between chemokine sequence and chemokine binding specificity, molecules with the appropriate characteristics can be chemically engineered to provide innovative therapeutic strategies in a cancer setting.
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10
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Bi O, Anene CA, Nsengimana J, Shelton M, Roberts W, Newton-Bishop J, Boyne JR. SFPQ promotes an oncogenic transcriptomic state in melanoma. Oncogene 2021; 40:5192-5203. [PMID: 34218270 PMCID: PMC8376646 DOI: 10.1038/s41388-021-01912-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 06/17/2021] [Indexed: 02/06/2023]
Abstract
The multifunctional protein, splicing factor, proline- and glutamine-rich (SFPQ) has been implicated in numerous cancers often due to interaction with coding and non-coding RNAs, however, its role in melanoma remains unclear. We report that knockdown of SFPQ expression in melanoma cells decelerates several cancer-associated cell phenotypes, including cell growth, migration, epithelial to mesenchymal transition, apoptosis, and glycolysis. RIP-seq analysis revealed that the SFPQ-RNA interactome is reprogrammed in melanoma cells and specifically enriched with key melanoma-associated coding and long non-coding transcripts, including SOX10, AMIGO2 and LINC00511 and in most cases SFPQ is required for the efficient expression of these genes. Functional analysis of two SFPQ-enriched lncRNA, LINC00511 and LINC01234, demonstrated that these genes independently contribute to the melanoma phenotype and a more detailed analysis of LINC00511 indicated that this occurs in part via modulation of the miR-625-5p/PKM2 axis. Importantly, analysis of a large clinical cohort revealed that elevated expression of SFPQ in primary melanoma tumours may have utility as a prognostic biomarker. Together, these data suggest that SFPQ is an important driver of melanoma, likely due to SFPQ-RNA interactions promoting the expression of numerous oncogenic transcripts.
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Affiliation(s)
- O Bi
- School of Applied Sciences, University of Huddersfield, Huddersfield, UK
| | - C A Anene
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - J Nsengimana
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
| | - M Shelton
- School of Applied Sciences, University of Huddersfield, Huddersfield, UK
| | - W Roberts
- School of Clinical and Applied Science, Leeds Beckett University, Leeds, UK
| | | | - J R Boyne
- School of Applied Sciences, University of Huddersfield, Huddersfield, UK.
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11
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Varela-Calviño R, Rodríguez-Quiroga M, Dias Carvalho P, Martins F, Serra-Roma A, Vázquez-Iglesias L, Páez de la Cadena M, Velho S, Cordero OJ. The mechanism of sitagliptin inhibition of colorectal cancer cell lines' metastatic functionalities. IUBMB Life 2021; 73:761-773. [PMID: 33615655 DOI: 10.1002/iub.2454] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 12/14/2022]
Abstract
The cell membrane glycoprotein CD26 with peptidase activity (DPP4) and/or its soluble CD26/DPP4 counterpart expression and/or activity are altered in several cancers. Its role in metastasis development was recently highlighted by the discovery of CD26+ cancer stem cell subsets and the fact that clinical DPP4 inhibitors showed antimetastatic effects in animal models. Also, diabetic patients treated with the DPP4 inhibitor sitagliptin showed greater overall survival after colorectal or lung cancer surgery than patients under other diabetic therapies. However, the mechanism of action of these inhibitors in this context is unclear. We studied the role of CD26 and its DPP4 enzymatic activity in malignant cell features such as cell-to-cell homotypic aggregation, cancer cell motility, and invasion in a panel of human colorectal cancer (CRC) cell lines, avoiding models that include the physiological role of DPP4 in chemotaxis. Present results indicate that CD26 participates in the induction of cell invasion, motility, and aggregation of CD26-positive CRC cell lines. Moreover, only invasion and motility assays, which are collagen matrix-dependent, showed a decrease upon treatment with the DPP4 inhibitor sitagliptin. Sitagliptin showed opposite effects to those of transforming growth factor-β1 on epithelial-to-mesenchymal transition and cell cycle, but this result does not explain its CD26/DPP4-dependent effect. These results contribute to the elucidation of the molecular mechanisms behind sitagliptin inhibition of metastatic traits. At the same time, this role of sitagliptin may help to define areas of medicine where DPP4 inhibitors might be introduced. However, they also suggest that additional tools against CD26 as a target might be used or developed for metastasis prevention in addition to gliptins.
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Affiliation(s)
- Rubén Varela-Calviño
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Marta Rodríguez-Quiroga
- Institute of Research in Health and Innovation, Universidade do Porto, Porto, Portugal.,IPATIMUP (Institute of Molecular Pathology and Immunology), University of Porto, Porto, Portugal.,Department of Biochemistry, Immunology and Genetics, University of Vigo, Vigo, Spain
| | - Patrícia Dias Carvalho
- Institute of Research in Health and Innovation, Universidade do Porto, Porto, Portugal.,IPATIMUP (Institute of Molecular Pathology and Immunology), University of Porto, Porto, Portugal
| | - Flavia Martins
- Institute of Research in Health and Innovation, Universidade do Porto, Porto, Portugal.,IPATIMUP (Institute of Molecular Pathology and Immunology), University of Porto, Porto, Portugal
| | - André Serra-Roma
- Institute of Research in Health and Innovation, Universidade do Porto, Porto, Portugal.,IPATIMUP (Institute of Molecular Pathology and Immunology), University of Porto, Porto, Portugal
| | | | | | - Sérgia Velho
- Institute of Research in Health and Innovation, Universidade do Porto, Porto, Portugal.,IPATIMUP (Institute of Molecular Pathology and Immunology), University of Porto, Porto, Portugal
| | - Oscar J Cordero
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Santiago de Compostela, Spain
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12
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Takagi S, Hirokawa M, Nagashima K, Higuchi M, Kadota K, Ishikawa R, Sato M, Miyauchi A, Miyake Y, Haba R. Diagnostic significance of apical membranous and cytoplasmic dot-like CD26 expression in encapsulated follicular variant of papillary thyroid carcinoma: a useful marker for capsular invasion. Endocr J 2020; 67:1207-1214. [PMID: 32879160 DOI: 10.1507/endocrj.ej19-0501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and invasive encapsulated follicular variant of papillary thyroid carcinoma (EFV-PTC) are indistinguishable preoperatively. CD26 expression in follicular tumor-uncertain malignant potential (FT-UMP) is reported to be clearly higher than in that without capsular invasion. To verify the diagnostic significance of CD26 immunostaining in EFV-PTC, we examined the expression pattern of CD26 in non-invasive EFV-PTC (NIFTP) and invasive EFV-PTC. We performed immunohistochemical analysis using CD26 antibody for 37 NIFTPs and 54 EFV-PTCs (34 minimally invasive EFV-PTCs and 20 widely invasive EFV-PTCs). Most NIFTP samples showed an apical membranous pattern or a cytoplasmic diffuse pattern of expression. Invasive EFV-PTCs more frequently showed a cytoplasmic dot-like pattern, and the labeling indices of tumor cells with cytoplasmic dot-like patterns were significantly higher than those in NIFTPs. The sizes of dots seen in NIFTPs (mean: 1.12 μm) were significantly smaller than in invasive EFV-PTCs (1.33 μm), minimally invasive EFV-PTC (1.27 μm), and widely invasive EFV-PTC (1.38 μm). We, therefore, conclude that cytoplasmic diffuse and/or cytoplasmic dot-like CD26 expression, particularly the larger CD26-positive dots, could be useful markers for capsular invasion in EFV-PTC. CD26 immunostaining, using cell blocks or cytological specimens, may preoperatively distinguish between NIFTP and invasive EFV-PTC.
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Affiliation(s)
- Shoji Takagi
- Department of Medical Life Science, Kurashiki University of Science and the Arts, Kurashiki, Okayama 712-8505, Japan
- Faculty of Medicine, Graduate School of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Mitsuyoshi Hirokawa
- Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Hyogo 650-0011, Japan
| | - Kenji Nagashima
- Department of Clinical Laboratory, Gifu University Hospital, Gifu, Gifu 501-1194, Japan
| | - Miyoko Higuchi
- Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Hyogo 650-0011, Japan
| | - Kyuichi Kadota
- Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Ryou Ishikawa
- Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Masakazu Sato
- Department of Medical Life Science, Kurashiki University of Science and the Arts, Kurashiki, Okayama 712-8505, Japan
| | - Akira Miyauchi
- Department of Surgery, Kuma Hospital, Kobe, Hyogo 650-0011, Japan
| | - Yasuyuki Miyake
- Department of Medical Life Science, Kurashiki University of Science and the Arts, Kurashiki, Okayama 712-8505, Japan
| | - Reiji Haba
- Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
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13
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Patel PM, Jones VA, Kridin K, Amber KT. The role of Dipeptidyl Peptidase-4 in cutaneous disease. Exp Dermatol 2020; 30:304-318. [PMID: 33131073 DOI: 10.1111/exd.14228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/21/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022]
Abstract
Dipeptidyl peptidase-4 (DPP4) is a multifunctional, transmembrane glycoprotein present on the cell surface of various tissues. It is present in multiple molecular forms including cell surface and soluble. The role of DPP4 and its inhibition in cutaneous dermatoses have been a recent point of investigation. DPP4 exerts a notable influence on T-cell biology, the induction of skin-specific lymphocytes, and the homeostasis between regulatory and effector T cells. Moreover, DPP4 interacts with a broad range of molecules, including adenosine deaminase, caveolin-1, CXCR4 receptor, M6P/insulin-like growth factor II-receptor and fibroblast activation protein-α, triggering downstream effects that modulate the immune response, cell adhesion and chemokine activity. DPP4 expression on melanocytes, keratinocytes and fibroblasts further alters cell function and, thus, has crucial implications in cutaneous pathology. As a result, DPP4 plays a significant role in bullous pemphigoid, T helper type 1-like reactions, cutaneous lymphoma, melanoma, wound healing and fibrotic disorders. This review illustrates the multifactorial role of DPP4 expression, regulation, and inhibition in cutaneous diseases.
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Affiliation(s)
- Payal M Patel
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Virginia A Jones
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Khalaf Kridin
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Kyle T Amber
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
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14
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Deficiency in Dipeptidyl Peptidase-4 Promotes Chemoresistance through the CXCL12/CXCR4/mTOR/TGFβ Signaling Pathway in Breast Cancer Cells. Int J Mol Sci 2020; 21:ijms21030805. [PMID: 31991851 PMCID: PMC7037814 DOI: 10.3390/ijms21030805] [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: 10/23/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 02/06/2023] Open
Abstract
Dipeptidyl peptidase (DPP)-4, a molecular target of DPP-4 inhibitors, which are type 2 diabetes drugs, is expressed in a variety of cell types, tissues and organs. DPP-4 has been shown to be involved in cancer biology, and we have recently shown that a DPP-4 inhibitor promoted the epithelial mesenchymal transition (EMT) in breast cancer cells. The EMT is known to associate with chemotherapy resistance via the induction of ATP-binding cassette (ABC) transporters in cancer cells. Here, we demonstrated that deficiency in DPP-4 promoted chemotherapy resistance via the CXCL12/CXCR4/mTOR axis, activating the TGFβ signaling pathway via the expression of ABC transporters. DPP-4 inhibition enhanced ABC transporters in vivo and in vitro. Doxorubicin (DOX) further induced ABC transporters in DPP-4-deficient 4T1 cells, and the induction of ABC transporters was suppressed by either the CXCR4 inhibitor AMD3100, the mTOR inhibitor rapamycin or a neutralizing TGFβ (1, 2 and 3) antibody(N-TGFβ). Knockdown of snail, an EMT-inducible transcription factor, suppressed ABC transporter levels in DOX-treated DPP-4-deficient 4T1 cells. In an allograft mouse model, however, the effects of DOX in either primary tumor or metastasis were not statistically different between control and DPP-4-kd 4T1. Taken together, our findings suggest that DPP-4 inhibitors potentiate chemotherapy resistance via the induction of ABC transporters by the CXCL12/CXCR4/mTOR/TGFβ signaling pathway in breast cancer cells.
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15
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Li L, van Breugel PC, Loayza-Puch F, Ugalde AP, Korkmaz G, Messika-Gold N, Han R, Lopes R, Barbera EP, Teunissen H, de Wit E, Soares RJ, Nielsen BS, Holmstrøm K, Martínez-Herrera DJ, Huarte M, Louloupi A, Drost J, Elkon R, Agami R. LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS. Nucleic Acids Res 2019; 46:4213-4227. [PMID: 29481642 PMCID: PMC5934637 DOI: 10.1093/nar/gky087] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 01/29/2018] [Indexed: 12/15/2022] Open
Abstract
Oncogene-induced senescence (OIS), provoked in response to oncogenic activation, is considered an important tumor suppressor mechanism. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt without a protein-coding capacity. Functional studies showed that deregulated lncRNA expression promote tumorigenesis and metastasis and that lncRNAs may exhibit tumor-suppressive and oncogenic function. Here, we first identified lncRNAs that were differentially expressed between senescent and non-senescent human fibroblast cells. Using RNA interference, we performed a loss-function screen targeting the differentially expressed lncRNAs, and identified lncRNA-OIS1 (lncRNA#32, AC008063.3 or ENSG00000233397) as a lncRNA required for OIS. Knockdown of lncRNA-OIS1 triggered bypass of senescence, higher proliferation rate, lower abundance of the cell-cycle inhibitor CDKN1A and high expression of cell-cycle-associated genes. Subcellular inspection of lncRNA-OIS1 indicated nuclear and cytosolic localization in both normal culture conditions as well as following oncogene induction. Interestingly, silencing lncRNA-OIS1 diminished the senescent-associated induction of a nearby gene (Dipeptidyl Peptidase 4, DPP4) with established role in tumor suppression. Intriguingly, similar to lncRNA-OIS1, silencing DPP4 caused senescence bypass, and ectopic expression of DPP4 in lncRNA-OIS1 knockdown cells restored the senescent phenotype. Thus, our data indicate that lncRNA-OIS1 links oncogenic induction and senescence with the activation of the tumor suppressor DPP4.
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Affiliation(s)
- Li Li
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Pieter C van Breugel
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Fabricio Loayza-Puch
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Alejandro Pineiro Ugalde
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Gozde Korkmaz
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Naama Messika-Gold
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, 69978, Tel Aviv University, Tel Aviv, Israel
| | - Ruiqi Han
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Rui Lopes
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Eric P Barbera
- Division of Molecular Genetics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Hans Teunissen
- Division of Gene Regulation, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Elzo de Wit
- Division of Gene Regulation, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | | | | | - Kim Holmstrøm
- Bioneer A/S, Kogle Allé 2, DK-2970 Hørsholm, Denmark
| | | | - Maite Huarte
- Institute of Health Research of Navarra (IdiSNA), 31008 Pamplona, Spain
| | - Annita Louloupi
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Jarno Drost
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Ran Elkon
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, 69978, Tel Aviv University, Tel Aviv, Israel
| | - Reuven Agami
- Division of Oncogenomics, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.,Erasmus MC, Rotterdam University, 3000 CA Rotterdam, The Netherlands.,Oncode institute, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
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16
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Nieto-Fontarigo JJ, González-Barcala FJ, San José E, Arias P, Nogueira M, Salgado FJ. CD26 and Asthma: a Comprehensive Review. Clin Rev Allergy Immunol 2019; 56:139-160. [PMID: 27561663 PMCID: PMC7090975 DOI: 10.1007/s12016-016-8578-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Asthma is a heterogeneous and chronic inflammatory family of disorders of the airways with increasing prevalence that results in recurrent and reversible bronchial obstruction and expiratory airflow limitation. These diseases arise from the interaction between environmental and genetic factors, which collaborate to cause increased susceptibility and severity. Many asthma susceptibility genes are linked to the immune system or encode enzymes like metalloproteases (e.g., ADAM-33) or serine proteases. The S9 family of serine proteases (prolyl oligopeptidases) is capable to process peptide bonds adjacent to proline, a kind of cleavage-resistant peptide bonds present in many growth factors, chemokines or cytokines that are important for asthma. Curiously, two serine proteases within the S9 family encoded by genes located on chromosome 2 appear to have a role in asthma: CD26/dipeptidyl peptidase 4 (DPP4) and DPP10. The aim of this review is to summarize the current knowledge about CD26 and to provide a structured overview of the numerous functions and implications that this versatile enzyme could have in this disease, especially after the detection of some secondary effects (e.g., viral nasopharyngitis) in type II diabetes mellitus patients (a subset with a certain risk of developing obesity-related asthma) upon CD26 inhibitory therapy.
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Affiliation(s)
- Juan J Nieto-Fontarigo
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Francisco J González-Barcala
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
- Respiratory Department, Clinic University Hospital (CHUS), Santiago de Compostela, Spain
| | - Esther San José
- Clinical Analysis Service, Clinic University Hospital (CHUS), Santiago de Compostela, Spain
| | - Pilar Arias
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Montserrat Nogueira
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain
| | - Francisco J Salgado
- Department of Biochemistry and Molecular Biology, Faculty of Biology-Biological Research Centre (CIBUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain.
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17
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Enz N, Vliegen G, De Meester I, Jungraithmayr W. CD26/DPP4 - a potential biomarker and target for cancer therapy. Pharmacol Ther 2019; 198:135-159. [PMID: 30822465 DOI: 10.1016/j.pharmthera.2019.02.015] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CD26/dipeptidyl peptidase (DPP)4 is a membrane-bound protein found in many cell types of the body, and a soluble form is present in body fluids. There is longstanding evidence that various primary tumors and also metastases express CD26/DPP4 to a variable extent. By cleaving dipeptides from peptides with a proline or alanine in the penultimate position at the N-terminus, it regulates the activity of incretin hormones, chemokines and many other peptides. Due to these effects and interactions with other molecules, a tumor promoting or suppressing role can be attributed to CD26/DPP4. In this review, we discuss the existing evidence on the expression of soluble or membrane-bound CD26/DPP4 in malignant diseases, along with the most recent findings on CD26/DPP4 as a therapeutic target in specific malignancies. The expression and possible involvement of the related DPP8 and DPP9 in cancer are also reviewed. A higher expression of CD26/DPP4 is found in a wide variety of tumor entities, however more research on CD26/DPP4 in the tumor microenvironment is needed to fully explore its use as a tumor biomarker. Circulating soluble CD26/DPP4 has also been studied as a cancer biomarker, however, the observed decrease in most cancer patients does not seem to be cancer specific. Encouraging results from experimental work and a recently reported first phase clinical trial targeting CD26/DPP4 in mesothelioma, renal and urological tumors pave the way for follow-up clinical studies, also in other tumor entities, possibly leading to the development of more effective complementary therapies against cancer.
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Affiliation(s)
- Njanja Enz
- Department of Thoracic Surgery, University Hospital Rostock, Schillingallee 35, 18057 Rostock, Germany
| | - Gwendolyn Vliegen
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Ingrid De Meester
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
| | - Wolfgang Jungraithmayr
- Department of Thoracic Surgery, University Hospital Rostock, Schillingallee 35, 18057 Rostock, Germany.
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18
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De S, Banerjee S, Kumar SA, Paira P. Critical Role of Dipeptidyl Peptidase IV: A Therapeutic Target for Diabetes and Cancer. Mini Rev Med Chem 2018; 19:88-97. [DOI: 10.2174/1389557518666180423112154] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 02/02/2018] [Accepted: 04/18/2018] [Indexed: 12/21/2022]
Abstract
Diabetes mellitus is an emerging predator and affecting around 422 million adults worldwide.
Higher levels of circulating insulin and increased pressure on the pancreas to produce insulin
have been inferred as possible etiology for diabetes leading to a higher risk of pancreatic cancer. Out of
several drug targets in hypoglycemic discovery, Dipeptidyl peptidase-IV (DPP-IV) has been considered
an emerging target. It is a protease enzyme which inactivates incretin hormones i.e., Glucagonlike
peptide 1 (GLP-1) and glucose-dependent insulin tropic polypeptide (GIP). Inhibition of DPP-4
results in the longer action of GLP-1 and GIP, therefore, DPP-4 inhibitors play an important role in
maintaining glucose homeostasis. In comparison to early oral hypoglycemic, DPP-IV inhibitors are
well tolerated and provide a better glycemic control over a longer period. These enzymes are expressed
in a dimeric form on the surface of different cells such as prostate, liver and small intestinal
epithelium cells. Disruption of the local signaling environment is an emerging factor in cancer development.
Till date, not even a single DPP-IV inhibitor as anticancer has been developed. This review
focuses on various features of the enzyme and their suitable inhibitors for target disease.
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Affiliation(s)
- Sourav De
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore-632014, Tamil Nadu, India
| | - Subhasis Banerjee
- Department of Chemistry, Gupta College of Technological Sciences, Asansol-713301, West Bengal, India
| | - S.K. Ashok Kumar
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore-632014, Tamil Nadu, India
| | - Priyankar Paira
- Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore-632014, Tamil Nadu, India
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19
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Karandikar S, Soni R, Soman SS, Umar S, Suresh B. 1,2-Benzisoxazole-3-acetamide derivatives as dual agents for DPP-IV inhibition and anticancer activity. SYNTHETIC COMMUN 2018. [DOI: 10.1080/00397911.2018.1508723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
| | - Rina Soni
- Department of Chemistry, The M. S. University of Baroda, Vadodara, India
| | - Shubhangi S. Soman
- Department of Chemistry, The M. S. University of Baroda, Vadodara, India
| | - Shweta Umar
- Department of Zoology Faculty of Science, The M. S. University of Baroda, Vadodara, India
| | - Balakrishnan Suresh
- Department of Zoology Faculty of Science, The M. S. University of Baroda, Vadodara, India
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20
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Juillerat-Jeanneret L, Tafelmeyer P, Golshayan D. Fibroblast activation protein-α in fibrogenic disorders and cancer: more than a prolyl-specific peptidase? Expert Opin Ther Targets 2017; 21:977-991. [DOI: 10.1080/14728222.2017.1370455] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Lucienne Juillerat-Jeanneret
- Transplantation Center and Transplantation Immunopathology Laboratory, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
- CHUV and UNIL, University Institute of Pathology, Lausanne, Switzerland
| | - Petra Tafelmeyer
- Hybrigenics Services, Laboratories and Headquarters, Paris, France
- Hybrigenics Corporation, Cambridge Innovation Center, Cambridge, MA, USA
| | - Dela Golshayan
- Transplantation Center and Transplantation Immunopathology Laboratory, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
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21
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Aliyari Serej Z, Ebrahimi Kalan A, Mehdipour A, Nozad Charoudeh H. Regulation and roles of CD26/DPPIV in hematopoiesis and diseases. Biomed Pharmacother 2017; 91:88-94. [PMID: 28448874 DOI: 10.1016/j.biopha.2017.04.074] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 04/15/2017] [Accepted: 04/17/2017] [Indexed: 01/15/2023] Open
Abstract
Dipeptidyl peptidase IV (DPPIV),1 on the surface of certain cells, where it is also referred to as CD26, is involved in a vast majority of biological and pathological processes. CD26/DPPIV function contributes to cancer and tumor metastasis as well as inhibition of its expression which alters the expression of immune response-related genes. CD26/DPPIV is a widely distributed multifunctional integral membrane and secreted protein that is defined as early predictive biomarker in HIV, cancer and autoimmunity diseases like diabetes and multiple sclerosis. CD26/DPPIV-chemokine interaction may have a functional role in T-cells and overall immune function. It is expressed at low density on resting T cells, but is upregulated with T cell activation. In this review, we summarize valuable information about detailed biological aspects and pharmacokinetic characteristics of CD26/DPPIV and its clinical efficacy, focusing particularly on the role of CD26/DPPIV in immunological and non-immunological diseases. We also describe our recent work about umbilical cord blood (UCB)2 hematopoietic stem cell transplantation strategies in which identified CD26+ cells can be differentiated to immune cells under certain culture condition.
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Affiliation(s)
- Zeynab Aliyari Serej
- School of Advanced Medical Sciences, Applied Cell Sciences Department, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Ebrahimi Kalan
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Neuroscience Department, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Mehdipour
- School of Advanced Medical Sciences, Tissue Engineering Department, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hojjatollah Nozad Charoudeh
- School of Advanced Medical Sciences, Applied Cell Sciences Department, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Matrasova I, Busek P, Balaziova E, Sedo A. Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2017; 161:252-260. [PMID: 28452380 DOI: 10.5507/bp.2017.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 03/17/2017] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND AND AIMS Proteolytic enzymes contribute to the progression of various cancers. We previously reported increased expression of the proline specific peptidases dipeptidyl peptidase-IV (DPP-IV) and its closest paralogue fibroblast activation protein (FAP) in human glioblastomas. Here we analyze the molecular heterogeneity of DPP-IV and FAP in glioblastomas. METHODS ELISA, isoelectric focusing, 1D and 2D electrophoresis followed by WB or enzyme overlay assay were utilized to analyze DPP-IV and FAP isoforms. Cell fractionation using a Percoll gradient and deglycosylation with PNGase F were performed to analyze the possible basis of DPP-IV and FAP microheterogeneity. RESULTS Molecular forms of DPP-IV with an estimated molecular weight of 140-160 kDa and a pI predominantly 5.8 were detected in human glioblastoma; in some tumors additional isoforms with a more acidic (3.5-5.5) as well as alkaline (8.1) pI were revealed. Using 2D electrophoresis, two to three molecular forms of FAP with an alkaline (7.0-8.5) pI and an estimated MW of 120-140 kDa were identified in glioblastoma tissues. In glioma cell lines in vitro, several isoforms of both enzymes were expressed, however the alkalic forms present in glioblastoma tissues were not detected. Removal of N-linked oligosaccharides decreased the estimated molecular weight of both enzymes; the overall pattern of molecular forms nevertheless remained unchanged. CONCLUSION Several isoforms of DPP-IV and FAP are present in glioblastoma tissue. The absence of alkaline isoforms of both enzymes in glioma cell lines however suggests that isoforms from other, most likely stromal, cell types contribute to the overall pattern seen in glioblastoma tissues.
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Affiliation(s)
- Ivana Matrasova
- Institute of Biochemistry and Experimental Oncology, 1st Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 12853 Prague 2, Czech Republic
| | - Petr Busek
- Institute of Biochemistry and Experimental Oncology, 1st Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 12853 Prague 2, Czech Republic
| | - Eva Balaziova
- Institute of Biochemistry and Experimental Oncology, 1st Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 12853 Prague 2, Czech Republic
| | - Aleksi Sedo
- Institute of Biochemistry and Experimental Oncology, 1st Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 12853 Prague 2, Czech Republic
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Song Y, Zhou M, Cao Y, Qi J, Geng J, Liu X. Expression of GLP-1 receptor and CD26 in human thyroid C-cells: The association of thyroid C-cell tumorigenesis with incretin-based medicine. Oncol Lett 2017; 13:2684-2690. [PMID: 28454451 PMCID: PMC5403711 DOI: 10.3892/ol.2017.5752] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 12/20/2016] [Indexed: 12/19/2022] Open
Abstract
Recent reports have demonstrated that long-term and high dosage treatments with incretin-based medicine, such as hormone glucagon-like peptide-1 (GLP-1) may induce thyroid C-cell pathological changes in rodents, rather than in humans. Doubts regarding the tumorigenic potential of GLP-1 analogues in human thyroid C-cells remain. The present study aimed to determine the expression levels of GLP-1 receptor (GLP-1R) and cluster of differentiation 26 (CD26) in the C-cells of thyroid tissues from non-neoplastic, medullary carcinoma and hyperplasia subjects, and to explore the potential clinical significance. The following cases were analyzed: Medullary thyroid carcinoma (n=62, including 59 paraffin-embedded samples and 3 fresh frozen samples), C-cell hyperplasia (n=20, paraffin-embedded samples) and non-neoplastic thyroid tissue samples (n=7, paraffin-embedded samples). GLP-1R and CD26 expression was detected using immunohistochemical staining and western blotting. There were significant differences in the expression levels of the two markers between medullary thyroid carcinoma and C-cell hyperplasia, in addition to between medullary thyroid carcinoma and non-neoplastic thyroid tissue following immunohistochemical staining. Similar significant differences in the expression of GLP-1R and CD26 were detected using western blot analysis in the medullary thyroid carcinoma compared with non-neoplastic thyroid tissue sectioned from the aforementioned fresh frozen samples. There was a significant negative correlation between GLP-1R and CD26 expression. In addition, the present data indicated that GLP-1R expression was associated with the age of the patients with medullary thyroid carcinoma. These results suggested that GLP-1R and CD26 may be closely associated with the development of thyroid C-cell hyperplasia and medullary thyroid carcinoma, and indicated the importance of being aware of the side effects of incretin medicine.
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Affiliation(s)
- Yuejia Song
- Department of Endocrinology, The First Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Min Zhou
- Department of Pathology, The First Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yang Cao
- Department of Endocrinology, The First Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jiping Qi
- Department of Pathology, The First Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jingshu Geng
- Department of Pathology, The Third Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xiaomin Liu
- Department of Endocrinology, The First Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Lu HY, Huang CY, Shih CM, Lin YW, Tsai CS, Lin FY, Shih CC. A potential contribution of dipeptidyl peptidase-4 by the mediation of monocyte differentiation in the development and progression of abdominal aortic aneurysms. J Vasc Surg 2016; 66:1217-1226.e1. [PMID: 27887857 DOI: 10.1016/j.jvs.2016.05.093] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/24/2016] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Abdominal aortic aneurysms (AAAs) are characterized by the destruction of elastin and collagen in the media and adventitia. Dipeptidyl peptidase-4 (DPP-4, an adipokine known as CD26) influences cell signaling, cell-matrix interactions, and the regulation of the functional activity of incretins in metabolic and inflammatory disorders. Although the role of DPP-4 in AAA evolution has been demonstrated, the underlying mechanisms of DPP-4-regulated AAA development remains unknown. METHODS Patients with AAA (n = 93) and healthy controls (CTL, n = 20) were recruited. Based on computed tomography image analyses, 93 patients were divided into two groups: those with a small AAA (SAA, aortic diameter <5 cm, n = 16) and those with a large AAA (LAA, aortic diameter ≥5 cm, n = 77). Plasma DPP-4, glucagon-like peptide-1 levels, and expression of CD26 on mononuclear cells were analyzed. In addition, phorbol 12-myristate 13-acetate (PMA)-induced THP-1 cells and angiotensin II-infused apolipoprotein EtmlUnc mice were used to explore the underlying mechanisms. RESULTS The levels of DPP-4 (μU/μg) increased while active glucagon-like peptide-1 (pM) decreased in patients with AAA in a diameter-dependent manner [CTL: 2.3 ± 1.5 and 3.7 ± 2.4, respectively; SAA: 10.0 ± 10.9 and 2.1 ± 0.9, respectively; LAA: 32.2 ± 15.0 and 1.8 ± 1.1, respectively]. A significant decline in monocyte CD26 expression in patients with AAAs was observed relative to the CTL group. In vitro studies demonstrated that the inhibition of DPP-4 promoted PMA-induced monocytic cells differentiation, with increased CD68 and p21 expression, regulated by extracellular signal-regulated protein kinase 1/2 activation. Furthermore, inhibition of DPP-4 significantly increased the phosphorylation of PYK2 and paxillin in PMA-induced THP-1 cell differentiation. Finally, the animal study was used to confirm the in vitro results that LAA mice showed marked macrophage infiltration in the adventitia with a decreased expression of DPP-4 as compared with SAA mice. CONCLUSIONS Increased plasma DPP-4 activity may correlate with aneurysmal development. CD26 on monocytes plays a critical role in cell differentiation, possibly mediated by extracellular signal-regulated protein kinase 1/2-p21 axis signaling pathways and cytoskeletal proteins reassembly. Exploring the role of DPP-4 further may yield potential therapeutic insights.
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Affiliation(s)
- Hsin-Ying Lu
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chun-Yao Huang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chun-Ming Shih
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yi-Wen Lin
- Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan
| | - Chein-Sung Tsai
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan; Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Feng-Yen Lin
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chun-Che Shih
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
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Flores IL, Santos-Silva AR, Coletta RD, Leme AFP, Lopes MA. Low expression of angiotensinogen and dipeptidyl peptidase 1 in saliva of patients with proliferative verrucous leukoplakia. World J Clin Cases 2016; 4:356-363. [PMID: 27900324 PMCID: PMC5112355 DOI: 10.12998/wjcc.v4.i11.356] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 06/14/2016] [Accepted: 09/18/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To elucidate the profile of the salivary proteome.
METHODS Unstimulated whole mouth saliva was collected from 30 volunteers [15 proliferative verrucous leukoplakia (PVL) patients and 15 controls] and proteins were submitted for mass spectrometry-based proteomics using the discovery approach, followed by analyses of variance and logistic regression tests.
RESULTS A total of two hundred and eighty-three proteins were confidently identified in saliva. By combining two low abundance proteins from the PVL group, angiotensinogen (AGT) and dipeptidyl peptidase 1 (DPP1), a model for group differentiation was built with a concordance index of 94.2%, identifying both proteins as potential etiologic biomarkers for PVL.
CONCLUSION This study suggests that both AGT and DPP1 may be involved in developmental mechanisms of PVL.
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Wesley UV, Hatcher JF, Ayvaci ER, Klemp A, Dempsey RJ. Regulation of Dipeptidyl Peptidase IV in the Post-stroke Rat Brain and In Vitro Ischemia: Implications for Chemokine-Mediated Neural Progenitor Cell Migration and Angiogenesis. Mol Neurobiol 2016; 54:4973-4985. [PMID: 27525674 DOI: 10.1007/s12035-016-0039-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 08/05/2016] [Indexed: 12/13/2022]
Abstract
Cerebral ischemia evokes abnormal release of proteases in the brain microenvironment that spatiotemporally impact angio-neurogenesis. Dipeptidyl peptidase IV (DPPIV), a cell surface and secreted protease, has been implicated in extracellular matrix remodeling by regulating cell adhesion, migration, and angiogenesis through modifying the functions of the major chemokine stromal-derived factor, SDF1. To elucidate the possible association of DPPIV in ischemic brain, we examined the expression of DPPIV in the post-stroke rat brain and under in vitro ischemia by oxygen glucose deprivation (OGD). We further investigated the effects of DPPIV on SDF1 mediated in vitro chemotactic and angiogenic functions. DPPIV protein and mRNA levels were significantly upregulated during repair phase in the ischemic cortex of the rat brain, specifically in neurons, astrocytes, and endothelial cells. In vitro exposure of Neuro-2a neuronal cells and rat brain endothelial cells to OGD resulted in upregulation of DPPIV. In vitro functional analysis showed that DPPIV decreases the SDF1-mediated angiogenic potential of rat brain endothelial cells and inhibits the migration of Neuro-2a and neural progenitor cells. Western blot analyses revealed decreased levels of phosphorylated ERK1/2 and AKT in the presence of DPPIV. DPPIV inhibitor restored the effects of SDF1. Proteome profile array screening further revealed that DPPIV decreases matrix metalloproteinase-9, a key downstream effector of ERK-AKT signaling pathways. Overall, delayed induction of DPPIV in response to ischemia/reperfusion suggests that DPPIV may play an important role in endogenous brain tissue remodeling and repair processes. This may be mediated through modulation of SDF1-mediated cell migration and angiogenesis.
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Affiliation(s)
- Umadevi V Wesley
- Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA.
| | - James F Hatcher
- Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA
| | - Emine R Ayvaci
- Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA
| | - Abby Klemp
- Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA
| | - Robert J Dempsey
- Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA.
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Beckenkamp A, Davies S, Willig JB, Buffon A. DPPIV/CD26: a tumor suppressor or a marker of malignancy? Tumour Biol 2016; 37:7059-73. [DOI: 10.1007/s13277-016-5005-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 02/25/2016] [Indexed: 12/12/2022] Open
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Zhao W, Mazar J, Lee B, Sawada J, Li JL, Shelley J, Govindarajan S, Towler D, Mattick JS, Komatsu M, Dinger ME, Perera RJ. The Long Noncoding RNA SPRIGHTLY Regulates Cell Proliferation in Primary Human Melanocytes. J Invest Dermatol 2016; 136:819-828. [PMID: 26829028 DOI: 10.1016/j.jid.2016.01.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 12/14/2015] [Accepted: 12/14/2015] [Indexed: 01/29/2023]
Abstract
The long noncoding RNA SPRIGHTLY (formerly SPRY4-IT1), which lies within the intronic region of the SPRY4 gene, is up-regulated in human melanoma cells compared to melanocytes. SPRIGHTLY regulates a number of cancer hallmarks, including proliferation, motility, and apoptosis. To better understand its oncogenic role, SPRIGHTLY was stably transfected into human melanocytes, which resulted in increased cellular proliferation, colony formation, invasion, and development of a multinucleated dendritic-like phenotype. RNA sequencing and mass spectrometric analysis of SPRIGHTLY-expressing cells revealed changes in the expression of genes involved in cell proliferation, apoptosis, chromosome organization, regulation of DNA damage responses, and cell cycle. The proliferation marker Ki67, minichromosome maintenance genes 2-5, antiapoptotic gene X-linked inhibitor of apoptosis, and baculoviral IAP repeat-containing 7 were all up-regulated in SPRIGHTLY-expressing melanocytes, whereas the proapoptotic tumor suppressor gene DPPIV/CD26 was down-regulated, followed by an increase in extracellular signal-regulated kinase 1/2 phosphorylation, suggesting an increase in mitogen-activated protein kinase activity. Because down-regulation of DPPIV is known to be associated with malignant transformation in melanocytes, SPRIGHTLY-mediated DPPIV down-regulation may play an important role in melanoma pathobiology. Together, these findings provide important insights into how SPRIGHTLY regulates cell proliferation and anchorage-independent colony formation in primary human melanocytes.
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Affiliation(s)
- Wei Zhao
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | - Joseph Mazar
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | - Bongyong Lee
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | - Junko Sawada
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | - Jian-Liang Li
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | - John Shelley
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | | | - Dwight Towler
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | - John S Mattick
- Garvan Institute of Medical Research and St. Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia
| | - Masanobu Komatsu
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA
| | - Marcel E Dinger
- Garvan Institute of Medical Research and St. Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia
| | - Ranjan J Perera
- Sanford-Burnham Medical Research Institute, Orlando, Florida, USA.
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Circulating FGF21 proteolytic processing mediated by fibroblast activation protein. Biochem J 2015; 473:605-14. [PMID: 26635356 PMCID: PMC4764976 DOI: 10.1042/bj20151085] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 12/03/2015] [Indexed: 01/08/2023]
Abstract
Fibroblast growth factor 21 (FGF21), a hormone implicated in the regulation of glucose homoeostasis, insulin sensitivity, lipid metabolism and body weight, is considered to be a promising therapeutic target for the treatment of metabolic disorders. Despite observations that FGF21 is rapidly proteolysed in circulation rending it potentially inactive, little is known regarding mechanisms by which FGF21 protein levels are regulated. We systematically investigated human FGF21 protein processing using mass spectrometry. In agreement with previous reports, circulating human FGF21 was found to be cleaved primarily after three proline residues at positions 2, 4 and 171. The extent of FGF21 processing was quantified in a small cohort of healthy human volunteers. Relative abundance of FGF21 proteins cleaved after Pro-2, Pro-4 and Pro-171 ranged from 16 to 30%, 10 to 25% and 10 to 34%, respectively. Dipeptidyl peptidase IV (DPP-IV) was found to be the primary protease responsible for N-terminal cleavages after residues Pro-2 and Pro-4. Importantly, fibroblast activation protein (FAP) was implicated as the protease responsible for C-terminal cleavage after Pro-171, rendering the protein inactive. The requirement of FAP for FGF21 proteolysis at the C-terminus was independently demonstrated by in vitro digestion, immunodepletion of FAP in human plasma, administration of an FAP-specific inhibitor and by human FGF21 protein processing patterns in FAP knockout mouse plasma. The discovery that FAP is responsible for FGF21 inactivation extends the FGF21 signalling pathway and may enable novel approaches to augment FGF21 actions for therapeutic applications.
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Cutler MJ, Lowthers EL, Richard CL, Hajducek DM, Spagnuolo PA, Blay J. Chemotherapeutic agents attenuate CXCL12-mediated migration of colon cancer cells by selecting for CXCR4-negative cells and increasing peptidase CD26. BMC Cancer 2015; 15:882. [PMID: 26552750 PMCID: PMC4640216 DOI: 10.1186/s12885-015-1702-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 10/07/2015] [Indexed: 12/14/2022] Open
Abstract
Background Recurrence of colorectal cancer (CRC) may arise due to the persistence of drug-resistant and cancer-initiating cells that survive exposure to chemotherapy. Proteins responsible for this recurrence include the chemokine receptor CXCR4, which is known to enable CRC metastasis, as well as the cancer-initiating cell marker and peptidase CD26, which terminates activity of its chemokine CXCL12. Methods We evaluated the expression and function of CXCR4 and CD26 in colon cancer cell lines and xenografts following treatment with common chemotherapies using radioligand binding, flow cytometry, immunofluorescence, and enzymatic assays. Results 5-Fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan), as well as cisplatin, methotrexate and vinblastine, each caused decreases in cell-surface CXCR4 and concomitant increases in CD26 on HT-29, T84, HRT-18, SW480 and SW620 CRC cell lines. Flow cytometry indicated that the decline in CXCR4 was associated with a significant loss of CXCR4+/CD26- cells. Elevations in CD26 were paralleled by increases in both the intrinsic dipeptidyl peptidase activity of CD26 as well as its capacity to bind extracellular adenosine deaminase. Orthotopic HT-29 xenografts treated with standard CRC chemotherapeutics 5-fluorouracil, irinotecan, or oxaliplatin showed dramatic increases in CD26 compared to untreated tumors. Consistent with the loss of CXCR4 and gain in CD26, migratory responses to exogenous CXCL12 were eliminated in cells pretreated with cytotoxic agents, although cells retained basal motility. Analysis of cancer-initiating cell CD44 and CD133 subsets revealed drug-dependent responses of CD26/CD44/CD133 populations, suggesting that the benefits of combining standard chemotherapies 5-fluoruracil and oxaliplatin may be derived from their complementary elimination of cell populations. Conclusion Our results indicate that conventional anticancer agents may act to inhibit chemokine-mediated migration through eradication of CXCR4+ cells and attenuation of chemokine gradients through elevation of CD26 activity. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1702-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Murray J Cutler
- School of Pharmacy, University of Waterloo, 200 University Ave. W., Waterloo, ON, N2L 3G1, Canada. .,Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
| | - Erica L Lowthers
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada. .,Sim & McBurney/Sim Lowman Ashton & McKay LLP, Toronto, Ontario, Canada.
| | - Cynthia L Richard
- School of Pharmacy, University of Waterloo, 200 University Ave. W., Waterloo, ON, N2L 3G1, Canada. .,Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
| | - Dagmar M Hajducek
- Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Ontario, Canada.
| | - Paul A Spagnuolo
- School of Pharmacy, University of Waterloo, 200 University Ave. W., Waterloo, ON, N2L 3G1, Canada.
| | - Jonathan Blay
- School of Pharmacy, University of Waterloo, 200 University Ave. W., Waterloo, ON, N2L 3G1, Canada. .,Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada. .,Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
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Beckenkamp A, Willig JB, Santana DB, Nascimento J, Paccez JD, Zerbini LF, Bruno AN, Pilger DA, Wink MR, Buffon A. Differential Expression and Enzymatic Activity of DPPIV/CD26 Affects Migration Ability of Cervical Carcinoma Cells. PLoS One 2015. [PMID: 26222679 PMCID: PMC4519168 DOI: 10.1371/journal.pone.0134305] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Dipeptidyl peptidase IV (DPPIV/CD26) is a transmembrane glycoprotein that inactivates or degrades some bioactive peptides and chemokines. For this reason, it regulates cell proliferation, migration and adhesion, showing its role in cancer processes. This enzyme is found mainly anchored onto the cell membrane, although it also has a soluble form, an enzymatically active isoform. In the present study, we investigated DPPIV/CD26 activity and expression in cervical cancer cell lines (SiHa, HeLa and C33A) and non-tumorigenic HaCaT cells. The effect of the DPPIV/CD26 inhibitor (sitagliptin phosphate) on cell migration and adhesion was also evaluated. Cervical cancer cells and keratinocytes exhibited DPPIV/CD26 enzymatic activity both membrane-bound and in soluble form. DPPIV/CD26 expression was observed in HaCaT, SiHa and C33A, while in HeLa cells it was almost undetectable. We observed higher migratory capacity of HeLa, when compared to SiHa. But in the presence of sitagliptin SiHa showed an increase in migration, indicating that, at least in part, cell migration is regulated by DPPIV/CD26 activity. Furthermore, in the presence of sitagliptin phosphate, SiHa and HeLa cells exhibited a significant reduction in adhesion. However this mechanism seems to be mediated independent of DPPIV/CD26. This study demonstrates, for the first time, the activity and expression of DPPIV/CD26 in cervical cancer cells and the effect of sitagliptin phosphate on cell migration and adhesion.
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Affiliation(s)
- Aline Beckenkamp
- Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Júlia Biz Willig
- Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Danielle Bertodo Santana
- Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Jéssica Nascimento
- Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Juliano Domiraci Paccez
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group, Cape Town, South Africa
| | - Luiz Fernando Zerbini
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group, Cape Town, South Africa
| | | | - Diogo André Pilger
- Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Márcia Rosângela Wink
- Laboratory of Cell Biology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS, Brazil
| | - Andréia Buffon
- Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- * E-mail:
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Co-expression of the homologous proteases fibroblast activation protein and dipeptidyl peptidase-IV in the adult human Langerhans islets. Histochem Cell Biol 2014; 143:497-504. [PMID: 25361590 DOI: 10.1007/s00418-014-1292-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2014] [Indexed: 02/05/2023]
Abstract
Fibroblast activation protein (FAP, seprase, EC 3.4.21.B28) and dipeptidyl peptidase-IV (DPP-IV, CD26, EC 3.4.14.5) are homologous serine proteases implicated in the modulation of the bioavailability and thus the function of a number of biologically active peptides. In spite of their generally nonoverlapping expression patterns, DPP-IV and FAP are co-expressed and probably co-regulated in certain cell types suggesting that for some biological processes their functional synergy is essential. By an in situ enzymatic activity assay, we show an abundant DPP-IV-like enzymatic activity sensitive to a highly specific DPP-IV inhibitor sitagliptin and corresponding DPP-IV immunoreactivity in the adult human islets of Langerhans. Moreover, the homologous protease FAP was present in the human endocrine pancreas and was co-expressed with DPP-IV. DPP-IV and FAP were found in the pancreatic alpha cells as determined by the co-localization with glucagon immunoreactivity. In summary, we show abundant enzymatic activity of the canonical DPP-IV (CD26) in Langerhans islets in the natural tissue context and demonstrate for the first time the co-expression of FAP and DPP-IV in pancreatic alpha cells in adult humans. Given their ability to proteolytically modify several biologically active peptides, both proteases have the potential to modulate the paracrine signaling in the human Langerhans islets.
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Nazarian A, Lawlor K, Yi SS, Philip J, Ghosh M, Yaneva M, Villanueva J, Saghatelian A, Assel M, Vickers AJ, Eastham JA, Scher HI, Carver BS, Lilja H, Tempst P. Inhibition of circulating dipeptidyl peptidase 4 activity in patients with metastatic prostate cancer. Mol Cell Proteomics 2014; 13:3082-96. [PMID: 25056937 DOI: 10.1074/mcp.m114.038836] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.
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Affiliation(s)
- Arpi Nazarian
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Kevin Lawlor
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - San San Yi
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - John Philip
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Mousumi Ghosh
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065; §Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Mariana Yaneva
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065; §Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Josep Villanueva
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065; §Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Alan Saghatelian
- **Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138
| | - Melissa Assel
- ‡‡Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Andrew J Vickers
- ‡‡Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - James A Eastham
- §§Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Howard I Scher
- ¶¶Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Brett S Carver
- §§Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065; ‖‖Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Hans Lilja
- §§Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065; ¶¶Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065; Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Department of Laboratory Medicine, Lund University, University Hospital UMAS, Malmö, Sweden
| | - Paul Tempst
- From the ‡Protein Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065; §Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065;
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Ding L, Ye L, Xu J, Jiang WG. Impact of fibroblast activation protein on osteosarcoma cell lines in vitro.. Oncol Lett 2014; 7:699-704. [PMID: 24520291 PMCID: PMC3919928 DOI: 10.3892/ol.2014.1788] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 12/06/2013] [Indexed: 11/28/2022] Open
Abstract
Fibroblast activation protein (FAP) or seprase, which belongs to the group type II integral serine proteases, is an integral membrane serine peptidase. Previous studies have demonstrated that FAP has an effect on tumor growth, proliferation and invasion. However, the cellular functional role that FAP plays in osteosarcoma (OS) remains unknown. The aim of the present study was to investigate the activities of FAP in OS cell lines. The gene expression of FAP was knocked down through a hammerhead ribozyme transgene, and the various functions between the knockdown cells and their control cells were tested using a series of functional assays in vitro. The results indicated that knockdown of FAP markedly reduced the ability of cellular growth, matrix adhesion, migration and invasion in MG-63 and HOS cell lines compared with the control cells (P<0.05). In conclusion, FAP influences OS cells and may play a role in OS tumor progression and metastasis.
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Affiliation(s)
- Lixiang Ding
- Cardiff University-Capital Medical University Joint Centre for Biomedical Research, Cardiff CF14 4XN, UK ; Metastasis and Angiogenesis Research Group, Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK ; Department of Orthopaedic Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China
| | - Lin Ye
- Cardiff University-Capital Medical University Joint Centre for Biomedical Research, Cardiff CF14 4XN, UK ; Metastasis and Angiogenesis Research Group, Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
| | - Jianli Xu
- Department of Orthopaedic Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China
| | - Wen G Jiang
- Cardiff University-Capital Medical University Joint Centre for Biomedical Research, Cardiff CF14 4XN, UK ; Metastasis and Angiogenesis Research Group, Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
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Zhao Y, Yang L, Zhou Z. Dipeptidyl peptidase-4 inhibitors: multitarget drugs, not only antidiabetes drugs. J Diabetes 2014; 6:21-9. [PMID: 23683065 DOI: 10.1111/1753-0407.12063] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 04/25/2013] [Accepted: 05/10/2013] [Indexed: 12/19/2022] Open
Abstract
Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antidiabetic agents that reduce blood glucose by preventing the degradation of the endogenous incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Protection by DPP-4 inhibitors of β-cell function has been demonstrated in patients with type 2 diabetes. Because DPP-4 is an enzyme widely expressed in humans, DPP-4 inhibitors are speculated to be multitarget agents. However, other potential therapeutic benefits of DPP-4 inhibitors remain unknown. Recently, some therapeutic effects of DPP-4 inhibitors, such as immune regulation, cardiovascular protection, and anti-inflammatory effects, have been observed. This article provides a systematic and comprehensive review of current research into the newly found effects and mechanism of action of DPP-4 inhibitors in a therapeutic context.
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Affiliation(s)
- Yunjuan Zhao
- Diabetes Center, Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, Changsha, China
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Park HS, Yeo HY, Chang HJ, Kim KH, Park JW, Kim BC, Baek JY, Kim SY, Kim DY. Dipeptidyl peptidase 10, a novel prognostic marker in colorectal cancer. Yonsei Med J 2013; 54:1362-9. [PMID: 24142639 PMCID: PMC3809881 DOI: 10.3349/ymj.2013.54.6.1362] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
PURPOSE The dipeptidyl peptidase IV (DPPIV) gene family exhibits multiple functions and is involved in the pathogenesis of various diseases. It has attracted pharmaceutical interest in the areas of metabolic disorders as well as cancer. However, clinicopathologic significance of DPPIV family in colorectal cancer is not fully understood. MATERIALS AND METHODS The clinical relevance of DPPIV and DPP10 expression was determined by immunohistochemical staining, and by assessing its clinicopathologic correlation in 383 colorectal cancer patients with known clinical outcomes. RESULTS DPPIV was not expressed in normal colon mucosa, but it showed luminal expression in 52 of the 383 colorectal cancers (13.5%). DPPIV expression in tumors was associated with right-sided location of the colon (p=0.010) and more advanced tumor stage (p=0.045). DPP10 was expressed in normal colonic mucosa, but its expression varied in primary colorectal cancer tissues. Loss of DPP10 expression was found in 11 colorectal cancers (CRCs) (2.9%), and multivariate analysis showed that loss of DPP10 expression was an independent factor for poor patient prognosis (p=0.008). CONCLUSION DPP10 may play a role in disease progression of colorectal cancer and loss of DPP10 expression in primary CRC is significantly associated with poor survival outcomes.
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Affiliation(s)
- Heae Surng Park
- Colorectal Cancer Branch, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 410-769, Korea.
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Juillerat-Jeanneret L. Dipeptidyl peptidase IV and its inhibitors: therapeutics for type 2 diabetes and what else? J Med Chem 2013; 57:2197-212. [PMID: 24099035 DOI: 10.1021/jm400658e] [Citation(s) in RCA: 154] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.
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Rao N, Ke Z, Liu H, Ho CJ, Kumar S, Xiang W, Zhu Y, Ge R. ADAMTS4 and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice. Int J Cancer 2013; 133:294-306. [DOI: 10.1002/ijc.28037] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Nithya Rao
- Department of Biological Sciences; Faculty of Science, National University of Singapore; Singapore; Singapore
| | - Zhiyuan Ke
- Department of Biological Sciences; Faculty of Science, National University of Singapore; Singapore; Singapore
| | - Hongrui Liu
- Department of Pharmacology; School of Pharmacy, Fudan University; Shanghai; People's Republic of China
| | - Chao-Jin Ho
- Department of Biological Sciences; Faculty of Science, National University of Singapore; Singapore; Singapore
| | - Saran Kumar
- Department of Biological Sciences; Faculty of Science, National University of Singapore; Singapore; Singapore
| | - Wei Xiang
- Department of Biological Sciences; Faculty of Science, National University of Singapore; Singapore; Singapore
| | - Yizhun Zhu
- Department of Pharmacology; School of Pharmacy, Fudan University; Shanghai; People's Republic of China
| | - Ruowen Ge
- Department of Biological Sciences; Faculty of Science, National University of Singapore; Singapore; Singapore
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Matić IZ, Đorđević M, Đorđić M, Grozdanić N, Damjanović A, Kolundžija B, Vidović A, Bila J, Ristić S, Mihaljević B, Tomin D, Milanović N, Ristić D, Purić M, Gavrilović D, Cordero OJ, Juranić ZD. Dipeptidyl peptidase IV: serum activity and expression on lymphocytes in different hematological malignancies. Leuk Lymphoma 2013; 54:2701-6. [DOI: 10.3109/10428194.2013.782611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Gracia E, Farré D, Cortés A, Ferrer-Costa C, Orozco M, Mallol J, Lluís C, Canela EI, McCormick PJ, Franco R, Fanelli F, Casadó V. The catalytic site structural gate of adenosine deaminase allosterically modulates ligand binding to adenosine receptors. FASEB J 2012. [PMID: 23193172 DOI: 10.1096/fj.12-212621] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The enzyme adenosine deaminase (ADA) is a multifunctional protein that can both degrade adenosine and bind extracellularly to adenosine receptors, acting as an allosteric modulator regulating the hormonal effects of adenosine. The molecular regions of ADA responsible for the latter are unknown. In this work, alanine scanning mutagenesis of various ADA amino acid stretches, selected through in silico docking experiments, allowed us to identify regions of the enzyme responsible for modulating both its catalytic activity and its ability to modulate agonist binding to A and A adenosine receptors (AR and AR). The combination of computational and in vitro experiments show that the structural gate to the catalytic site; i.e., the α-1 helix containing residues L58-I72 and the loop containing residues A184-I188 of ADA, were important to maintain both the catalytic efficiency of the enzyme and its action as an allosteric modulator of the adenosine receptors. These data are consistent with a predicted supramolecular assembly, in which ADA bridges AR and CD26 and are in line with the notion that the interaction of ADA with adenosine receptors has an important role in the immunosynapse. We propose that it is the ADA open form, but not the closed one, that is responsible for the functional interaction with A₁R and A₂AR.
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Affiliation(s)
- Eduard Gracia
- Laboratory of Molecular Neurobiology, Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
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Matić IZ, Ðorđić M, Grozdanić N, Damjanović A, Kolundžija B, Erić-Nikolić A, Džodić R, Šašić M, Nikolić S, Dobrosavljević D, Rašković S, Andrejević S, Gavrilović D, Cordero OJ, Juranić ZD. Serum activity of DPPIV and its expression on lymphocytes in patients with melanoma and in people with vitiligo. BMC Immunol 2012; 13:48. [PMID: 22908963 PMCID: PMC3464610 DOI: 10.1186/1471-2172-13-48] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 08/16/2012] [Indexed: 02/07/2023] Open
Abstract
Background Dipeptidyl peptidase IV, a multifunctional serine protease, is implicated in regulation of malignant transformation, promotion and further progression of cancer, exerting tumor-suppressing or even completely opposite - tumor-promoting activities. The aim of present research was to determine the serum DPPIV activity, as well as the percentages of CD26+ lymphocytes, CD26+ overall white blood cells and the mean fluorescence intensity of CD26 expression on lymphocytes in patients with melanoma, people with vitiligo and in healthy controls. Methods The activity of DPPIV in serum was determined by colorimetric test. Expression of DPPIV (as CD26) on immunocompetent peripheral white blood cells was done using flow cytometry analysis. Results Data from our study show for the first time statistically significant decrease: in the serum DPPIV activity, in the percentage of CD26+ overall white blood cells and in the percentage of lymphocytes in patients with melanoma in comparison to healthy control people. In addition, significantly lower serum DPPIV activity was found in the group of patients with melanoma in relation to people with vitiligo too. Conclusion This study indicates the need for exploring the cause and the importance of the disturbances in the serum DPPIV activity and in the CD26 expression on immunocompetent cells in complex molecular mechanisms underlying the development and progression of melanoma.
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Affiliation(s)
- Ivana Z Matić
- Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia
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Fröhlich E, Maier E, Wahl R. Interspecies differences in membrane-associated protease activities of thyrocytes and their relevance for thyroid cancer studies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2012; 31:45. [PMID: 22591973 PMCID: PMC3423041 DOI: 10.1186/1756-9966-31-45] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 05/16/2012] [Indexed: 11/27/2022]
Abstract
Background To understand the role of proteases involved in human thyroid cancer progression and tissue invasion, thyrocytes from other species could potentially be used provided their characteristics are similar. It is not known whether dipeptidyl peptidase IV and aminopeptidase N activities, which are overexpressed in human thyroid cancer, are, as in human, also absent in normal thyrocytes of other species, making them suitable models for studies on the regulation of these proteases. Methods To assess the role of these proteases, activity was measured in thyroid tissue of human, mouse, rat, porcine, bovine and ovine origin. The lysosomal protease, dipeptidyl peptidase II, was used for comparison. Results Murine, rat, ovine, bovine and human thyrocytes all lacked dipeptidyl peptidase IV and aminopeptidase N activity, but porcine thyrocytes were found to possess both. In contrast, lysosomal dipeptidyl peptidase II was strongly expressed in all species. These activity patterns were maintained in cultured cells. Cultured porcine thyrocytes formed follicles with typical morphology upon stimulation with TSH but differed from human thyrocytes in their response to thiamazole. Conclusions These species differences in the expression of dipeptidyl peptidase IV and aminopeptidase N, indicate that porcine thyrocytes cannot be considered appropriate for the study of proteases in human cancer development.
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Affiliation(s)
- Eleonore Fröhlich
- Department of Endocrinology, University of Tuebingen, Tuebingen, Germany
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Busek P, Stremenova J, Sromova L, Hilser M, Balaziova E, Kosek D, Trylcova J, Strnad H, Krepela E, Sedo A. Dipeptidyl peptidase-IV inhibits glioma cell growth independent of its enzymatic activity. Int J Biochem Cell Biol 2012; 44:738-47. [DOI: 10.1016/j.biocel.2012.01.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 01/10/2012] [Accepted: 01/17/2012] [Indexed: 11/16/2022]
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Zhang F, Dai X, Wang Y. 5-Aza-2'-deoxycytidine induced growth inhibition of leukemia cells through modulating endogenous cholesterol biosynthesis. Mol Cell Proteomics 2012; 11:M111.016915. [PMID: 22398368 DOI: 10.1074/mcp.m111.016915] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
5-Aza-2'-deoxycytidine (5-Aza-CdR), a nucleoside analog that can inhibit DNA cytosine methylation, possesses potent antitumorigenic activities for myeloid disorders. Although 5-Aza-CdR is known to be incorporated into DNA and inhibit DNA (cytosine-5)-methyltransferases, the precise mechanisms underlying the drug's antineoplastic activity remain unclear. Here we utilized a mass spectrometry-based quantitative proteomic method to analyze the 5-Aza-CdR-induced perturbation of protein expression in Jurkat-T cells at the global proteome scale. Among the ≈ 2780 quantified proteins, 188 exhibited significant alteration in expression levels upon a 24-hr treatment with 5 μm 5-Aza-CdR. In particular, we found that drug treatment led to substantially reduced expression of farnesyl diphosphate synthase (FDPS) and farnesyl diphosphate farnesyltransferase (FDFT1), two important enzymes involved in de novo cholesterol synthesis. Consistent with this finding, 5-Aza-CdR treatment of leukemia (Jurkat-T, K562 and HL60) and melanoma (WM-266-4) cells led to a marked decrease in cellular cholesterol content and pronounced growth inhibition, which could be rescued by externally added cholesterol. Exposure of these cells to 5-Aza-CdR also led to epigenetic reactivation of dipeptidyl peptidase 4 (DPP4) gene. Additionally, suppression of DPP4 expression with siRNA induced elevated protein levels of FDPS and FDFT1, and increased cholesterol biosynthesis in WM-266-4 cells. Together, the results from the present study revealed, for the first time, that 5-Aza-CdR exerts its cytotoxic effects in leukemia and melanoma cells through epigenetic reactivation of DPP4 gene and the resultant inhibition of cholesterol biosynthesis in these cells.
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Affiliation(s)
- Fan Zhang
- Department of Chemistry, University of California, Riverside, California 92521-0403, USA
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Stromal expression of CD34, α-smooth muscle actin and CD26/DPPIV in squamous cell carcinoma of the skin: a comparative immunohistochemical study. Pathol Oncol Res 2011; 18:25-31. [PMID: 21674250 DOI: 10.1007/s12253-011-9412-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 05/03/2011] [Indexed: 12/16/2022]
Abstract
Invasion pathogenesis is one of the most complicated issues in the literature. There are numerous studies concerning the tumor markers implicated in the preinvasive-invasive tumor sequence. Despite ample studies on the invasion pathogenesis of cutaneous melanomas, there is limited and dispersed work presently available on non-melanoma skin cancer. The vast knowledge in the literature concerning this issue in squamous cell carcinoma comes mostly from the studies of the oral cavity, esophagus, larynx, and cervix. In this study, we investigated tumor-free neighboring stroma and tumor stroma in squamous cell carcinomas (SCCs) of the skin as well as keratoacanthomas (KAs) with respect to the presence of stromal CD34-positive (CD34+) fibrocytes and α-smooth muscle actin-positive (α-SMA+) myofibroblasts using seborrheic keratosis (SKs) and non-tumoral skin samples as controls. We also evaluated the stromal expression pattern of CD26/DPPIV (CD26), a tumor suppressor gene product that also has immunoregulatory properties. Immunohistochemistry was performed on samples of 31 SCC, 8 KA, 15 SK and 10 non-tumoral skin samples. Peri-tumoral stroma from resection margins was also evaluated. We found that CD34 and α-SMA demonstrated significantly different staining between benign and malignant squamous skin lesions consisting of a loss of CD34+ fibrocytes paralleled by a gain of α-SMA+ myofibroblasts in malignant tumor stroma. Additionally, it was shown that CD26 expression was lower in tumor stroma when compared to that of tumor neighboring stroma. However, we concluded that this finding may be attributable to the solar elastosis areas in the peritumoral tissue, which shows diffuse strong positivity for this marker.
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Cordero OJ, Imbernon M, Chiara LD, Martinez-Zorzano VS, Ayude D, de la Cadena MP, Rodriguez-Berrocal FJ. Potential of soluble CD26 as a serum marker for colorectal cancer detection. World J Clin Oncol 2011; 2:245-61. [PMID: 21773075 PMCID: PMC3139035 DOI: 10.5306/wjco.v2.i6.245] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 03/28/2011] [Accepted: 04/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is characterized by a low survival rate even though the basis for colon cancer development, which involves the evolution of adenomas to carcinoma, is known. Moreover, the mortality rates continue to rise in economically transitioning countries although there is the opportunity to intervene in the natural history of the adenoma–cancer sequence through risk factors, screening, and treatment. Screening in particular accounted for most of the decline in colorectal cancer mortality achieved in the USA during the period 1975-2000. Patients show a better prognosis when the neoplasm is diagnosed early. Among the variety of screening strategies, the methods range from invasive and costly procedures such as colonoscopy to more low-cost and non-invasive tests such as the fecal occult blood test (guaiac and immunochemical). As a non-invasive biological serum marker would be of great benefit because of the performance of the test, several biomarkers, including cytologic assays, DNA and mRNA, and soluble proteins, have been studied. We found that the soluble CD26 (sCD26) concentration is diminished in serum of colorectal cancer patients compared to healthy donors, suggesting the potential utility of a sCD26 immunochemical detection test for early diagnosis. sCD26 originates from plasma membrane CD26 lacking its transmembrane and cytoplasmic domains. Some 90%–95% of sCD26 has been associated with serum dipeptidyl peptidase IV (DPP-IV) activity. DPP-IV, assigned to the CD26 cluster, is a pleiotropic enzyme expressed mainly on epithelial cells and lymphocytes. Our studies intended to validate this test for population screening to detect colorectal cancer and advanced adenomas are reviewed here.
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Affiliation(s)
- Oscar J Cordero
- Oscar J Cordero, Monica Imbernon, Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, School of Biology, CIBUS Building, Campus Vida, 15782 Santiago de Compostela, Spain
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Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS One 2011; 6:e20758. [PMID: 21674054 PMCID: PMC3107231 DOI: 10.1371/journal.pone.0020758] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Accepted: 05/08/2011] [Indexed: 11/19/2022] Open
Abstract
Malignant melanoma represents the third common cause of brain metastasis, having the highest propensity to metastasize to the brain of all primary neoplasms in adults. Since the central nervous system lacks a lymphatic system, the only possibility for melanoma cells to reach the brain is via the blood stream and the blood-brain barrier. Despite the great clinical importance, mechanisms of transmigration of melanoma cells through the blood-brain barrier are incompletely understood. In order to investigate this question we have used an in vitro experimental setup based on the culture of cerebral endothelial cells (CECs) and the A2058 and B16/F10 melanoma cell lines, respectively. Melanoma cells were able to adhere to confluent brain endothelial cells, a process followed by elimination of protrusions and transmigration from the luminal to the basolateral side of the endothelial monolayers. The transmigration process of certain cells was accelerated when they were able to use the routes preformed by previously transmigrated melanoma cells. After migrating through the endothelial monolayer several melanoma cells continued their movement beneath the endothelial cell layer. Melanoma cells coming in contact with brain endothelial cells disrupted the tight and adherens junctions of CECs and used (at least partially) the paracellular transmigration pathway. During this process melanoma cells produced and released large amounts of proteolytic enzymes, mainly gelatinolytic serine proteases, including seprase. The serine protease inhibitor Pefabloc® was able to decrease to 44–55% the number of melanoma cells migrating through CECs. Our results suggest that release of serine proteases by melanoma cells and disintegration of the interendothelial junctional complex are main steps in the formation of brain metastases in malignant melanoma.
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Balaziova E, Busek P, Stremenova J, Sromova L, Krepela E, Lizcova L, Sedo A. Coupled expression of dipeptidyl peptidase-IV and fibroblast activation protein-α in transformed astrocytic cells. Mol Cell Biochem 2011; 354:283-9. [PMID: 21526345 DOI: 10.1007/s11010-011-0828-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Accepted: 04/15/2011] [Indexed: 12/17/2022]
Abstract
Dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein-α (FAP) are speculated to participate in the regulation of multiple biological processes, because of their unique enzymatic activity, as well as by non-hydrolytic molecular interactions. At present, the role of DPP-IV and FAP in the development and progression of various types of tumors, including glioblastoma, is intensively studied, and their functional crosstalk is hypothesized. In this article, we describe the correlative expression of DPP-IV and FAP mRNA in primary cell cultures derived from human glioblastoma and associated expression dynamics of both molecules in astrocytoma cell lines depending on culture conditions. Although the molecular mechanisms of DPP-IV and FAP co-regulations remain unclear, uncoupled expression of transgenic DPP-IV and the endogenous FAP suggests that it occurs rather at the transcriptional than at the posttranscriptional level. Understanding of the expressional and functional coordinations of DPP-IV and FAP may help clarify the mechanisms of biological roles of both molecules in transformed astrocytic cells.
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Affiliation(s)
- Eva Balaziova
- Institute of Biochemistry and Experimental Oncology of the 1st Faculty of Medicine, Charles University in Prague, U Nemocnice 5, Prague 2, 12853, Czech Republic
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Lefort EC, Blay J. The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells. Clin Exp Metastasis 2011; 28:337-49. [PMID: 21298326 DOI: 10.1007/s10585-010-9364-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 11/29/2010] [Indexed: 12/27/2022]
Abstract
There is accumulating evidence that secondary plant metabolites such as flavonoids may have anti-cancer properties, and yet the molecular pathways that lead to alterations in cancer cell behaviour remain unclear. We investigated the possible actions of apigenin, a flavone present in leafy vegetables like parsley, on the levels of CD26 in carcinoma cells. CD26 is a multifunctional cell-surface protein that through its associated dipeptidyl peptidase (DPPIV) and ecto-adenosine deaminase (eADA) enzyme activities is able to suppress pathways involved in tumour metastasis. CD26 is down-regulated in various cancers including colorectal carcinoma. Apigenin substantially up-regulated cell-surface CD26 on HT-29 and HRT-18 human colorectal cancer cells. Levels of CD26 protein, along with its associated DPPIV enzyme activity, capacity to bind eADA, and ability to link cells to fibronectin, were increased with a maximum after 24-48 h. Elevation of CD26 occurred at concentrations that were at least 10-fold less than those shown to affect cell growth, and 100-fold below those that could affect cell viability. Furthermore, the CD26 effect was enhanced when apigenin was paired with chemotherapeutic agents utilized in the treatment of advanced colorectal cancer including irinotecan, 5-fluorouracil and oxaliplatin. For irinotecan, apigenin caused a 4-fold increase in the potency of the drug. These results demonstrate that apigenin can increase the cellular levels of CD26 and its multiple functions, and may oppose the predicted effect of decreased DPPIV and eADA activities on carcinoma cells, which is to facilitate tumour growth and metastasis.
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Affiliation(s)
- Emilie C Lefort
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
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The Potential Role of MT and Vimentin Immunoreactivity in the Remodeling of the Microenvironment of Parotid Adenocarcinoma. CANCER MICROENVIRONMENT 2010; 4:105-13. [PMID: 21505565 PMCID: PMC3047632 DOI: 10.1007/s12307-010-0058-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2010] [Accepted: 11/25/2010] [Indexed: 11/01/2022]
Abstract
A tumor stimulates the remodeling of its microenvironment in order to control and accelerate its own growth and to initiate metastases. To create metastases the tumor cells must first acquire the ability to detach from the main tumor and to adhere to, invade, and degrade the adjacent extracellular matrix. The cells must then be able to enter the lumen of the vessels where they home the distant tissues and organs by forming secondary tumors. The acquisition of this phenotype is related to the phenomenon of epithelial-to-mesenchymal transition. On the molecular level, this process is typified by a change in the expression of epithelial markers and by the enhancement of the expression of mesenchymal markers like vimentin that are responsible for cell migration and invasion. Metallothioneins have been shown to help protect against apoptosis. The expression of MT by tumor cells plays an important and complex role not only because of its pro-proliferative, anti-apoptotic activity, but also because it inhibits the immune response. The aim of the present study was to evaluate the immunoreactivity of vimentin and MT in the salivary gland adenocarcinoma and its stroma in order to observe the phenomenon of stromal remodeling. The tissue samples of salivary gland adenocarcinomas and their stromas and the palatine tonsils which constituted the reference group were obtained during routine surgical procedures. The immunoreactivity of vimentin, metalothionein, CD56, CD57 antigens was evaluated by the immunohistochemistry method in 30 tissue samples of parotid adenocarcinoma. The patient's consent was obtained in each case. A statistically significantly higher level of MT immunoreactivity was observed in the adenocarcinoma tissue slides than in either the stromal slides or the reference slides while no differences in MT immunoreactivity were detected when the stroma and reference tissue slides were compared. A statistically significantly higher vimentin immunoreactivity level was identified in the tumor microenvironment tissue slides than in the tumor tissue slides, and a statistically significantly higher level of vimentin immunoreactivity was identified in the tumor microenvironment slides than in the slides of the reference tissue, while no differences were identified between the adenocarcinoma tissue slides and the reference slides with respect to vimentin immunoreactivity. A statistically significantly higher number of CD56- and CD57-expressing cells were identified in the reference tissue slides than in either the adenocarcinoma or stromal slides. In conclusion, the stroma of salivary gland adenocarcinoma in this study has been characterized by remodeling. The remodeling is represented by the expression of both vimentin and MT and by a deficit of CD57- and CD58-expressing cell infiltration. This situation would seem to be the result of immune tolerance for the tumor developing within the tumor microenvironment. Furthermore, the presence of MT and vimentin immunoreactivity in the fibroblasts of the tumor stroma may constitute a marker of active tissue remodeling.
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