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Wang N, Tong X, Li YK. The mouse pubic symphysis: a narrative review. Front Physiol 2025; 16:1497250. [PMID: 40206383 PMCID: PMC11978666 DOI: 10.3389/fphys.2025.1497250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 03/17/2025] [Indexed: 04/11/2025] Open
Abstract
Remodeling and relaxation of the mouse pubic symphysis (PS) are responsible for separating the pubic bone, allowing the passage of the full-term fetus, and ensuring safe delivery. PS in postpartum mice can rapidly return to a similar non-pregnant state, providing mechanical stability for the reproductive tract. During pregnancy and postpartum recovery, PS changes in mice are involved in many aspects, including extracellular matrix (ECM), matrix metalloproteinases (MMPs), cell phenotypes, hormones, and immune cells. The changes in PS in mice during pregnancy and postpartum convalescence were reviewed, and the possible mechanisms were discussed. We hope to attract more research interest to explore the biological mechanisms of this process better.
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Affiliation(s)
- Ning Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xue Tong
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Yi-kai Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
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2
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Vatankhah A, Moghaddam SH, Afshari S, Afshari AR, Kesharwani P, Sahebkar A. Recent update on anti-tumor mechanisms of valproic acid in glioblastoma multiforme. Pathol Res Pract 2024; 263:155636. [PMID: 39395298 DOI: 10.1016/j.prp.2024.155636] [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] [Received: 08/23/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
Glioblastoma multiforme (GBM) is a malignant tumor of the brain that is considered to be incurable. Currently, surgical removal of tumors, chemotherapy with temozolomide, and radiation treatment remain established options for treatment. Nevertheless, the prognosis of those with GBM continues to be poor owing to the inherent characteristics of tumor growth and spread, as well as the resistance to treatment. To effectively deal with the present circumstances, it is vital to do extensive study to understand GBM thoroughly. The following piece provides a concise overview of the most recent advancements in using valproic acid, an antiseizure medication licensed by the FDA, for treating GBM. In this review, we outline the most recent developments of valproic acid in treating GBM, as well as its fundamental mechanisms and practical consequences. Our goal is to provide a greater understanding of the clinical use of valproic acid as a potential therapeutic agent for GBM.
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Affiliation(s)
- Abulfazl Vatankhah
- School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | | | - Sadaf Afshari
- Student Research Committee, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir R Afshari
- Department of Basic Sciences, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran; Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran.
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Amirhossein Sahebkar
- Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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3
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Gozdz A, Maksym RB, Ścieżyńska A, Götte M, Kieda C, Włodarski PK, Malejczyk J. Expression of Reversion-Inducing Cysteine-Rich Protein with Kazal Motifs ( RECK) Gene and Its Regulation by miR200b in Ovarian Endometriosis. Int J Mol Sci 2024; 25:11594. [PMID: 39519143 PMCID: PMC11547164 DOI: 10.3390/ijms252111594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Endometriosis is a common chronic disorder characterized by the growth of endometrium-like tissue outside the uterine cavity. The disease is associated with chronic inflammation and pelvic pain and may have an impact on the patient's fertility. The causative factors and pathophysiology of the disease are still poorly recognized. The dysregulation of the immune system, aberrant tissue remodeling, and angiogenesis contribute to the disease progression. In endometriosis patients, the proteins regulating the breakdown and reorganization of the connective tissue, e.g., collagenases, and other proteases, as well as their inhibitors, show an incorrect pattern of expression. Here, we report that the expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK), one of the inhibitors of connective tissue proteases, is elevated in endometrioma cysts as compared to normal endometrium from unaffected women. We also demonstrate a reduced level of miR200b in endometriotic tissue that correlates with RECK mRNA levels. Furthermore, we employ the 12Z cell line, derived from a peritoneal endometriotic lesion, and the Ishikawa cell line, originating from endometrial adenocarcinoma to identify RECK as a direct target of miR200b. The described effect of miR200b on RECK, together with the aberrant expression of both genes in endometrioma, may help to understand the role played by the tissue remodeling system in the pathogenesis of endometriosis.
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Affiliation(s)
- Agata Gozdz
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, ul. T. Chałubińskiego 5, 02-004 Warsaw, Poland; (R.B.M.); (A.Ś.); (P.K.W.)
| | - Radosław B. Maksym
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, ul. T. Chałubińskiego 5, 02-004 Warsaw, Poland; (R.B.M.); (A.Ś.); (P.K.W.)
- 1st Department of Obstetrics and Gynecology, Centre for Postgraduate Medical Education, ul. Żelazna 90, 01-004 Warsaw, Poland
- Center for Molecular Biophysics UPR 4301 CNRS, 45071 Orleans, France;
| | - Aneta Ścieżyńska
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, ul. T. Chałubińskiego 5, 02-004 Warsaw, Poland; (R.B.M.); (A.Ś.); (P.K.W.)
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine-National Research Institute, 04-141 Warsaw, Poland
| | - Martin Götte
- Department of Obstetrics and Gynecology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany;
- Cells-in-Motion Interfaculty Centre (CiMIC), University of Münster, 48149 Münster, Germany
| | - Claudine Kieda
- Center for Molecular Biophysics UPR 4301 CNRS, 45071 Orleans, France;
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine-National Research Institute, 04-141 Warsaw, Poland
| | - Paweł K. Włodarski
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, ul. T. Chałubińskiego 5, 02-004 Warsaw, Poland; (R.B.M.); (A.Ś.); (P.K.W.)
| | - Jacek Malejczyk
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, ul. T. Chałubińskiego 5, 02-004 Warsaw, Poland; (R.B.M.); (A.Ś.); (P.K.W.)
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Yu H, Kohno S, Voon DC, Hussein NH, Zhang Y, Nakayama J, Takegami Y, Takahashi C. RECK/GPR124-driven WNT signaling in pancreatic and gastric cancer cells. Cancer Sci 2024; 115:3013-3025. [PMID: 38923741 PMCID: PMC11462976 DOI: 10.1111/cas.16258] [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] [Received: 04/23/2024] [Revised: 06/05/2024] [Accepted: 06/16/2024] [Indexed: 06/28/2024] Open
Abstract
RECK has been described to modulate extracellular matrix components through negative regulation of MMP activities. Recently, RECK was demonstrated to bind to an orphan G protein-coupled receptor GPR124 to mediate WNT7 signaling in nontumor contexts. Here, we attempted to clarify the role of RECK in driving WNT signaling in cancer cells. RECK and GPR124 formed a complex in 293T cells, and when both were expressed, WNT signaling was significantly enhanced in a WNT7-dependent manner. This cooperation was abolished when RECK mutants unable to bind to GPR124 were transduced. RECK stimulated the growth of KRAS-mutated pancreatic ductal adenocarcinoma (PDAC) cells with increased sensitivity to WNT inhibitor in a GPR124-dependent manner. A gastric cancer cell line SH10TC endogenously expresses both RECK and GPR124 under regular culture conditions. In this cell line, inhibited cell growth and WNT signaling as well as increased apoptosis in the GPR124 depletion was dominantly found over those in the RECK deletion. These findings suggest that RECK promotes tumor cell growth by positively modulating WNT signaling through GPR124. This study proposes that the RECK/GPR124 complex might be a good therapeutic target in PDAC and gastric cancer.
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Affiliation(s)
- Hai Yu
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | - Susumu Kohno
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | | | - Nada Hamdy Hussein
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | - Yuanyuan Zhang
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | - Joji Nakayama
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
| | | | - Chiaki Takahashi
- Division of Oncology and Molecular Biology, Cancer Research InstituteKanazawa UniversityKanazawaIshikawaJapan
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Zhang W, Gao X. Bioinformatics and meta-analysis of the clinical significance of RECK expression and its genetic polymorphisms in cancer. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024:1-14. [PMID: 38557395 DOI: 10.1080/15257770.2024.2336222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
RECK plays an important role in the development of cancer. The current study focuses on exploring the clinical significance of RECK expression in cancer by mining public data and also evaluating the relationship between genetic polymorphisms of the RECK gene and cancer risk through meta-analysis. The results showed that RECK expression was not only associated with survival prognosis and immune infiltration in many types of cancers, but also with multiple drug sensitivity in pan-cancer. In addition, the RECK rs10814325 polymorphism was also associated with cancer risk under the homozygote comparison model (CC vs. TT: OR = 1.64, 95%CI = 1.03-2.61, p = 0.04) and the recessive genetic model [CC vs. (CT + TT): OR = 1.55, 95%CI = 1.27-1.89, p < 0.01]. In conclusion, these findings suggest that RECK expression levels may serve as a valuable indicator for assessing cancer prognosis in some cancers as well as drug sensitivity in pan-cancer, and its rs10814325 polymorphism may be used to assess cancer risk.
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Affiliation(s)
- Weichao Zhang
- School of Pharmacy, Yancheng Teachers' University, Yancheng, China
| | - Xueren Gao
- School of Pharmacy, Yancheng Teachers' University, Yancheng, China
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Wang J, Su Y, Liu H, Li Y, Fang X, Yu X, Li Q, Han W. Association between the Reduced Expression of RECK and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease. Int Arch Allergy Immunol 2024; 185:480-488. [PMID: 38387446 DOI: 10.1159/000536021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 11/27/2023] [Indexed: 02/24/2024] Open
Abstract
INTRODUCTION Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a recently discovered inhibitor of matrix metalloproteinase (MMP). There is a large number of chronic obstructive pulmonary disease (COPD) patients worldwide; however, the role of RECK on COPD has not been studied. This study explored the expression of RECK in COPD patients and its effect on neutrophil function to provide a new scientific basis for the prevention and treatment of COPD. METHOD Fifty patients with acute exacerbation of COPD and fifty healthy controls were enrolled in the study. RECK was detected in lung tissue, sputum, and plasma of subjects as well as in BEAS-2B cells stimulated with cigarette smoke extract (CSE) by immunohistochemistry, ELISA, and qRT-PCR. Meanwhile, lung function (FEV1%pred) and inflammatory cytokines (IL-6 and IL-8) were examined, and correlation analysis was performed with RECK expression. The effect of RECK on proliferation, apoptosis, migration, and inflammatory cytokines and its potential mechanism was further quantified by neutrophil stimulated with recombinant human RECK protein (rhRECK) combined with CSE using CCK8, flow cytometry, Transwell assay, qRT-PCR, ELISA, and Western analysis. RESULTS RECK was mainly expressed on airway epithelial cells in normal lung tissue and was significantly diminished in COPD patients. The levels of RECK in sputum and plasma were also significantly decreased in COPD patients. Pearson correlation analysis showed that RECK level in plasma was positively correlated with FEV1%pred (r = 0.458, p < 0.001) and negatively correlated with IL-6 and IL-8 (r = -0.386, -0.437; p = 0.006, 0.002) in COPD patients. The expression of RECK was decreased in BEAS-2B stimulated with CSE. The migration, inflammation, and MMP-9 expression of neutrophils were promoted by CSE, while inhibited by rhRECK. CONCLUSION RECK is low expressed in COPD patients and negatively correlated with inflammation. It may inhibit the inflammation and migration of neutrophils by downregulating MMP-9.
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Affiliation(s)
- Jiahui Wang
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Yi Su
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Hong Liu
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Yongchun Li
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Xuejie Fang
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
- School of Clinical Medicine, Shandong Second Medical University, Wei Fang, China
| | - Xinjuan Yu
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
- Clinical Research Center, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Qinghai Li
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Wei Han
- Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
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Fetsko AR, Sebo DJ, Taylor MR. Brain endothelial cells acquire blood-brain barrier properties in the absence of Vegf-dependent CNS angiogenesis. Dev Biol 2023; 494:46-59. [PMID: 36502932 PMCID: PMC9870987 DOI: 10.1016/j.ydbio.2022.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/08/2022] [Accepted: 11/22/2022] [Indexed: 12/13/2022]
Abstract
During neurovascular development, brain endothelial cells (BECs) respond to secreted signals from the neuroectoderm that regulate CNS angiogenesis, the formation of new blood vessels in the brain, and barriergenesis, the acquisition of blood-brain barrier (BBB) properties. Wnt/β-catenin signaling and Vegf signaling are both required for CNS angiogenesis; however, the relationship between these pathways is not understood. Furthermore, while Wnt/β-catenin signaling is essential for barriergenesis, the role of Vegf signaling in this vital process remains unknown. Here, we provide the first direct evidence, to our knowledge, that Vegf signaling is not required for barriergenesis and that activation of Wnt/β-catenin in BECs is independent of Vegf signaling during neurovascular development. Using double transgenic glut1b:mCherry and plvap:EGFP zebrafish (Danio rerio) to visualize the developing brain vasculature, we performed a forward genetic screen and identified a new mutant allele of kdrl, an ortholog of mammalian Vegfr2. The kdrl mutant lacks CNS angiogenesis but, unlike the Wnt/β-catenin pathway mutant gpr124, acquires BBB properties in BECs. To examine Wnt/β-catenin pathway activation in BECs, we chemically inhibited Vegf signaling and found robust expression of the Wnt/β-catenin transcriptional reporter line 7xtcf-Xla.Siam:EGFP. Taken together, our results establish that Vegf signaling is essential for CNS angiogenesis but is not required for Wnt/β-catenin-dependent barriergenesis. Given the clinical significance of either inhibiting pathological angiogenesis or stimulating neovascularization, our study provides valuable new insights that are critical for the development of effective therapies that target the vasculature in neurological disorders.
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Affiliation(s)
- Audrey R Fetsko
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Dylan J Sebo
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael R Taylor
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA.
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Yoshida Y, Yuki K, Dan S, Yamazaki K, Noda M. Suppression of tumor metastasis by a RECK-activating small molecule. Sci Rep 2022; 12:2319. [PMID: 35149728 PMCID: PMC8837781 DOI: 10.1038/s41598-022-06288-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
RECK encodes a membrane-anchored protease-regulator which is often downregulated in a wide variety of cancers, and reduced RECK expression often correlates with poorer prognoses. In mouse models, forced expression of RECK in tumor xenografts results in suppression of tumor angiogenesis, invasion, and metastasis. RECK mutations, however, are rare in cancer genomes, suggesting that agents that re-activate dormant RECK may be of clinical value. We found a potent RECK-inducer, DSK638, that inhibits spontaneous lung metastasis in our mouse xenograft model. Induction of RECK expression involves SP1 sites in its promoter and may be mediated by KLF2. DSK638 also upregulates MXI1, an endogenous MYC-antagonist, and inhibition of metastasis by DSK638 is dependent on both RECK and MXI1. This study demonstrates the utility of our approach (using a simple reporter assay followed by multiple phenotypic assays) and DSK638 itself (as a reference compound) in finding potential metastasis-suppressing drugs.
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Affiliation(s)
- Yoko Yoshida
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan. .,Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.
| | - Kanako Yuki
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan
| | - Kanami Yamazaki
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan
| | - Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan.
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Gutiérrez J, Gonzalez D, Escalona-Rivano R, Takahashi C, Brandan E. Reduced RECK levels accelerate skeletal muscle differentiation, improve muscle regeneration, and decrease fibrosis. FASEB J 2021; 35:e21503. [PMID: 33811686 DOI: 10.1096/fj.202001646rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 02/07/2021] [Accepted: 02/19/2021] [Indexed: 12/15/2022]
Abstract
The muscle regeneration process requires a properly assembled extracellular matrix (ECM). Its homeostasis depends on the activity of different matrix-metalloproteinases (MMPs). The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) is a membrane-anchored protein that negatively regulates the activity of different MMPs. However, the role of RECK in the process of skeletal muscle differentiation, regeneration, and fibrosis has not been elucidated. Here, we show that during skeletal muscle differentiation of C2C12 myoblasts and in satellite cells on isolated muscle fibers, RECK is transiently up regulated. C2C12 myoblasts with reduced RECK levels are more prone to enter the differentiation program, showing an accelerated differentiation process. Notch-1 signaling was reduced, while p38 and AKT signaling were augmented in myoblasts with decreased RECK levels. Overexpression of RECK restores the normal differentiation process but diminished the ability to form myotubes. Transient up-regulation of RECK occurs during skeletal muscle regeneration, which was accelerated in RECK-deficient mice (Reck±). RECK, MMPs and ECM proteins augmented in chronically damaged WT muscle, a model of muscle fibrosis. In this model, RECK ± mice showed diminished fibrosis compared to WT. These results strongly suggest that RECK is acting as a potential myogenic repressor during muscle formation and regeneration, emerging as a new player in these processes, and as a potential target to treat individuals with the muscle-wasting disease.
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Affiliation(s)
- Jaime Gutiérrez
- Cellular Signaling and Differentiation Laboratory (CSDL), School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Santiago, Chile.,Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - David Gonzalez
- Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo Escalona-Rivano
- Cellular Signaling and Differentiation Laboratory (CSDL), School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Santiago, Chile
| | - Chiaki Takahashi
- Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Enrique Brandan
- Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
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Dong ZR, Chen ZQ, Yang XY, Ding ZN, Liu KX, Yan LJ, Meng GX, yang YF, Yan YC, Yao SY, Yang CC, Zhi XT, Li T. RECK expression is associated with angiogenesis and immunogenic Tumor Microenvironment in Hepatocellular Carcinoma, and is a prognostic factor for better survival. J Cancer 2021; 12:3827-3840. [PMID: 34093791 PMCID: PMC8176247 DOI: 10.7150/jca.56167] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 04/25/2021] [Indexed: 12/24/2022] Open
Abstract
Angiogenesis and immunosuppression have been described as closely related processes that can occur in parallel. As an inhibitor of matrix metalloproteinase, whether the level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in hepatocellular carcinoma (HCC) reflects a link between angiogenesis and immunosuppression is still unknown. We analyzed RNA expression, immune infiltration and survival of HCC from The Cancer Genome Atlas databases. Immune scores and stromal scores were calculated based on the ESTIMATE algorithm to quantify the immune and stromal components in HCC. The association between RECK and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high RECK expression was significantly better than that of patients with low RECK expression. High RECK expression was associated with high ESTIMATE Score, recruitment of more tumor-infiltrating lymphocytes, low tumor purity, and high PD-L1 expression. In addition, positive RECK expression was associated with a lower incidence of vascular invasion and recurrence, a lower level of alpha fetoprotein (AFP) and microvessel density and a better tumor differentiation. Multivariate analyses revealed that reduced RECK expression was an independent prognostic factor for recurrence and poor prognosis. In conclusion, high RECK expression reflects an immunogenic and hypovascularity status in HCC. RECK is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive anti-angiogenic therapy or immunotherapy.
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Affiliation(s)
- Zhao-Ru Dong
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Zhi-Qiang Chen
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Xiao-Yun Yang
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Zi-Niu Ding
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Kai-Xuan Liu
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Lun-Jie Yan
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Guang-Xiao Meng
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Ya-Fei yang
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Yu-Chuan Yan
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Sheng-Yu Yao
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Chun-Cheng Yang
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Xu-Ting Zhi
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Tao Li
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, China
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Bao WW, Shi YL, Ma Y, Qu XH, Pang GM, Yang L. MiR-590-5p regulates cell proliferation, apoptosis, migration and invasion in oral squamous cell carcinoma by targeting RECK. Histol Histopathol 2021; 36:355-365. [PMID: 33447989 DOI: 10.14670/hh-18-306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To discover the role of miR-590-5p in oral squamous cell carcinoma (OSCC) progression and the corresponding mechanism via the targeting RECK. METHODS OSCC (n=85) and normal oral tissues (n=60) were collected to quantify the miR-590-5p expression by using qRT-PCR. Then SCC-15 and OEC-M1 cells were selected and divided into Mock, inhibitor NC, miR-590-5p inhibitor, si-RECK and miR-590-5p inhibitor + si-RECK groups. Dual-luciferase reporter gene assay was used to verify if miR-590-5p could target RECK. The biological behaviors of OSCC cells were evaluated by MTT, Wound-healing, Transwell and Flow cytometry. The expression of miR-590-5p and RECK was measured by qRT-PCR and Western blotting , respectively. RESULTS Overexpression of miR-590-5p was found in OSCC tissues. The expression of miR-590-5p was significantly associated with the clinical TNM stage, differentiation degree, and lymph node metastasis of OSCC. RECK was identified as a direct target of miR-590-5p. Compared with the Mock group, cells in the miR-590-5p inhibitor group were decreased in terms of proliferation, invasion, and migration, and increased in cell apoptosis, accompanied by down-regulated miR-590-5p, Bcl-2/Bax and MMP-9, and up-regulated RECK. By contrast, si-RECK group presented completely opposite changes, and si-RECK reversed the inhibitory effect of miR-590-5p inhibitor on the OSCC cell growth. CONCLUSION MiR-590-5p expression was obviously increased in OSCC, and inhibiting miR-590-5p enhanced the expression of its target gene RECK, thereby suppressing proliferation, migration and invasion of OSCC cells and promoting apoptosis of OSCC cells.
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Affiliation(s)
- Wei-Wei Bao
- Department of Orthodontics, Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - You-Ling Shi
- Department of Orthodontics, Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Yan Ma
- Department of Orthodontics, Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Xing-Hui Qu
- Department of Orthodontics, Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Guang-Ming Pang
- Department of Orthodontics, Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Lei Yang
- Department of Orthodontics, Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China.
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Ogawa S, Matsuzaki T, Noda M. Abundant expression of the membrane-anchored protease-regulator RECK in the anterior pituitary gland and its implication in the growth hormone/insulin-like growth factor 1 axis in mice. Mol Cell Endocrinol 2020; 508:110790. [PMID: 32165171 DOI: 10.1016/j.mce.2020.110790] [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] [Received: 10/16/2019] [Revised: 03/04/2020] [Accepted: 03/08/2020] [Indexed: 10/24/2022]
Abstract
The tumor suppressor gene Reversion-inducing cysteine-rich protein with Kazal motifs (Reck) encodes a membrane-anchored protease regulator expressed in multiple tissues in mouse embryos and is essential for embryonic development. In postnatal mice, however, physiological roles for the RECK protein remain unclear. We found in this study that Reck is abundantly expressed in growth hormone (GH)-producing cells (somatotrophs) in the anterior pituitary gland (AP). We also found that two types of viable Reck mutant mice, one with reduced RECK expression (Hypo mice) and the other with induced Reck deficiency from 10 days after birth (iKO mice treated with tamoxifen), exhibit common phenotypes including decreases in body size and plasma levels of insulin-like growth factor-1 (IGF1). To gain insights into the function of RECK in the AP, we characterized several somatotroph-associated molecules in the AP of these mice. Immunoreactivity of GH was greatly reduced in tamoxifen-treated iKO mice; in these mice, two membrane receptors involved in the stimulation of GH secretion [growth hormone secretagogue receptor (GHSR) and growth hormone releasing hormone receptor (GHRHR)] were decreased, however, their mRNAs were increased. Decrease in GHSR immunoreactivity and concomitant increase in its mRNA were also found in the other mutant line, Hypo. Furthermore, reduced immunoreactivity of growth hormone receptor (GHR) and concomitant increase in its mRNA was also found in the liver of Hypo mice. These results raise the possibility that RECK supports proper functioning of the GH/IGF1 axis in mice, thereby affecting their growth and metabolism.
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Affiliation(s)
- Shuichiro Ogawa
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Tomoko Matsuzaki
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
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Zheng H, Wang JJ, Zhao LJ, Yang XR, Yu YL. Exosomal miR-182 regulates the effect of RECK on gallbladder cancer. World J Gastroenterol 2020; 26:933-946. [PMID: 32206004 PMCID: PMC7081010 DOI: 10.3748/wjg.v26.i9.933] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/08/2020] [Accepted: 01/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As the most common biliary malignancy, gallbladder cancer (GC) is an elderly-biased disease. Although extensive studies have elucidated the molecular mechanism of microRNA 182 (miR-182) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) in various cancers, the specific role of exosomal miR-182 and RECK in GC remains poorly understood.
AIM To explore the relationship between exosomal miR-182/RECK and metastasis of GC.
METHODS Paired GC and adjacent normal tissues were collected from 78 patients. Quantitative polymerase chain reaction was employed to detect miR-182 and exosomal miR-182 expression, and Western blotting was conducted to determine RECK expression. In addition, the effects of exosomal miR-182/RECK on the biological function of human GC cells were observed. Moreover, the double luciferase reporter gene assay was applied to validate the targeting relationship between miR-182 and RECK.
RESULTS Compared with normal gallbladder epithelial cells, miR-182 was highly expressed in GC cells, while RECK had low expression. Exosomal miR-182 could be absorbed and transferred by cells. Exosomal miR-182 inhibited RECK expression and promoted the migration and invasion of GC cells.
CONCLUSION Exosomal miR-182 can significantly promote the migration and invasion of GC cells by inhibiting RECK; thus miR-182 can be used as a therapeutic target for GC.
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Affiliation(s)
- Hong Zheng
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Jin-Jing Wang
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Li-Jin Zhao
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Xiao-Rong Yang
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Yong-Lin Yu
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
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Ekinci E, Rohondia S, Khan R, Dou QP. Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents. Recent Pat Anticancer Drug Discov 2020; 14:113-132. [PMID: 31084595 DOI: 10.2174/1574892814666190514104035] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/30/2019] [Accepted: 05/10/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity. OBJECTIVE To summarize the anti-cancer effects of Disulfiram through a thorough patent review. METHODS This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy. RESULTS Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug. CONCLUSION For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.
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Affiliation(s)
- Elmira Ekinci
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
| | - Sagar Rohondia
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
| | - Raheel Khan
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
| | - Qingping P Dou
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
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Shen Z, Jiao K, Teng M, Li Z. Activation of STAT-3 signalling by RECK downregulation via ROS is involved in the 27-hydroxycholesterol-induced invasion in breast cancer cells. Free Radic Res 2020; 54:126-136. [PMID: 31933392 DOI: 10.1080/10715762.2020.1715965] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Breast cancer is an important and common tumour among women worldwide. We previously showed that 27-hydroxycholesterol (27HC) promoted the invasion and migration of breast cancer cells and activated signal transducer and activator of transcription 3 (STAT-3) signalling through reactive oxygen species (ROS). However, the regulation of STAT-3 signalling by ROS needs to be further explored. Here, we showed that 27HC caused the accumulation of cellular ROS, which upregulated matrix metalloproteinase 9 (MMP9) and increased the invasive ability of MCF7 and T47D cells. 27HC decreased the protein and mRNA levels of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) in a time- and dose-dependent manner in MCF7 and T47D cells. RECK downregulation was mediated by 27HC-induced DNA methylation via ROS in MCF7 cells. RECK knockdown increased the activity and mRNA levels of MMP9, and promoted the invasion of MCF7 cells. We also found RECK knockdown upregulated the level of p-STAT-3 in MCF7 cells. Furthermore, overexpression of RECK attenuated 27HC-induced invasion in MCF7 cells. RECK overexpression also inhibited p-STAT-3 upregulation induced by 27HC. Collectively, the results showed that DNA methylation induced by 27HC via ROS downregulated RECK, thereby activating the STAT-3 signalling pathway. RECK could serve as a novel target mediating the effect of 27HC on breast cancer.
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Affiliation(s)
- Zhaoxia Shen
- Department of Child Health, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Kailin Jiao
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Mengying Teng
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhong Li
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, China
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16
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Lin J, Liu Z, Liao S, Li E, Wu X, Zeng W. Elevation of long non-coding RNA GAS5 and knockdown of microRNA-21 up-regulate RECK expression to enhance esophageal squamous cell carcinoma cell radio-sensitivity after radiotherapy. Genomics 2019; 112:2173-2185. [PMID: 31866421 DOI: 10.1016/j.ygeno.2019.12.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/04/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Lately, lncRNAs have been proposed to function in the radio-sensitivity of tumor cells, yet the role of lncRNA GAS5 in that of esophageal squamous cell carcinoma (ESCC) has scarcely been studied. This study aims to examine GAS5's effects on ESCC cell radio-sensitivity. METHODS GAS5, miR-21 and RECK expression in radiation-sensitive and radiation-resistant ESCC tissues, and TE-1 and TE-1-R cells was determined. TE-1 and TE-1-R cells were treated with pcDNA-GAS5 or miR-21 inhibitors to figure out their roles in ESCC cell proliferation, radio-sensitivity, and apoptosis via gain- and loss-of-function experiments. RESULTS We found underexpressed GAS5 and RECK, and overexpressed miR-21 in ESCC. GAS5 elevation and miR-21 inhibition reduced viability and the colony formation ability, and enhanced the apoptosis of ESCC cells under radiation. CONCLUSION Our study reveals that GAS5 elevation up-regulates RECK expression by down-regulating miR-21 to increase ESCC cell apoptosis after radiation therapy, thus enhancing cell radio-sensitivity.
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Affiliation(s)
- Jing Lin
- Department of Oncology, The First Affiliated Hospital of Shantou Univresity Medical College, Shantou 515041, China.
| | - Zewa Liu
- Department of Oncology, The First Affiliated Hospital of Shantou Univresity Medical College, Shantou 515041, China
| | - Shasha Liao
- Department of Oncology, Shantou Longhu people's Hospital, Shantou 515041, Guangdong, China
| | - E Li
- Department of Oncology, Shantou Longhu people's Hospital, Shantou 515041, Guangdong, China
| | - Xiaohua Wu
- Department of Oncology, Shantou Longhu people's Hospital, Shantou 515041, Guangdong, China
| | - Wanting Zeng
- Division of Medical University College, London WCIE 6BT, United Kingdom
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Covarrubias-Zambrano O, Yu J, Bossmann SH. Nano-Inspired Technologies for Peptide Delivery. Curr Protein Pept Sci 2019; 21:379-400. [PMID: 31793426 DOI: 10.2174/1389203720666191202112429] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 08/26/2019] [Accepted: 10/02/2019] [Indexed: 12/15/2022]
Abstract
Nano-inspired technologies offer unique opportunities to treat numerous diseases by using therapeutic peptides. Therapeutic peptides have attractive pharmacological profiles and can be manufactured at relatively low costs. The major advantages of using a nanodelivery approach comprises significantly lower required dosages compared to systemic delivery, and thus reduced toxicity and immunogenicity. The combination of therapeutic peptides with delivery peptides and nanoparticles or small molecule drugs offers systemic treatment approaches, instead of aiming for single biological targets or pathways. This review article discusses exemplary state-of-the-art nanosized delivery systems for therapeutic peptides and antibodies, as well as their biochemical and biophysical foundations and emphasizes still remaining challenges. The competition between using different nanoplatforms, such as liposome-, hydrogel-, polymer-, silica nanosphere-, or nanosponge-based delivery systems is still "on" and no clear frontrunner has emerged to date.
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Affiliation(s)
| | - Jing Yu
- Department of Chemistry, Kansas State University, 419 CBC Building, Manhattan, KS 66506-0401, United States.,Johns Hopkins University, Department of Radiology, Baltimore, MD, United States
| | - Stefan H Bossmann
- Department of Chemistry, Kansas State University, 419 CBC Building, Manhattan, KS 66506-0401, United States
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18
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Curcumin suppresses wilms' tumor metastasis by inhibiting RECK methylation. Biomed Pharmacother 2019; 111:1204-1212. [DOI: 10.1016/j.biopha.2018.12.111] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 12/18/2018] [Accepted: 12/23/2018] [Indexed: 12/18/2022] Open
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Higashi Y, Mummidi S, Sukhanov S, Yoshida T, Noda M, Delafontaine P, Chandrasekar B. Minocycline inhibits PDGF-BB-induced human aortic smooth muscle cell proliferation and migration by reversing miR-221- and -222-mediated RECK suppression. Cell Signal 2019; 57:10-20. [PMID: 30716386 DOI: 10.1016/j.cellsig.2019.01.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 01/31/2019] [Accepted: 01/31/2019] [Indexed: 12/24/2022]
Abstract
Minocycline, a tetracycline antibiotic, is known to exert vasculoprotective effects independent of its anti-bacterial properties; however the underlying molecular mechanisms are not completely understood. Reversion Inducing Cysteine Rich Protein with Kazal Motifs (RECK) is a cell surface expressed, membrane anchored protein, and its overexpression inhibits cancer cell migration. We hypothesized that minocycline inhibits platelet-derived growth factor (PDGF)-induced human aortic smooth muscle cell (SMC) proliferation and migration via RECK upregulation. Our data show that the BB homodimer of recombinant PDGF (PDGF-BB) induced SMC migration and proliferation, effects significantly blunted by pre-treatment with minocycline. Further investigations revealed that PDGF-BB induced PI3K-dependent AKT activation, ERK activation, reactive oxygen species generation, Nuclear Factor-κB and Activator Protein-1 activation, microRNA (miR)-221 and miR-222 induction, RECK suppression, and matrix metalloproteinase (MMP2 and 9) activation, effects that were reversed by minocycline. Notably, minocycline induced RECK expression dose-dependently within the therapeutic dose of 1-100 μM, and silencing RECK partially reversed the inhibitory effects of minocycline on PDGF-BB-induced MMP activation, and SMC proliferation and migration. Further, targeting MMP2 and MMP9 blunted PDGF-BB-induced SMC migration. Together, these results demonstrate that minocycline inhibits PDGF-BB-induced SMC proliferation and migration by restoring RECK, an MMP inhibitor. These results indicate that the induction of RECK is one of the mechanisms by which minocycline exerts vasculoprotective effects.
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Affiliation(s)
- Yusuke Higashi
- Medicine/Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA
| | - Srinivas Mummidi
- Department of Human Genetics, South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA; Medicine/Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA
| | - Sergiy Sukhanov
- Medicine/Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA
| | - Tadashi Yoshida
- Medicine/Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA
| | - Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan
| | - Patrice Delafontaine
- Medicine/Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA
| | - Bysani Chandrasekar
- Medicine/Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
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GAS5 Regulates RECK Expression and Inhibits Invasion Potential of HCC Cells by Sponging miR-135b. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2973289. [PMID: 30733959 PMCID: PMC6348854 DOI: 10.1155/2019/2973289] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 11/08/2018] [Accepted: 12/04/2018] [Indexed: 02/08/2023]
Abstract
Objectives Long noncoding RNA (LncRNA) growth arrest-specific 5 (GAS5) has been characterized as a tumor suppressor in numerous kinds of human cancers. Its anticancer function in hepatocellular carcinoma (HCC) includes repression of cell proliferation and metastasis, leaving the internal mechanisms unclear. In this study, we intended to examine the anti-invasion effects of GAS5 on HCC and explore the downstream regulatory mechanisms. Methods Expression of GAS5 and microRNA-135b (miR-135b) was analyzed by qRT-PCR in paired HCC tissue samples. Their correlation with HCC patients' survival was determined. Transwell assays were done to evaluate in vitro invasion ability. Targeting of GAS5 and RECK by miR-135b was confirmed by qRT-PCR, western blot, and luciferase reporter assays. Results Decreased GAS5 and increased miR-135b in HCC inversely correlate with each other and both correlate with poor prognosis of HCC patients. Functionally, GAS5 suppresses while miR-135b promotes HCC cell invasion capacities in vitro. Mechanistically, GAS5 is a target of miR-135b. Furthermore, GAS5 positively regulates expression of RECK, also a target of miR-135b, which further inhibits MMP-2 expression and contributes to invasion repression. Conclusion GAS5 acted as a tumor suppressor in HCC invasion in a competing endogenous RNA manner. Our findings indicate that GAS5 is a promising therapeutic target for HCC treatment.
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Benzon Z, Benzon S, Tomaš SZ, Prusac IK, Vulić L, Vulić M, Stefanovic V. Immunohistochemical demonstration of RECK protein and interleukin-6 in fetal membranes from singleton pregnancies with late preterm delivery, intact membranes and histological chorioamnionitis. Biotech Histochem 2018; 93:575-580. [PMID: 30230382 DOI: 10.1080/10520295.2018.1511061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
We investigated whether chorioamnionitis affects immunohistochemical demonstration of RECK protein and interleukin-6 (IL-6) expression in fetal placental membranes following late preterm delivery with intact membranes. Fetal membranes of 28 women with single pregnancy, preterm delivery and histologically documented chorioamnionitis at gestational age 34-366/7 weeks constituted the chorioamnionitis study group. The control group consisted of 28 fetal membranes from women with preterm deliveries at the same gestational age without histological chorioamnionitis. Immunohistochemistry was performed using monoclonal antibodies against RECK protein and IL-6. We found a statistically significant difference in RECK expression between the chorioamnionitis and control groups; however, we found no difference in IL-6 expression between the groups. We demonstrated that RECK expression is down-regulated in fetal membranes from pregnancies with spontaneous late preterm birth and intact membranes, which suggests its role in preterm parturition. Equal expression of IL-6 in fetal membranes of pregnancies with and without histological chorioamnionitis is an intriguing and unexpected observation that requires further investigation.
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Affiliation(s)
- Z Benzon
- a Department of Obstetrics and Gynecology , Split University Hospital, University of Split , Split , Croatia
| | - S Benzon
- a Department of Obstetrics and Gynecology , Split University Hospital, University of Split , Split , Croatia
| | - S Z Tomaš
- b Institute of Pathology , Split University Hospital, University of Split , Split , Croatia
| | - I K Prusac
- b Institute of Pathology , Split University Hospital, University of Split , Split , Croatia
| | - L Vulić
- c School of Medicine , Split University Hospital, University of Split , Split , Croatia
| | - M Vulić
- a Department of Obstetrics and Gynecology , Split University Hospital, University of Split , Split , Croatia
| | - V Stefanovic
- d Department of Obstetrics and Gynecology , Helsinki University Hospital, University of Helsinki , Helsinki , Finland
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Matsuzaki T, Wang H, Imamura Y, Kondo S, Ogawa S, Noda M. Generation and characterization of a mouse line carrying Reck-CreERT2 knock-in allele. Genesis 2018; 56:e23099. [PMID: 29508517 DOI: 10.1002/dvg.23099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 02/06/2018] [Accepted: 03/01/2018] [Indexed: 11/07/2022]
Abstract
Reck encodes a membrane-anchored glycoprotein implicated in the regulation of extracellular metalloproteinases, Notch-signaling, and Wnt7-signaling and shown to play critical roles in embryogenesis and tumor suppression. Precise mechanisms of its actions in vivo, however, remain largely unknown. By homologous recombination, we generated a new Reck allele, ReckCreERT2 (MGI symbol: Reck<tm3.1(cre/ERT2)Noda>). This allele is defective in terms of Reck function but expected to induce loxP-mediated recombination in the cells committed to express Reck. Similarity in the expression patterns of the ReckCreERT2 transgene and the endogenous Reck gene was confirmed in five tissues. In the adult hippocampus, induction of Reck expression after transient cerebral ischemia could be demonstrated using this allele. These results indicate the utility of this Cre-driver allele in further studies.
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Affiliation(s)
- Tomoko Matsuzaki
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Huan Wang
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yukio Imamura
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Shunya Kondo
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Shuichiro Ogawa
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
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Yang F, He K, Huang L, Zhang L, Liu A, Zhang J. Casticin inhibits the activity of transcription factor Sp1 and the methylation of RECK in MGC803 gastric cancer cells. Exp Ther Med 2016; 13:745-750. [PMID: 28352361 DOI: 10.3892/etm.2016.4003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 09/27/2016] [Indexed: 02/06/2023] Open
Abstract
The present study investigated the effect of casticin on reversion-inducing-cysteine-rich protein with kazal motifs (RECK) gene expression and intracellular methylation levels in MGC803 gastric cancer cells. Cells were treated with 1, 10 and 30 µmol/l casticin. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were performed to determine the protein expression and mRNA levels of RECK and DNA methyltransferase 1 (DNMT1), respectively. High-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry was used to detect RECK methylation. In addition, MGC803 cell proliferation was measured by an MTT assay and the DNA-binding activity of transcription factor Sp1 was determined using an enzyme-linked immunosorbent assay. The results demonstrated that treatment with 1, 10 and 30 µmol/l casticin significantly increased RECK protein expression and mRNA levels. In addition, casticin (30 µmol/l) decreased RECK promoter methylation levels by 31%, global DNA methylation levels by 39% and nuclear methylation activity by 71.6%. Furthermore, casticin downregulated the mRNA levels and protein expression of DNMT1. The MTT assay demonstrated that MGC803 cell proliferation was inhibited by casticin treatment and DNA binding assays indicated that casticin reduced the DNA-binding activity of Sp1. The present study therefore indicated that casticin inhibits the proliferation of gastric cancer MGC803 cells by upregulating RECK gene expression and reducing intracellular methylation levels.
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Affiliation(s)
- Fan Yang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China; Department of Basic Medicine, Xiangnan University, Chenzhou, Hunan 423000, P.R. China
| | - Kefei He
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Li Huang
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Lingyan Zhang
- Medical Department of Chongqing Bishan People's Hospital, Chongqing 402760, P.R. China
| | - Aixue Liu
- Department of Oncology, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518000, P.R. China
| | - Jiren Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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Wang Z, Murakami R, Yuki K, Yoshida Y, Noda M. Bioinformatic Studies to Predict MicroRNAs with the Potential of Uncoupling RECK Expression from Epithelial-Mesenchymal Transition in Cancer Cells. Cancer Inform 2016; 15:91-102. [PMID: 27226706 PMCID: PMC4874744 DOI: 10.4137/cin.s34141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 02/24/2016] [Accepted: 03/07/2016] [Indexed: 12/21/2022] Open
Abstract
RECK is downregulated in many tumors, and forced RECK expression in tumor cells often results in suppression of malignant phenotypes. Recent findings suggest that RECK is upregulated after epithelial-mesenchymal transition (EMT) in normal epithelium-derived cells but not in cancer cells. Since several microRNAs (miRs) are known to target RECK mRNA, we hypothesized that certain miR(s) may be involved in this suppression of RECK upregulation after EMT in cancer cells. To test this hypothesis, we used three approaches: (1) text mining to find miRs relevant to EMT in cancer cells, (2) predicting miR targets using four algorithms, and (3) comparing miR-seq data and RECK mRNA data using a novel non-parametric method. These approaches identified the miR-183-96-182 cluster as a strong candidate. We also looked for transcription factors and signaling molecules that may promote cancer EMT, miR-183-96-182 upregulation, and RECK downregulation. Here we describe our methods, findings, and a testable hypothesis on how RECK expression could be regulated in cancer cells after EMT.
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Affiliation(s)
- Zhipeng Wang
- Laboratory for Malignancy Control Research, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryusuke Murakami
- Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kanako Yuki
- Laboratory for Malignancy Control Research, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoko Yoshida
- Laboratory for Malignancy Control Research, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Makoto Noda
- Laboratory for Malignancy Control Research, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; Department of Molecular Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Abd-Elfatah G, Gad-Allah ANAA. RASSF1A, RECK genotypes and haplotypes in Egyptian population with Hepatocellular carcinoma. Immunol Lett 2016; 173:36-41. [PMID: 26921475 DOI: 10.1016/j.imlet.2016.02.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 02/21/2016] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND OBJECTIVES The development of HCC is multifactorial, resulting from the interaction of environmental factors (possibly hepatitis viruses) and host factors (genetic factors). So identification of risk factors that contribute to HCC and thus early diagnosis and therapy is necessary. This study aimed to investigate the role of tumor suppressor genes RASSF1A Ala133Ser and RECK rs11788747polymorphisms and their haplotypes in HCC. SUBJECTS AND METHODS 104 cases of HCC and 100 healthy controls were included in a case-control study. RASSF1A and RECK genotypes, allele and haplotypes were detected by PCR-RFLP. RESULTS Risk of HCC was significantly associated with carriers of A1a/Ser, Ser/Ser, Ser allele and A1a/Ser +GA haplotypes (OR=20.57, p<0.001, OR=7.26, p=0.05, OR=10.64, p<0.001, OR=12.52, p=0.005) respectively. More over RECK GG, G allele and haplotype A1a/A1a+GG were protective to HCC (OR=0.11, p<0.001, & OR=0.53, p=0.001 & OR=0.16, p=0.002) respectively. Also, it was found that RASSF1A gene polymorphism significantly associated with bad pathological features but no association with RECK gene polymorphism. CONCLUSIONS The RASSF1AAla133Ser polymorphism, RECK gene polymorphism and for the first time haplotype of both genes influence molecular carcinogenesis and clinic pathological features of HCC within the Egyptian population.
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Affiliation(s)
- Gehan Abd-Elfatah
- Clinical Pathology Department, Faculty of Medicine, Menoufia University, Egypt.
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26
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Critical roles for murine Reck in the regulation of vascular patterning and stabilization. Sci Rep 2015; 5:17860. [PMID: 26658478 PMCID: PMC4675993 DOI: 10.1038/srep17860] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 10/28/2015] [Indexed: 12/31/2022] Open
Abstract
Extracellular matrix (ECM) is known to play several important roles in vascular development, although the molecular mechanisms behind these remain largely unknown. RECK, a tumor suppressor downregulated in a wide variety of cancers, encodes a membrane-anchored matrix-metalloproteinase-regulator. Mice lacking functional Reck die in utero, demonstrating its importance for mammalian embryogenesis; however, the underlying causes of mid-gestation lethality remain unclear. Using Reck conditional knockout mice, we have now demonstrated that the lack of Reck in vascular mural cells is largely responsible for mid-gestation lethality. Experiments using cultured aortic explants further revealed that Reck is essential for at least two events in sprouting angiogenesis; (1) correct association of mural and endothelial tip cells to the microvessels and (2) maintenance of fibronectin matrix surrounding the vessels. These findings demonstrate the importance of appropriate cell-cell interactions and ECM maintenance for angiogenesis and the involvement of Reck as a critical regulator of these events.
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Gomes LR, Fujita A, Mott JD, Soares FA, Labriola L, Sogayar MC. RECK is not an independent prognostic marker for breast cancer. BMC Cancer 2015; 15:660. [PMID: 26449734 PMCID: PMC4599748 DOI: 10.1186/s12885-015-1666-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 09/30/2015] [Indexed: 12/13/2022] Open
Abstract
Background The REversion-inducing Cysteine-rich protein with Kazal motif (RECK) is a well-known inhibitor of matrix metalloproteinases (MMPs) and cellular invasion. Although high expression levels of RECK have already been correlated with a better clinical outcome for several tumor types, its main function, as well as its potential prognostic value for breast cancer patients, remain unclear. Methods The RECK expression profile was investigated in a panel of human breast cell lines with distinct aggressiveness potential. RECK functional analysis was undertaken using RNA interference methodology. RECK protein levels were also analyzed in 1040 cases of breast cancer using immunohistochemistry and tissue microarrays (TMAs). The association between RECK expression and different clinico-pathological parameters, as well as the overall (OS) and disease-free (DFS) survival rates, were evaluated. Results Higher RECK protein expression levels were detected in more aggressive breast cancer cell lines (T4-2, MDA-MB-231 and Hs578T) than in non-invasive (MCF-7 and T47D) and non-tumorigenic (S1) cell lines. Indeed, silencing RECK in MDA-MB-231 cells resulted in elevated levels of pro-MMP-9 and increased invasion compared with scrambled (control) cells, without any effect on cell proliferation. Surprisingly, by RECK immunoreactivity analysis on TMAs, we found no association between RECK positivity and survival (OS and DFS) in breast cancer patients. Even considering the different tumor subtypes (luminal A, luminal B, Her2 type and basal-like) or lymph node status, RECK remained ineffective for predicting the disease outcome. Moreover, by multivariate Cox regression analysis, we found that RECK has no prognostic impact for OS and DFS, relative to standard clinical variables. Conclusions Although it continues to serve as an invasion and MMP inhibitor in breast cancer, RECK expression analysis is not useful for prognosis of these patients.
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Affiliation(s)
- Luciana R Gomes
- Departamento de Bioquímica, Instituto de Química, and NUCEL/NETCEM (Núcleo de Terapia Celular e Molecular), Faculdade de Medicina, Departamento de Clínica Médica, Universidade de São Paulo, Rua Pangaré, 100, São Paulo, 05360-130, SP, Brazil.
| | - André Fujita
- Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brazil.
| | - Joni D Mott
- Lawrence Berkeley National Laboratory, Life Science Division, Berkeley, CA, USA.
| | - Fernando A Soares
- Departamento de Anatomia Patológica, Hospital A. C. Camargo, Fundação Antônio Prudente, São Paulo, SP, Brazil.
| | - Leticia Labriola
- Departamento de Bioquímica, Instituto de Química, and NUCEL/NETCEM (Núcleo de Terapia Celular e Molecular), Faculdade de Medicina, Departamento de Clínica Médica, Universidade de São Paulo, Rua Pangaré, 100, São Paulo, 05360-130, SP, Brazil.
| | - Mari C Sogayar
- Departamento de Bioquímica, Instituto de Química, and NUCEL/NETCEM (Núcleo de Terapia Celular e Molecular), Faculdade de Medicina, Departamento de Clínica Médica, Universidade de São Paulo, Rua Pangaré, 100, São Paulo, 05360-130, SP, Brazil.
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Liu W, Song N, Yao H, Zhao L, Liu H, Li G. miR-221 and miR-222 Simultaneously Target RECK and Regulate Growth and Invasion of Gastric Cancer Cells. MEDICAL SCIENCE MONITOR : INTERNATIONAL MEDICAL JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2015. [PMID: 26364844 DOI: 10.12659/msm.89432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Although Helicobacter pylori infection is necessary for development of gastric adenocarcinoma (GAC), the underlying mechanism remains poorly defined. This study aimed to explore how miR-221 and miR-222 are dysregulated after H. pylori infection and how these 2 miRNAs are involved in pathological development of gastric cancer. MATERIAL AND METHODS qRT-PCR analysis was performed to quantify miR-221 and miR-222 expression in patients with H. pylori - induced chronic gastritis, H. pylori-negative healthy controls, and in gastric cancer tissues and the corresponding adjacent normal tissues. Cell models were used to verify the expression profile. Dual luciferase assay was performed to verify putative binding between miR-221 or miR-222 and RECK. A loss-and-gain function study was performed to assess the miR-221/miR-222-RECK axis in gastric cancer cells. RESULTS H. pylori infection leads to significantly higher miR-221 and miR-222 expression. MiR-221 and miR-222 can bind the same sequence of RECK 3'UTR, thereby modulating its expression. Through simultaneous regulation over RECK, miR-221 and miR-222 can promote gastric cancer cell growth and invasion. CONCLUSIONS The miR-221/miR-222-RECK axis might be an important path modulating H. pylori infection-related gastric cancer development.
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Affiliation(s)
- Wenneng Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (mainland)
| | - Nian Song
- Department of General Surgery, The First People's Hospital of Chengdu, Chengdu, Sichuan, China (mainland)
| | - Huihua Yao
- Department of General Surgery, The First People's Hospital of Chengdu, Chengdu, Sichuan, China (mainland)
| | - Liying Zhao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (mainland)
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (mainland)
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (mainland)
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Liu W, Song N, Yao H, Zhao L, Liu H, Li G. miR-221 and miR-222 Simultaneously Target RECK and Regulate Growth and Invasion of Gastric Cancer Cells. Med Sci Monit 2015; 21:2718-2725. [PMID: 26364844 PMCID: PMC4576921 DOI: 10.12659/msm.894324] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 05/28/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although Helicobacter pylori infection is necessary for development of gastric adenocarcinoma (GAC), the underlying mechanism remains poorly defined. This study aimed to explore how miR-221 and miR-222 are dysregulated after H. pylori infection and how these 2 miRNAs are involved in pathological development of gastric cancer. MATERIAL AND METHODS qRT-PCR analysis was performed to quantify miR-221 and miR-222 expression in patients with H. pylori - induced chronic gastritis, H. pylori-negative healthy controls, and in gastric cancer tissues and the corresponding adjacent normal tissues. Cell models were used to verify the expression profile. Dual luciferase assay was performed to verify putative binding between miR-221 or miR-222 and RECK. A loss-and-gain function study was performed to assess the miR-221/miR-222-RECK axis in gastric cancer cells. RESULTS H. pylori infection leads to significantly higher miR-221 and miR-222 expression. MiR-221 and miR-222 can bind the same sequence of RECK 3'UTR, thereby modulating its expression. Through simultaneous regulation over RECK, miR-221 and miR-222 can promote gastric cancer cell growth and invasion. CONCLUSIONS The miR-221/miR-222-RECK axis might be an important path modulating H. pylori infection-related gastric cancer development.
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Affiliation(s)
- Wenneng Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Department of General Surgery, The First People’s Hospital of Chengdu, Chengdu, Sichuan, P.R. China
| | - Nian Song
- Department of General Surgery, The First People’s Hospital of Chengdu, Chengdu, Sichuan, P.R. China
| | - Huihua Yao
- Department of General Surgery, The First People’s Hospital of Chengdu, Chengdu, Sichuan, P.R. China
| | - Liying Zhao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
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Pan Y, Wang L, Kang SG, Lu Y, Yang Z, Huynh T, Chen C, Zhou R, Guo M, Zhao Y. Gd-Metallofullerenol Nanomaterial Suppresses Pancreatic Cancer Metastasis by Inhibiting the Interaction of Histone Deacetylase 1 and Metastasis-Associated Protein 1. ACS NANO 2015; 9:6826-36. [PMID: 26083726 DOI: 10.1021/nn506782f] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The treatment of pancreatic cancer frequently fails due to local recurrence and hepatic metastasis. Our previous study found that Gd@C82(OH)22 can suppress pancreatic cancer by inhibiting MMP-2/9 expression. In this study, we further explored the epigenetic mechanism of Gd@C82(OH)22 in human pancreatic cancer metastasis. Gd@C82(OH)22 suppressed tumor metastasis through down-regulation of metastasis-associated protein 1 (MTA1), HDAC1, HIF-1α, and MMP-2/9 and up-regulation of reversion-cysteine protein with the Kazal motif (RECK). The level of acetylation was increased in the promoter region of the RECK gene after Gd@C82(OH)22 treatment. The interaction of MTA1, HDAC1, and HIF-1α was inhibited by Gd@C82(OH)22. Furthermore, large-scale molecular dynamics simulations revealed Gd@C82(OH)22 could serve as an effective HDAC inhibitor to the protein-protein association between HDAC1 and MTA1, especially through MTA1's SANT and ELM2 dimerization domains. Our findings implicate Gd@C82(OH)22 as a novel HDAC inhibitor acting to increase RECK expression by suppressing the MTA1/HDAC1 co-repressor complex. Gd@C82(OH)22 may serve as a potential HDAC1 inhibitor to suppress pancreatic cancer cell invasion and metastasis both in vitro and in vivo. According to computer analysis and experimental validation, Gd@C82(OH)22 activates RECK expression by inhibiting the interaction of HDAC1 and MTA1.
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Affiliation(s)
| | - Liming Wang
- ‡CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology and Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100190, China
| | - Seung-gu Kang
- §Computational Biology Center, IBM Thomas J. Watson Research Center,1101 Kitchawan Road, Yorktown Heights, New York 10598, United States
| | | | - Zaixing Yang
- ⊥Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Soochow University, Suzhou 215123, China
| | - Tien Huynh
- §Computational Biology Center, IBM Thomas J. Watson Research Center,1101 Kitchawan Road, Yorktown Heights, New York 10598, United States
| | - Chunying Chen
- ‡CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology and Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100190, China
| | - Ruhong Zhou
- §Computational Biology Center, IBM Thomas J. Watson Research Center,1101 Kitchawan Road, Yorktown Heights, New York 10598, United States
- ⊥Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Soochow University, Suzhou 215123, China
| | | | - Yuliang Zhao
- ‡CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology and Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100190, China
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The S100P/RAGE signaling pathway regulates expression of microRNA-21 in colon cancer cells. FEBS Lett 2015; 589:2388-93. [PMID: 26193421 DOI: 10.1016/j.febslet.2015.07.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 06/30/2015] [Accepted: 07/07/2015] [Indexed: 12/28/2022]
Abstract
S100P signaling through the receptor for advanced glycation end-products (RAGE) contributes to colon cancer invasion and metastasis, but the mechanistic features of this process are obscure. Here, we investigate whether activation of S100P/RAGE signaling regulates oncogenic microRNA-21 (miR-21). We show that exogenous S100P up-regulates miR-21 levels in human colon cancer cells, whereas knockdown of S100P results in a decrease of miR-21. Furthermore, blockage of RAGE with anti-RAGE antibody suppresses S100P induction of miR-21. In addition, we found that S100P induction of miR-21 expression involves ERK and is suppressed by the MEK inhibitor U0126. Also, S100P treatment stimulates the enrichment of c-Fos, and AP-1 family members, at the miR-21 gene promoter.
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32
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Chiou YH, Liou SH, Wong RH, Chen CY, Lee H. Nickel may contribute to EGFR mutation and synergistically promotes tumor invasion in EGFR-mutated lung cancer via nickel-induced microRNA-21 expression. Toxicol Lett 2015; 237:46-54. [PMID: 26026961 DOI: 10.1016/j.toxlet.2015.05.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 05/20/2015] [Accepted: 05/25/2015] [Indexed: 02/08/2023]
Abstract
We recently reported that nickel accumulation in lung tissues may be associated with an increased in p53 mutation risk via reduced DNA repair activity. Here, we hypothesized that nickel accumulation in lung tissues could contribute to EGFR mutations in never-smokers with lung cancer. We enrolled 76 never-smoking patients to evaluate nickel level in adjacent normal lung tissues by ICP-MS. The prevalence of EGFR mutations was significantly higher in the high-nickel subgroup than in the low-nickel subgroup. Intriguingly, the OR for the occurrence of EGFR mutations in female, adenocarcinoma, and female adenocarcinoma patients was higher than that of all patients. Mechanistically, SPRY2 and RECK expressions were decreased by nickel-induced miR-21 via activation of the EGFR/NF-κB signaling pathway, which promoted invasiveness in lung cancer cells, and particularly in the cells with EGFR L858R expression vector transfection. The patients' nickel levels were associated with miR-21 expression levels. Kaplan-Meier analysis revealed poorer overall survival (OS) and shorter relapse free survival (RFS) in the high-nickel subgroup than in low-nickel subgroup. The high-nickel/high-miR-21 subgroup had shorter OS and RFS periods when compared to the low-nickel/low-miR-21 subgroup. Our findings support previous epidemiological studies indicating that nickel exposure may not only contribute to cancer incidence but also promote tumor invasion in lung cancer.
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Affiliation(s)
- Yu-Hu Chiou
- Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Saou-Hsing Liou
- Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Miaoli, Taiwan, ROC
| | - Ruey-Hong Wong
- School of Public Health, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Chih-Yi Chen
- Department of Surgery, Chung Shan Medical University, Taichung, Taiwan, ROC
| | - Huei Lee
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC.
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Pézeron G, Millen K, Boukhatmi H, Bray S. Notch directly regulates the cell morphogenesis genes Reck, talin and trio in adult muscle progenitors. J Cell Sci 2014; 127:4634-44. [PMID: 25217625 DOI: 10.1242/jcs.151787] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
There is growing evidence that activation of the Notch pathway can result in consequences on cell morphogenesis and behaviour, both during embryonic development and cancer progression. In general, Notch is proposed to coordinate these processes by regulating expression of key transcription factors. However, many Notch-regulated genes identified in genome-wide studies are involved in fundamental aspects of cell behaviour, suggesting a more direct influence on cellular properties. By testing the functions of 25 such genes we confirmed that 12 are required in developing adult muscles, consistent with roles downstream of Notch. Focusing on three, Reck, rhea/talin and trio, we verify their expression in adult muscle progenitors and identify Notch-regulated enhancers in each. Full activity of these enhancers requires functional binding sites for Su(H), the DNA-binding transcription factor in the Notch pathway, validating their direct regulation. Thus, besides its well-known roles in regulating the expression of cell-fate-determining transcription factors, Notch signalling also has the potential to directly affect cell morphology and behaviour by modulating expression of genes such as Reck, rhea/talin and trio. This sheds new light on the functional outputs of Notch activation in morphogenetic processes.
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Affiliation(s)
- Guillaume Pézeron
- Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
| | - Kat Millen
- Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
| | - Hadi Boukhatmi
- Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
| | - Sarah Bray
- Department of Physiology Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
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Prasad NB, Fischer AC, Chuang AY, Wright JM, Yang T, Tsai HL, Westra WH, Liegeois NJ, Hess AD, Tufaro AP. Differential expression of degradome components in cutaneous squamous cell carcinomas. Mod Pathol 2014; 27:945-57. [PMID: 24356192 PMCID: PMC4251465 DOI: 10.1038/modpathol.2013.217] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 10/25/2013] [Indexed: 12/16/2022]
Abstract
Although the cure rate for cutaneous squamous cell carcinoma is high, the diverse spectrum of squamous cell carcinoma has made it difficult for early diagnosis, particularly the aggressive tumors that are highly associated with mortality. Therefore, molecular markers are needed as an adjunct to current staging methods for diagnosing high-risk lesions, and stratifying those patients with aggressive tumors. To identify such biomarkers, we have examined a comprehensive set of 200 histologically defined squamous cell carcinoma and normal skin samples by using a combination of microarray, QRT-PCR and immunohistochemistry analyses. A characteristic and distinguishable profile including matrix metalloproteinase (MMP) as well as other degradome components was differentially expressed in squamous cell carcinoma compared with normal skin samples. The expression levels of some of these genes including matrix metallopeptidase 1 (MMP1), matrix metallopeptidase 10 (MMP10), parathyroid hormone-like hormone (PTHLH), cyclin-dependent kinase inhibitor 2A (CDKN2A), A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), FBJ osteosarcoma oncogene (FOS), interleukin 6 (IL6) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) were significantly differentially expressed (P≤0.02) in squamous cell carcinoma compared with normal skin. Furthermore, based on receiver operating characteristic analyses, the mRNA and protein levels of MMP1 are significantly higher in aggressive tumors compared with non-aggressive tumors. Given that MMPs represent the most prominent family of proteinases associated with tumorigenesis, we believe that they may have an important role in modulating the tumor microenvironment of squamous cell carcinoma.
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Affiliation(s)
- Nijaguna B Prasad
- Department of Plastic and Reconstructive Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anne C Fischer
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Alice Y Chuang
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jerry M Wright
- Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ting Yang
- Department of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hua-Ling Tsai
- Department of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - William H Westra
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Allan D Hess
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anthony P Tufaro
- Department of Plastic and Reconstructive Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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SIDDESHA JALAHALLIM, VALENTE ANTHONYJ, SAKAMURI SIVAS, GARDNER JASOND, DELAFONTAINE PATRICE, NODA MAKOTO, CHANDRASEKAR BYSANI. Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK. J Cell Physiol 2014; 229:845-55. [PMID: 24265116 PMCID: PMC4408083 DOI: 10.1002/jcp.24511] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 11/18/2013] [Indexed: 01/01/2023]
Abstract
The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H(2)O(2) generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H(2)O(2) generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms.
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Affiliation(s)
- JALAHALLI M. SIDDESHA
- Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana
| | - ANTHONY J. VALENTE
- Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, Texas
| | - SIVA S.V.P. SAKAMURI
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana
| | - JASON D. GARDNER
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - PATRICE DELAFONTAINE
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana
| | - MAKOTO NODA
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - BYSANI CHANDRASEKAR
- Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana
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EMMPRIN reduction via scFv-M6-1B9 intrabody affects α3β1-integrin and MCT1 functions and results in suppression of progressive phenotype in the colorectal cancer cell line Caco-2. Cancer Gene Ther 2014; 21:246-55. [DOI: 10.1038/cgt.2014.24] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 04/30/2014] [Accepted: 04/30/2014] [Indexed: 12/15/2022]
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Viral oncolysis - can insights from measles be transferred to canine distemper virus? Viruses 2014; 6:2340-75. [PMID: 24921409 PMCID: PMC4074931 DOI: 10.3390/v6062340] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 06/03/2014] [Accepted: 06/04/2014] [Indexed: 12/12/2022] Open
Abstract
Neoplastic diseases represent one of the most common causes of death among humans and animals. Currently available and applied therapeutic options often remain insufficient and unsatisfactory, therefore new and innovative strategies and approaches are highly needed. Periodically, oncolytic viruses have been in the center of interest since the first anecdotal description of their potential usefulness as an anti-tumor treatment concept. Though first reports referred to an incidental measles virus infection causing tumor regression in a patient suffering from lymphoma several decades ago, no final treatment concept has been developed since then. However, numerous viruses, such as herpes-, adeno- and paramyxoviruses, have been investigated, characterized, and modified with the aim to generate a new anti-cancer treatment option. Among the different viruses, measles virus still represents a highly interesting candidate for such an approach. Numerous different tumors of humans including malignant lymphoma, lung and colorectal adenocarcinoma, mesothelioma, and ovarian cancer, have been studied in vitro and in vivo as potential targets. Moreover, several concepts using different virus preparations are now in clinical trials in humans and may proceed to a new treatment option. Surprisingly, only few studies have investigated viral oncolysis in veterinary medicine. The close relationship between measles virus (MV) and canine distemper virus (CDV), both are morbilliviruses, and the fact that numerous tumors in dogs exhibit similarities to their human counterpart, indicates that both the virus and species dog represent a highly interesting translational model for future research in viral oncolysis. Several recent studies support such an assumption. It is therefore the aim of the present communication to outline the mechanisms of morbillivirus-mediated oncolysis and to stimulate further research in this potentially expanding field of viral oncolysis in a highly suitable translational animal model for the benefit of humans and dogs.
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Lee YM, Lee SH, Lee KB, Nguyen MP, Lee MY, Park GH, Kwon MJ. Silencing of reversion-inducing cysteine-rich protein with Kazal motifs stimulates hyperplastic phenotypes through activation of epidermal growth factor receptor and hypoxia-inducible factor-2α. PLoS One 2013; 8:e84520. [PMID: 24376819 PMCID: PMC3869844 DOI: 10.1371/journal.pone.0084520] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 11/14/2013] [Indexed: 01/16/2023] Open
Abstract
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK, a tumor suppressor) is down-regulated by the oncogenic signals and hypoxia, but the biological function of RECK in early tumorigenic hyperplastic phenotypes is largely unknown. Knockdown of RECK by small interfering RNA (siRECK) or hypoxia significantly promoted cell proliferation in various normal epithelial cells. Hypoxia as well as knockdown of RECK by siRNA increased the cell cycle progression, the levels of cyclin D1 and c-Myc, and the phosphorylation of Rb protein (p-pRb), but decreased the expression of p21cip1, p27kip1, and p16ink4A. HIF-2α was upregulated by knockdown of RECK, indicating HIF-2α is a downstream target of RECK. As knockdown of RECK induced the activation of epidermal growth factor receptor (EGFR) and treatment of an EGFR kinase inhibitor, gefitinib, suppressed HIF-2α expression induced by the silencing of RECK, we can suggest that the RECK silenicng-EGFR-HIF-2α axis might be a key molecular mechanism to induce hyperplastic phenotype of epithelial cells. It was also found that shRNA of RECK induced larger and more numerous colonies than control cells in an anchorage-independent colony formation assay. Using a xenograft assay, epithelial cells with stably transfected with shRNA of RECK formed a solid mass earlier and larger than those with control cells in nude mice. In conclusion, the suppression of RECK may promote the development of early tumorigenic hyperplastic characteristics in hypoxic stress.
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Affiliation(s)
- You Mie Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
- * E-mail:
| | - Sun-Hee Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
| | - Kheun Byeol Lee
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
| | - Minh Phuong Nguyen
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
- School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea
| | - Min-Young Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Gyu Hwan Park
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
| | - Mi Jeong Kwon
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
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Siddesha JM, Valente AJ, Sakamuri SS, Yoshida T, Gardner JD, Somanna N, Takahashi C, Noda M, Chandrasekar B. Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK. J Mol Cell Cardiol 2013; 65:9-18. [PMID: 24095877 PMCID: PMC3896127 DOI: 10.1016/j.yjmcc.2013.09.015] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/17/2013] [Accepted: 09/24/2013] [Indexed: 11/16/2022]
Abstract
Sustained induction and activation of matrixins (matrix metalloproteinases or MMPs), and the destruction and deposition of extracellular matrix (ECM), are the hallmarks of cardiac fibrosis. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is a unique membrane-anchored endogenous MMP regulator. We hypothesized that elevated angiotensin II (Ang II), which is associated with fibrosis in the heart, differentially regulates MMPs and RECK both in vivo and in vitro. Continuous infusion of Ang II into male C57Bl/6 mice for 2weeks resulted in cardiac fibrosis, with increased expressions of MMPs 2, 7, 9 and 14, and of collagens Ia1 and IIIa1. The expression of RECK, however, was markedly suppressed. These effects were inhibited by co-treatment with the Ang II type 1 receptor (AT1) antagonist losartan. In vitro, Ang II suppressed RECK expression in adult mouse cardiac fibroblasts (CF) via AT1/Nox4-dependent ERK/Sp1 activation, but induced MMPs 2, 14 and 9 via NF-κB, AP-1 and/or Sp1 activation. Further, while forced expression of RECK inhibits, its knockdown potentiates Ang II-induced CF migration. Notably, RECK overexpression reduced Ang II-induced MMPs 2, 9 and 14 activation, but enhanced collagens Ia1 and IIIa1 expression and soluble collagen release. These results demonstrate for the first time that Ang II suppresses RECK, but induces MMPs both in vivo and in vitro, and RECK overexpression blunts Ang II-induced MMP activation and CF migration in vitro. Strategies that upregulate RECK expression in vivo have the potential to attenuate sustained MMP expression, and blunt fibrosis and adverse remodeling in hypertensive heart diseases.
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Affiliation(s)
- Jalahalli M. Siddesha
- Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112
| | - Anthony J. Valente
- Medicine, University of Texas Health Science Center, San Antonio, TX 78229
| | | | - Tadashi Yoshida
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112
| | - Jason D. Gardner
- Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112
| | - Naveen Somanna
- Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112
| | - Chiaki Takahashi
- Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Makoto Noda
- Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan
| | - Bysani Chandrasekar
- Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112
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Chen Y, Tsai YH, Tseng SH. RECK regulated endoplasmic reticulum stress response and enhanced cisplatin-induced cell death in neuroblastoma cells. Surgery 2013; 154:968-79. [DOI: 10.1016/j.surg.2013.05.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Accepted: 05/16/2013] [Indexed: 10/26/2022]
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Khoi PN, Park JS, Kim JH, Xia Y, Kim NH, Kim KK, Jung YD. (-)-Epigallocatechin-3-gallate blocks nicotine-induced matrix metalloproteinase-9 expression and invasiveness via suppression of NF-κB and AP-1 in endothelial cells. Int J Oncol 2013; 43:868-76. [PMID: 23835612 DOI: 10.3892/ijo.2013.2006] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 06/17/2013] [Indexed: 11/05/2022] Open
Abstract
Cigarette smoke, specifically the nicotine contained within, has been shown to correlate closely with cell invasion and strategies to downregulate their expression may ultimately be of clinical utility. Matrix metalloproteinase-9 (MMP-9) is critically involved in the cell invasion and metastasis processes. Since nicotine plays a crucial role in the regulation of MMP-9 expression, the investigation of plant-derived compounds capable of modulating nicotine-induced signaling is an issue of concern. In this study, the effects of (-)-epigallocatechin-3-gallate (EGCG), a major green tea catechin, on nicotine-induced cell invasion and MMP-9 activity in ECV304 human endothelial cells were examined. EGCG treatment was found to reduce the MMP-9 expression and transcriptional activity in a dose-dependent manner. EGCG inhibited nicotine-activated production of reactive oxygen species (ROS), which are known as important signaling molecules to activate MMP-9. To further study the mechanisms for the EGCG-mediated regulation of MMP-9, the transcription factors NF-κB and AP-1 activities were examined. EGCG suppressed the nicotine-induced NF-κB and AP-1 activation. Studies with expression vectors encoding mutated NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the nicotine-stimulated MMP-9 expression. EGCG also abrogated the nicotine-induced activation of AP-1 subunits c-fos and c-jun. The above studies demonstrate that EGCG may exert at least part of its anti-invasive effect in ECV304 human endothelial cells by controlling MMP-9 expression through the suppression of ROS, NF-κB and AP-1.
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Affiliation(s)
- Pham Ngoc Khoi
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea
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Lin HY, Chiang CH, Hung WC. STAT3 upregulates miR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells. Br J Cancer 2013; 109:731-8. [PMID: 23820254 PMCID: PMC3738132 DOI: 10.1038/bjc.2013.349] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 06/10/2013] [Accepted: 06/13/2013] [Indexed: 12/19/2022] Open
Abstract
Background: Signal transducer and activator of transcription 3 (STAT3) activation is frequently found in human lung cancer and is associated with increased metastasis and reduced survival. How STAT3 enhances invasiveness is unclear. Methods: The expression of microRNAs and target genes was measured by real-time RT–PCR. Protein level was studied by western blotting. Luciferase reporter assay was used to confirm the direct targeting of microRNAs. Gelatin zymography was used to study matrix metalloproteinase (MMP) activity. Transwell assay was used to investigate cell migration and invasion. Results: Enforced expression of STAT3 decreases the endogenous MMP inhibitor RECK protein but not mRNA level in H460 cells. Conversely, STAT3 inhibitor S3I-201 increases RECK protein in STAT3-activating H1299 cells. We demonstrate that STAT3 upregulates miR-92a to repress RECK via post-transcriptional inhibition. The RECK 3′-untranslated region (3′UTR) reporter activity assay suggests that RECK is a direct repression target of miR-92a. Delivery of pre-miR-92a reduces RECK protein level whereas transfection of anti-miR-92a restores STAT3-induced downregulation of RECK. Anti-miR-92a attenuates MMP activity, migration and invasion of H1299 cells and STAT3-overexpressing H460 cells, suggesting miR-92a is critical for STAT3-induced invasiveness. Conclusion: The STAT3-induced miR-92a promotes cancer invasion by suppressing RECK and targeting of the STAT3/miR-92a axis may be helpful for cancer treatment.
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Affiliation(s)
- H-Y Lin
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Lu XX, Zhang SM, Fang Y, Wang ZT, Xie JJ, Zhan Q, Deng XX, Chen H, Jin JB, Peng CH, Li HW, Shen BY. Clinical significance of RECK promoter methylation in pancreatic ductal adenocarcinoma. Tumour Biol 2013; 34:3339-43. [PMID: 23749490 DOI: 10.1007/s13277-013-0903-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 05/27/2013] [Indexed: 12/23/2022] Open
Abstract
The aim of this study was to analyze the clinical significance of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) promoter methylation in pancreatic ductal adenocarcinoma (PDA). Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of RECK in 60 pairs of PDA tissue samples and adjacent non-cancerous tissue samples. Statistical analyses were applied to test the associations between RECK promoter methylation status, clinicopathologic factors, and prognosis. The rate of RECK promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (P < 0.001). RECK methylation status was significantly associated with clinical stage (P = 0.017), histological differentiation (P = 0.046), and lymph node metastasis (P = 0.003), but was not associated with gender, age, and tumor location (all P > 0.05). Additionally, RECK promoter methylation is associated with malignant behavior and poor prognosis. In conclusion, determination of RECK promoter methylation status in tumor tissues may assist in the identification of patients who require aggressive postoperative intervention in order to improve prognosis.
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Affiliation(s)
- Xiong-Xiong Lu
- Center of Organ Transplantation, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, No. 197, Ruijiner Road, Shanghai, 200025, China
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Zhou L, Yang ZX, Song WJ, Li QJ, Yang F, Wang DS, Zhang N, Dou KF. MicroRNA-21 regulates the migration and invasion of a stem-like population in hepatocellular carcinoma. Int J Oncol 2013; 43:661-9. [PMID: 23708209 DOI: 10.3892/ijo.2013.1965] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 03/01/2013] [Indexed: 12/23/2022] Open
Abstract
Due to invasion and intrahepatic metastasis, the prognosis for patients with hepatocellular carcinoma (HCC) is poor. However, the mechanisms underlying these processes of HCC remain unclear. Cancer stem cells may be involved in early systemic dissemination and metastasis formation and side population (SP) cells isolated from diverse cancer cells possess stem cell-like properties. However, the mechanisms involved in migration and invasion of cancer stem cells are not well understood. In this study, we identified and isolated populations of SP cells from HCC cell lines using flow cyto-metry. SP cells showed higher levels of migration and invasion capability. Higher expression of miR-21 was observed in SP cells. Silencing of miR-21 led to a reduction in the migration and invasion of these cells and overexpression of miR-21 can increase in cell migration and invasion. Overexpression of miR-21 did not cause degradation of PTEN or RECK or PDCD4 mRNA but drastically inhibited its protein expression. Consistent with these results, silencing miR-21 increased the levels of PTEN, RECK and PDCD4 protein, respectively. The role of silencing miR-21 was partially attenuated by silencing of PTEN or RECK or PDCD4 mRNA. The results of this study revealed the aberrant expression of miR-21 in SP cells and showed that miR-21 regulates the expression of multiple target proteins that are associated with tumor dissemination. MiR-21 is a pro-metastatic miRNA in SP cells and raises the possibility that therapy of HCC may be improved by pharmaceutical strategies directed towards miR-21.
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Affiliation(s)
- Liang Zhou
- Department of General Surgery, The 155 Central Hospital of PLA, Kaifeng, He'nan 471000, PR China
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Feng X, Li C, Liu W, Chen H, Zhou W, Wang L, Zhu B, Yao K, Jiang X, Ren C. DLC-1, a candidate tumor suppressor gene, inhibits the proliferation, migration and tumorigenicity of human nasopharyngeal carcinoma cells. Int J Oncol 2013; 42:1973-84. [PMID: 23588806 DOI: 10.3892/ijo.2013.1885] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Accepted: 02/25/2013] [Indexed: 11/06/2022] Open
Abstract
In our previous study we demonstrated the downregulation or loss of deleted in liver cancer‑1 (DLC-1) gene expression in nasopharyngeal carcinoma (NPC). In this study, we report the effects of the DLC-1 gene on NPC cells and its mechanisms of action. DLC-1 expression was restored in the 5-8F NPC cell line, which lacks DLC-1 expression, and the biological characteristics of 5-8F-DLC‑1 cells were analyzed by MTT assay, colony formation assay, flow cytometry (FCM), tumorigenesis analysis in nude mice, as well as invasion and migration assay. Differentially expressed genes in response to DLC-1 expression were screened using microarray analysis and identified by RT-PCR. The re-expression of DLC-1 in the NPC cells attenuated the proliferation and colony formation ability of the cells in vitro, blocked NPC cells at the G0/G1 phase, reduced tumorigenicity potential in vivo, inhibited the invasion and migration ability of NPC cells and resulted in the reorganization of the actin cytoskeleton. DLC-1 altered the gene expression profile in 5-8F cells. Some tumor suppressor genes (TSGs) were upregulated and some oncogenes were downregulated. These results demonstrate that DLC-1 gene can partially reverse the malignant phenotype of NPC cells by changing the tumor-related gene expression profile, and may be a candidate tumor suppressor gene and a promising diagnostic and therapeutic target in NPC.
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Affiliation(s)
- Xiangling Feng
- Cancer Research Institute, Xiang-Ya School of Medicine, Central South University, Key Laboratory for Carcinogenesis of Chinese Ministry of Health, Key Laboratory for Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Changsha, Hunan 410078, P.R. China
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Chiang CH, Hou MF, Hung WC. Up-regulation of miR-182 by β-catenin in breast cancer increases tumorigenicity and invasiveness by targeting the matrix metalloproteinase inhibitor RECK. Biochim Biophys Acta Gen Subj 2013; 1830:3067-76. [PMID: 23333633 DOI: 10.1016/j.bbagen.2013.01.009] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Revised: 01/08/2013] [Accepted: 01/09/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND MiR-182 is a member of the miR-183 cluster located at human chromosome 7q32 region and is up-regulated in human cancers. We study the regulation of miR-182 expression and its oncogenic role. METHODS MiR-182 level was investigated by real-time reverse transcription-PCR. Chromatin immunoprecipitation assay was used to confirm promoter binding of transcription factors. The correlation between miR-182 and RECK was analyzed by Western blotting, real-time RT-PCR and 3(')-untranslated region reporter assay. Zymography, matrix metalloproteinase activity, invasion and colony formation were used to study the tumorigenic activity. RESULTS MiR-182 is over-expressed in human breast tumor tissues and cell lines. Inhibition or knockdown of β-catenin reduced miR-182 level in MDA-MB-231 cells. ChIP assay confirmed the binding of β-catenin on miR-182 promoter. Anti-miR-182 increased the MMP inhibitor RECK protein in MDA-MB-231 cells while pre-miR-182 reduced RECK protein but not mRNA in normal mammary epithelial H184B5F5/M10 cells. Restoration of RECK protein by anti-miR-182 attenuated MMP-9 activity, cell invasion and colony formation. Ectopic expression of miR-182 inhibited restoration of RECK protein by β-catenin inhibitor indicating miR-182 is important for β-catenin-induced down-regulation of RECK. An inverse association between miR-182 and RECK was demonstrated in breast tumor tissues. CONCLUSIONS We provide evidence that miR-182 is up-regulated by β-catenin signaling pathway in breast cancer and its up-regulation increases tumorigenicity and invasiveness by repressing RECK. GENERAL SIGNIFICANCE Our data demonstrate for the first time that miR-182 expression is controlled by β-catenin. In addition, we identify a new miR-182 target RECK which is important for miR-182-induced tumorigenesis.
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Affiliation(s)
- Chi-Hsiang Chiang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
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Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer. PLoS One 2012; 7:e51056. [PMID: 23226455 PMCID: PMC3511415 DOI: 10.1371/journal.pone.0051056] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 10/29/2012] [Indexed: 12/16/2022] Open
Abstract
Onco-miR-182-5p has been reported to be over-expressed in bladder cancer (BC) tissues however a detailed functional analysis of miR-182-5p has not been carried out in BC. Therefore the purpose of this study was to: 1. conduct a functional analysis of miR-182-5p in bladder cancer, 2. assess its usefulness as a tumor marker, 3. identify miR-182-5p target genes in BC. Initially we found that miR-182-5p expression was significantly higher in bladder cancer compared to normal tissues and high miR-182-5p expression was associated with shorter overall survival in BC patients. To study the functional significance of miR-182-5p, we over-expressed miR-182-5p with miR-182-5p precursor and observed that cell proliferation, migration and invasion abilities were increased in BC cells. However cell apoptosis was inhibited by miR-182-5p. We also identified Smad4 and RECK as potential target genes of miR-182-5p using several algorithms. 3′UTR luciferase activity of these target genes was significantly decreased and protein expression of these target genes was significantly up-regulated in miR-182-5p inhibitor transfected bladder cancer cells. MiR-182-5p also increased nuclear beta-catenin expression and while Smad4 repressed nuclear beta-catenin expression. In conclusion, our data suggests that miR-182-5p plays an important role as an oncogene by knocking down RECK and Smad4, resulting in activation of the Wnt-beta-catenin signaling pathway in bladder cancer.
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Kunz M, Dannemann M, Kelso J. High-throughput sequencing of the melanoma genome. Exp Dermatol 2012; 22:10-7. [PMID: 23174022 DOI: 10.1111/exd.12054] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2012] [Indexed: 12/16/2022]
Abstract
Next-generation sequencing technologies are now common for whole-genome, whole-exome and whole-transcriptome sequencing (RNA-seq) of tumors to identify point mutations, structural or copy number alterations and changes in gene expression. A substantial number of studies have already been performed for melanoma. One study analysed eight melanoma cell lines with RNA-Seq technology and identified 11 novel melanoma gene fusions. Whole-exome sequencing of seven melanoma cell lines identified overlapping gain of function mutations in MAP2K1 (MEK1) and MAP2K2 (MEK2) genes. Integrative sequencing of cutaneous melanoma metastases using different sequencing platforms revealed a new somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C (a CDK4 inhibitor). These latter sequencing-based discoveries may be used to motivate the inclusion of the affected patients into clinical trials with specific signalling pathway inhibitors. Taken together, we are at the beginning of an era with new sequencing technologies providing a more comprehensive view of cancer mutational landscapes and hereby a better understanding of their pathogenesis. This will also open interesting perspectives for new treatment approaches and clinical trial designs.
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Affiliation(s)
- Manfred Kunz
- Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig, Germany.
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Eve HE, Carey S, Richardson SJ, Heise CC, Mamidipudi V, Shi T, Radford JA, Auer RL, Bullard SH, Rule SAJ. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br J Haematol 2012; 159:154-63. [PMID: 22881386 DOI: 10.1111/bjh.12008] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Accepted: 06/30/2012] [Indexed: 12/15/2022]
Abstract
We present data from a phase II study investigating a novel treatment strategy for relapsed/refractory mantle cell lymphoma (MCL). Twenty-six patients received lenalidomide 25 mg/d (days 1-21 of a 28-d cycle) for up to 6 cycles followed by low-dose maintenance lenalidomide (15 mg) in responding patients. Eight patients achieved complete or partial response to give an overall response rate of 31% with median response duration of 22·2 months [95% confidence interval (CI) 0·0-53·6] and median progression-free survival (PFS) of 3·9 months (95% CI 0·0-11·1). An additional six patients (23%) achieved stable disease. Eleven patients received maintenance with median PFS of 14·6 months (95% CI 7·3-21·9). Correlative studies showed that peripheral T and Natural Killer (NK) cells increased in responding patients by 40-60% over the first 6 cycles with an initial dip in NK cells suggestive of tumour infiltration. Peripheral regulatory T cells were increased in MCL patients (P = 0·001) and expanded further following lenalidomide. Sequential plasma analysis showed increased IL12 p40 and IL7 alongside decreased MMP9, IL10, and adiponectin. Finally, a significant correlation (P = 0·02) between gender and response suggested that female MCL patients were more sensitive to lenalidomide than males. In summary, we confirm the activity, safety and immunomodulatory properties of lenalidomide in MCL and highlight its potential as a low-dose maintenance agent.
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Affiliation(s)
- Heather E Eve
- Department of Haematology, Derriford Hospital, Plymouth, UK.
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Zhang X, Healy C, Nothnick WB. Estrogen suppresses expression of the matrix metalloproteinase inhibitor reversion-inducing cysteine-rich protein with Kazal motifs (RECK) within the mouse uterus. Endocrine 2012; 42:97-106. [PMID: 22302680 DOI: 10.1007/s12020-012-9614-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/19/2012] [Indexed: 12/19/2022]
Abstract
RECK (reversion-inducing cysteine-rich protein with Kazal motifs) is a membrane-anchored glycoprotein which regulates MMP2 and MMP9 activity and has been proposed to play a role in embryo implantation while misexpression of RECK has been associated with a variety of carcinomas. Unfortunately, understanding on the steroidal regulation of uterine RECK is lacking. To address this gap in our knowledge, we examined steroidal regulation and cellular expression of Reck mRNA and protein within the mouse uterus in vivo. Uterine Reck mRNA and protein were decreased by estrogen, while progesterone alone had no effect. The estrogen-induced down regulation could be partially blocked by progesterone. RECK was localized primarily to luminal and glandular epithelial cells and the level of expression was regulated in a similar fashion as in whole tissue by the steroids. Knock-down of endogenous RECK in human endometrial epithelial and stromal cells resulted in a significant increase in active MMP9 expression but not that of pro-MMP9 or MMP2. These studies demonstrate that RECK expression in the mouse uterus is steroidally regulated and that within endometrial epithelial and stromal cells, RECK regulates MMP9, but not MMP2 activity.
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Affiliation(s)
- Xuan Zhang
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
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