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Qin Y, Liao S, Sun J, Ye H, Li J, Pan J, He J, Xia Z, Shao Y. RECK as a Potential Crucial Molecule for the Targeted Treatment of Sepsis. J Inflamm Res 2025; 18:1787-1813. [PMID: 39931174 PMCID: PMC11809362 DOI: 10.2147/jir.s501856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 01/19/2025] [Indexed: 02/13/2025] Open
Abstract
Reversion inducing cysteine rich protein with kazal motifs (RECK), a Kazal motif-containing protein, regulates pro-inflammatory cytokines production, migration of inflammatory cells, vascular endothelial growth factor (VEGF) and Wnt pathways and plays critical roles in septic inflammatory storms and vascular endothelial dysfunction. Recently, RECK has been defined as the negative regulator of adisintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs), which are both membrane "molecular scissors" and aggravate the poor prognosis of sepsis. To better understand the roles of RECK and the related mechanisms, we make here a systematic and in-depth review of RECK. We first summarize the findings on structural characteristics of RECK protein and the regulation at the transcription, post-transcription, or protein level of RECK. Then, we discuss the roles of RECK in inflammation, infection, and vascular injury by focusing on the RECK function on ADAMs and MMPs, as well as the pathways of VEGF, WNT, angiopoietin, and notch signaling. In conclusion, RECK participation as a guardian in the development of sepsis provides insight into the strategies of precisely intervening in RECK dysregulationfor the treatment of sepsis.
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Affiliation(s)
- Yuting Qin
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Shuanglin Liao
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Jianbo Sun
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Huiyun Ye
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Jiafu Li
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Jiahui Pan
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Junbing He
- The Key Laboratory of Organ Dysfunction and Protection Translational Medicine, Jieyang Medical Research Center, Jieyang People’s Hospital, Jieyang, Guangdong, People’s Republic of China
| | - Zhengyuan Xia
- Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, People’s Republic of China
| | - Yiming Shao
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
- The Key Laboratory of Sepsis Translational Medicine, Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China
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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 S, Liu Y, Wang M, Ponikwicka-Tyszko D, Ma W, Krentowska A, Kowalska I, Huhtaniemi I, Wolczynski S, Rahman NA, Li X. Role and mechanism of miR-335-5p in the pathogenesis and treatment of polycystic ovary syndrome. Transl Res 2023; 252:64-78. [PMID: 35931409 DOI: 10.1016/j.trsl.2022.07.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 07/23/2022] [Accepted: 07/25/2022] [Indexed: 01/14/2023]
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder of unknown etiology that occurs in women of reproductive age. Despite being considered to affect up to one-fifth of women in this cohort, the condition lacks generally accepted diagnostic biomarkers and options for targeted therapy. Hereby, we analyzed the diagnostic, therapeutic, and functional potential of a recently discovered miR-335-5p that was observed to be reduced in the follicular fluid (FF) of PCOS patients as compared with healthy women. We found miR-335-5p to be significantly decreased in the serum and FF samples of PCOS patients (n = 40) vs healthy women (n = 30), as well as in primary human granulosa cells (hGCs), and in 3 different hormonally induced PCOS-like murine models vs. wild-type (WT) mice. The level of circulating miR-335-5p was found to significantly correlate with the impaired endocrine and clinical features associated with PCOS in human patients. Ovarian intrabursal injection of the miR-335-5p antagomir in WT mice ovaries induced a PCOS-like reproductive phenotype. Treatment with the miR-335-5p agomir rescued the dihydrotestosterone-induced PCOS-phenotype in mice, thereby providing a functional link between miR-335-5p and PCOS. We identified SP1 as a miR-335-5p target gene by using the dual-luciferase reporter assay. Both the luciferase reporter assay and chromatin immunoprecipitation assay showed that SP1 bound to the promoter region of human CYP19A1 and inhibited its transcription. miR-335-5p increased the production of estradiol via the SP1/CYP19A1 axis in hGCs, thereby suggesting its mechanistic pathway of action. In conclusion, these results provide evidence that miR-335-5p may function as a mediator in the etiopathogenesis of PCOS, as well as has the potential as both a novel diagnostic biomarker and therapeutic target for PCOS.
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Affiliation(s)
- Shanshan Zhang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yajing Liu
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China; Hainan Yazhou Bay Seed Lab
| | - Mingming Wang
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Donata Ponikwicka-Tyszko
- Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland; Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland
| | - Wenqiang Ma
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Anna Krentowska
- Department of Internal Medicine and Metabolic Diseases, Medical University of Białystok, Bialystok, Poland
| | - Irina Kowalska
- Department of Internal Medicine and Metabolic Diseases, Medical University of Białystok, Bialystok, Poland
| | - Ilpo Huhtaniemi
- Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland; Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
| | - Slawomir Wolczynski
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, 15276, Poland
| | - Nafis A Rahman
- Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland; Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
| | - Xiangdong Li
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China; Hainan Yazhou Bay Seed Lab; Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; Department of Nutrition and Health, China Agricultural University, Beijing, China.
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Ivanenko KA, Prassolov VS, Khabusheva ER. Transcription Factor Sp1 in the Expression of Genes Encoding Components of Mapk, JAK/STAT, and PI3K/Akt Signaling Pathways. Mol Biol 2022. [DOI: 10.1134/s0026893322050089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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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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The alternatively spliced RECK transcript variant 3 is a predictor of poor survival for melanoma patients being upregulated in aggressive cell lines and modulating MMP gene expression in vitro. Melanoma Res 2021; 30:223-234. [PMID: 31764436 DOI: 10.1097/cmr.0000000000000650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The reversion-inducing cysteine-rich protein with kazal motifs (RECK) gene was described as a tumor suppressor gene two decades ago. Recently, novel alternatively spliced products of this gene have been identified. Of these, the transcript variant 3 (RECKVar3) was shown to display tumor-facilitating effects in astrocytoma cells in vitro, with a higher RECKVar3/canonical RECK expression ratio being correlated with lower survival rates of patients. However, the regulatory mechanisms through which the cell controls the production and maintenance of these alternative transcripts, as well as their expression in other tumor types, remain elusive. Thus, the aim of this study is to investigate the role of the alternatively spliced transcripts from the RECK gene in melanoma progression as well as their regulation mechanism. To this end, we analyzed data from the Cancer Genome Atlas network and experimental data obtained from a panel of cell lines to show that high levels of RECKVar3 are predictive of poor survival. We also show that the MAPK and PI3K signaling pathways clearly play a role in determining the alternative-to-canonical ratio in vitro. Finally, we show that overexpression of the RECKVar3 protein upregulates matrix metalloproteinases (MMP)-9 and MMP-14 mRNA, while downregulating their inhibitor, tissue inhibitor of metalloproteinase (TIMP)3, and that RECKVar3-specific knockdown in the 1205Lu melanoma cell line hampered upregulation of the MMP9 mRNA promoted by the MEK1/2 inhibitor U0126. Taken together, our data complement the evidence that the RECK gene has a dual role in cancer, contributing to better understanding of the signaling cues, which dictate the melanoma invasive potential.
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Russell JJ, Grisanti LA, Brown SM, Bailey CA, Bender SB, Chandrasekar B. Reversion inducing cysteine rich protein with Kazal motifs and cardiovascular diseases: The RECKlessness of adverse remodeling. Cell Signal 2021; 83:109993. [PMID: 33781845 DOI: 10.1016/j.cellsig.2021.109993] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/19/2022]
Abstract
The Reversion Inducing Cysteine Rich Protein With Kazal Motifs (RECK) is a glycosylphosphatidylinositol (GPI) anchored membrane-bound regulator of matrix metalloproteinases (MMPs). It is expressed throughout the body and plays a role in extracellular matrix (ECM) homeostasis and inflammation. In initial studies, RECK expression was found to be downregulated in various invasive cancers and associated with poor prognostic outcome. Restoring RECK, however, has been shown to reverse the metastatic phenotype. Downregulation of RECK expression is also reported in non-malignant diseases, such as periodontal disease, renal fibrosis, and myocardial fibrosis. As such, RECK induction has therapeutic potential in several chronic diseases. Mechanistically, RECK negatively regulates various matrixins involved in cell migration, proliferation, and adverse remodeling by targeting the expression and/or activation of multiple MMPs, A Disintegrin And Metalloproteinase Domain-Containing Proteins (ADAMs), and A Disintegrin And Metalloproteinase With Thrombospondin Motifs (ADAMTS). Outside of its role in remodeling, RECK has also been reported to exert anti-inflammatory effects. In cardiac diseases, for example, it has been shown to counteract several downstream effectors of Angiotensin II (Ang-II) that play a role in adverse cardiac and vascular remodeling, such as Interleukin-6 (IL-6)/IL-6 receptor (IL-6R)/glycoprotein 130 (IL-6 signal transducer) signaling and Epidermal Growth Factor Receptor (EGFR) transactivation. This review article focuses on the current understanding of the multifunctional effects of RECK and how its downregulation may contribute to adverse cardiovascular remodeling.
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Affiliation(s)
- Jacob J Russell
- Biomedical Sciences, University of Missouri, Columbia, MO, United States of America; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States of America.
| | - Laurel A Grisanti
- Biomedical Sciences, University of Missouri, Columbia, MO, United States of America.
| | - Scott M Brown
- Biomedical Sciences, University of Missouri, Columbia, MO, United States of America; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States of America.
| | - Chastidy A Bailey
- Biomedical Sciences, University of Missouri, Columbia, MO, United States of America; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States of America.
| | - Shawn B Bender
- Biomedical Sciences, University of Missouri, Columbia, MO, United States of America; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States of America; Dalton Cardiovascular Center, University of Missouri, Columbia, MO, United States of America.
| | - B Chandrasekar
- Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States of America; Medicine, University of Missouri School of Medicine, Columbia, MO, United States of America; Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, United States of America; Dalton Cardiovascular Center, University of Missouri, Columbia, MO, United States of America.
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Trombetta-Lima M, Assis-Ribas T, Cintra RC, Campeiro JD, Guerreiro JR, Winnischofer SMB, Nascimento ICC, Ulrich H, Hayashi MAF, Sogayar MC. Impact of Reck expression and promoter activity in neuronal in vitro differentiation. Mol Biol Rep 2021; 48:1985-1994. [PMID: 33619662 DOI: 10.1007/s11033-021-06175-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 01/20/2021] [Indexed: 02/07/2023]
Abstract
Reck (REversion-inducing Cysteine-rich protein with Kazal motifs) tumor suppressor gene encodes a multifunctional glycoprotein which inhibits the activity of several matrix metalloproteinases (MMPs), and has the ability to modulate the Notch and canonical Wnt pathways. Reck-deficient neuro-progenitor cells undergo precocious differentiation; however, modulation of Reck expression during progression of the neuronal differentiation process is yet to be characterized. In the present study, we demonstrate that Reck expression levels are increased during in vitro neuronal differentiation of PC12 pheochromocytoma cells and P19 murine teratocarcinoma cells and characterize mouse Reck promoter activity during this process. Increased Reck promoter activity was found upon induction of differentiation in PC12 cells, in accordance with its increased mRNA expression levels in mouse in vitro models. Interestingly, Reck overexpression, prior to the beginning of the differentiation protocol, led to diminished efficiency of the neuronal differentiation process. Taken together, our findings suggest that increased Reck expression at early stages of differentiation diminishes the number of neuron-like cells, which are positive for the beta-3 tubulin marker. Our data highlight the importance of Reck expression evaluation to optimize in vitro neuronal differentiation protocols.
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Affiliation(s)
- Marina Trombetta-Lima
- Núcleo de Terapia Celular e Molecular (NUCEL), Faculdade de Medicina, Universidade de São Paulo (USP), Rua Pangaré, 100 (Cidade Universitária), São Paulo, SP, 05360-130, Brazil
| | - Thais Assis-Ribas
- Núcleo de Terapia Celular e Molecular (NUCEL), Faculdade de Medicina, Universidade de São Paulo (USP), Rua Pangaré, 100 (Cidade Universitária), São Paulo, SP, 05360-130, Brazil
| | - Ricardo C Cintra
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, 05508-000, Brazil
| | - Joana D Campeiro
- Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Rua 3 de Maio 100, Ed INFAR, 3º andar, São Paulo, SP, 04044-020, Brazil
| | - Juliano R Guerreiro
- Faculdade de Farmácia, Universidade Paulista (UNIP), São Paulo, SP, 05347-020, Brazil
| | - Sheila M B Winnischofer
- Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná (UFPR), Curitiba, PR, 81531-990, Brazil
- Departamento de Biologia Celular, Universidade Federal do Paraná (UFPR), Curitiba, PR, 81531-990, Brazil
| | - Isis C C Nascimento
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, 05508-000, Brazil
| | - Henning Ulrich
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, 05508-000, Brazil
| | - Mirian A F Hayashi
- Departamento de Farmacologia, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), Rua 3 de Maio 100, Ed INFAR, 3º andar, São Paulo, SP, 04044-020, Brazil.
| | - Mari C Sogayar
- Núcleo de Terapia Celular e Molecular (NUCEL), Faculdade de Medicina, Universidade de São Paulo (USP), Rua Pangaré, 100 (Cidade Universitária), São Paulo, SP, 05360-130, Brazil.
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo (USP), São Paulo, SP, 05508-000, Brazil.
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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: 85] [Impact Index Per Article: 17.0] [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: 6] [Impact Index Per Article: 1.2] [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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Matsuzaki T, Kitayama H, Omura A, Nishimoto E, Alexander DB, Noda M. The RECK tumor-suppressor protein binds and stabilizes ADAMTS10. Biol Open 2018; 7:7/10/bio033985. [PMID: 30287421 PMCID: PMC6215420 DOI: 10.1242/bio.033985] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The tumor suppressor protein RECK has been implicated in the regulation of matrix metalloproteinases (MMPs), NOTCH-signaling and WNT7-signaling. It remains unclear, however, how broad the spectrum of RECK targets extends. To find novel RECK binding partners, we took the unbiased approach of yeast two-hybrid screening. This approach detected ADAMTS10 as a RECK-interactor. ADAMTS10 has been characterized as a metalloproteinase involved in fibrillin-rich microfibril biogenesis, and its mutations have been implicated in the connective tissue disorder Weill-Marchesani syndrome. Experiments in vitro using recombinant proteins expressed in mammalian cells indicated that RECK indeed binds ADAMTS10 directly, that RECK protects ADAMTS10 from fragmentation following chemical activation and that ADAMTS10 interferes with the activity of RECK to inhibit MT1-MMP. In cultured cells, RECK increases the amount of ADAMTS10 associated with the cells. Hence, the present study has uncovered novel interactions between two molecules of known clinical importance, RECK and ADAMTS10.This article has an associated First Person interview with the first author of the paper.
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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
| | - Hitoshi Kitayama
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Akira Omura
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Emi Nishimoto
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - David B Alexander
- Department of Molecular Toxicology, Nagoya City University, Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, 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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MMP-9 Overexpression Due to TIMP-1 and RECK Underexpression is Associated with Prognosis in Prostate Cancer. Int J Biol Markers 2018; 26:255-61. [DOI: 10.5301/jbm.2011.8831] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2011] [Indexed: 11/20/2022]
Abstract
Background Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their inhibitors. The purpose of this study was to investigate whether the expression of MMP-9 and its specific inhibitors, TIMP-1 and RECK, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis and clinical outcome in prostate cancer (PC). Methods MMP-9, TIMP-1, and RECK expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in fresh-frozen malignant tissue specimens collected from 79 patients with clinically localized PC submitted to radical prostatectomy (RP). Frozen benign prostatic tissue from another 10 men with prostate cancer, also submitted to RP, was analyzed to determine if the profile of gene expression was maintained. The control group consisted of 11 patients with benign prostate hyperplasia (BPH). Results In the tumor samples, MMP-9 was overexpressed by 9.2 times, and TIMP-1 and RECK were underexpressed (0.75 and 0.80 times, respectively). Overexpression of MMP-9 was significantly related to PSA levels above 10 ng/mL (p=0.033). In addition, MMP-9 overexpression was related to biochemical recurrence, with a marginal statistical significance (p=0.089). MMP-9 was also overexpressed in benign tissues of patients with PC, as were TIMP-1 and RECK, in contrast to their underexpression in tumor samples. Conclusion Our results show that MMP-9 is overexpressed and its negative regulators are underexpressed in PC tissue, emphasizing a possible role of MMP-9 in the carcinogenesis process. Additionally, we noticed a relationship between MMP-9 overexpression and increased levels of PSA, an important prognostic factor. In benign tissue adjacent to tumors, the MMP-9 equilibrium is likely maintained because the expression of its negative regulators is preserved.
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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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14
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Shi G, Yoshida Y, Yuki K, Nishimura T, Kawata Y, Kawashima M, Iwaisako K, Yoshikawa K, Kurebayashi J, Toi M, Noda M. Pattern of RECK CpG methylation as a potential marker for predicting breast cancer prognosis and drug-sensitivity. Oncotarget 2018; 7:82158-82169. [PMID: 27058625 PMCID: PMC5347682 DOI: 10.18632/oncotarget.8620] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 03/28/2016] [Indexed: 02/03/2023] Open
Abstract
The membrane-anchored glycoprotein RECK negatively regulates multiple metalloproteinases and is frequently downregulated in tumors. Forced RECK expression in cancer cells results in suppression of tumor angiogenesis, invasion, and metastasis in xenograft models. A previous methylome study on breast cancer tissues detected inverse correlation between RECK CpG methylation (in an intron-1 region) and relapse-free survival. In this study, we focused on another region of the RECK CpG island (a promoter/exon-1 region) and found an inverse correlation between its methylation and RECK-inducibility by an HDAC inhibitor, MS275, among a panel of breast cancer cell lines (n=15). In clinical samples (n=62), RECK intron-1 methylation was prevalent among luminal breast cancers as reported previously (26 of 38 cases; 68%) and particularly enriched in tumors of the ER+PR- subclass (10 of 10 cases) and of higher histological grades (Grade 2 and 3; 28 of 43 cases; P=0.006). In about a half of these cases, promoter/exon-1 methylation was absent, and hence, RECK may be inducible by certain drugs such as MS275. Our results indicate the value of combined use of two RECK methylation markers for predicting prognosis and drug-sensitivity of breast cancers.
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Affiliation(s)
- Gongping Shi
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoko Yoshida
- Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kanako Yuki
- Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Tomomi Nishimura
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yukiko Kawata
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Masahiro Kawashima
- Department of Breast Surgery, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Keiko Iwaisako
- Department of Target Therapy and Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kiyotsugu Yoshikawa
- Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Junichi Kurebayashi
- Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, 701-0192, Japan
| | - Masakazu Toi
- Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.,Department of Breast Surgery, 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.,Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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Paiva KBS, Granjeiro JM. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 148:203-303. [PMID: 28662823 DOI: 10.1016/bs.pmbts.2017.05.001] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering.
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Affiliation(s)
- Katiucia B S Paiva
- Laboratory of Extracellular Matrix Biology and Cellular Interaction (LabMec), Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
| | - José M Granjeiro
- National Institute of Metrology, Quality and Technology (InMetro), Bioengineering Laboratory, Duque de Caxias, RJ, Brazil; Fluminense Federal University, Dental School, Niterói, RJ, Brazil
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16
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Pramanik KK, Singh AK, Alam M, Kashyap T, Mishra P, Panda AK, Dey RK, Rana A, Nagini S, Mishra R. Reversion-inducing cysteine-rich protein with Kazal motifs and its regulation by glycogen synthase kinase 3 signaling in oral cancer. Tumour Biol 2016; 37:15253-15264. [PMID: 27696293 DOI: 10.1007/s13277-016-5362-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 09/07/2016] [Indexed: 12/19/2022] Open
Abstract
The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and glycogen synthase kinase (GSK3) are novel tumor suppressors, and emerging evidence has suggested their active role in oral cancer pathogenesis. In the present study, 112 human samples, including 55 fresh samples of 14 adjacent normal tissues, 25 noninvasive oral tumors, and 18 invasive tumors, were included. The messenger RNA (mRNA) expression, protein expression, and promoter methylation of the RECK gene, as well as the expression of GSK3β, phospho/total β-catenin, and c-myc, were measured by RT-PCR, bisulphate modification-PCR, immunohistochemistry, and Western blot analysis. Additionally, ectopic expression of in/active GSK3β was performed in cell culture experiments. This study provided information on the progressive silencing of RECK gene expression at the protein and mRNA levels paralleled with promoter hypermethylation at various stages of oral tumor invasion. RECK expression and the hypermethylation of the RECK gene promoter were negatively and positively correlated with pS9GSK3β/c-myc expression, respectively. Further, a negative trend of RECK protein expression with nuclear β-catenin expression was observed. Induced expression of active GSK3β reversed the RECK silencing in SCC9 cells. Collectively, our results demonstrated that the silencing of the RECK gene, possibly regulated by the GSK3β pathway, is an important event in oral cancer invasion and this pathway could be exploited for therapeutic interventions.
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Affiliation(s)
- Kamdeo K Pramanik
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India
| | - Abhay K Singh
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India
| | - Manzar Alam
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India
| | - Tanushree Kashyap
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India
| | - Prajna Mishra
- Centre for Applied Chemistry, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India
| | - Aditya K Panda
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India
| | - Ratan K Dey
- Centre for Applied Chemistry, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India
| | - Ajay Rana
- Division of Surgical Oncology, Department of Surgery, College of Medicine, The University of Illinois at Chicago, 840 S. Wood Street, Suite 601 Clinical Sciences Building, MC 958, Chicago, IL, 60612, USA
| | - Siddavaram Nagini
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, 608 002, India
| | - Rajakishore Mishra
- Centre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, Brambe, Ranchi, Jharkhand, 835205, India.
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Histone deacetyltransferase inhibitors Trichostatin A and Mocetinostat differentially regulate MMP9, IL-18 and RECK expression, and attenuate Angiotensin II-induced cardiac fibroblast migration and proliferation. Hypertens Res 2016; 39:709-716. [PMID: 27278287 DOI: 10.1038/hr.2016.54] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/08/2016] [Accepted: 04/14/2016] [Indexed: 01/19/2023]
Abstract
Histone acetylation/deacetylation plays a key role in the epigenetic regulation of multiple pro-fibrotic genes. Here we investigated the effects of histone deacetyltransferase (HDAC) inhibition on angiotensin (Ang)-II-induced pro-fibrotic changes in adult mouse cardiac fibroblasts (CF). CF express class I HDACs 1 and 2, and Ang-II induces their activation. Notably, silencing HDAC1 or HDAC2 attenuated Ang-II induced CF proliferation and migration. Under basal conditions, HDAC1 dimerizes with HDAC2 in CF and Ang-II reversed this interaction. Treatment with Trichostatin A (TSA), a broad-spectrum HDAC inhibitor, restored their physical association, and attenuated Ang-II-induced MMP9 expression, IL-18 induction, and extracellular matrix (collagen I, collagen III and fibronectin) production. Further, TSA inhibited Ang-II-induced MMP9 and Il18 transcription by blocking NF-κB and AP-1 binding to their respective promoter regions. By inhibiting Sp1 binding to RECK promoter, TSA reversed Ang-II-induced RECK suppression, collagen and fibronectin expression, and CF migration and proliferation. The class I-specific HDAC inhibitor Mocetinostat (MGCD) recapitulated TSA effects on Ang-II-treated CF. Together, these results demonstrate that targeting HDACs attenuates the pro-inflammatory and pro-fibrotic effects of Ang-II on CF.
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18
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Noda M, Vallon M, Kuo CJ. The Wnt7's Tale: A story of an orphan who finds her tie to a famous family. Cancer Sci 2016; 107:576-82. [PMID: 26934061 PMCID: PMC4970824 DOI: 10.1111/cas.12924] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 02/22/2016] [Accepted: 02/29/2016] [Indexed: 12/11/2022] Open
Abstract
The transformation suppressor gene RECK was isolated by cDNA expression cloning (1998), and GPR124/TEM5 was detected as a tumor endothelial marker by differential screening (2000). The importance of Wnt7a/b and Gpr124 in brain angiogenesis was demonstrated by reverse genetics in mice (2008–2010). A series of recent studies using genetically engineered mice and zebrafish as well as luciferase reporter assays in cultured cells led to the discovery of functional interactions among Reck, Gpr124, and Wnt7a/b in triggering canonical Wnt signaling with relevance to embryonic brain angiogenesis and blood–brain barrier formation.
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Affiliation(s)
- Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Mario Vallon
- Hematology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Calvin J Kuo
- Hematology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
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19
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MicroRNA-135b, a HSF1 target, promotes tumor invasion and metastasis by regulating RECK and EVI5 in hepatocellular carcinoma. Oncotarget 2016; 6:2421-33. [PMID: 25537516 PMCID: PMC4385861 DOI: 10.18632/oncotarget.2965] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 12/10/2015] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) often localize to chromosomal fragile sites and are associated with cancer. In this study, we screened for the aberrant and functional miRNAs in the regions of copy number alterations (CNAs) in hepatocellular carcinoma (HCC), and found that miR-135b was frequently amplified and upregulated in HCC tissues. The expression level of miR-135b was inversely correlated with the occurrence of tumor capsules. In addition, miR-135b promoted HCC cell migration and invasion in vitro and metastasis in vivo. The reversion-inducing-cysteine-rich protein with kazal motifs (RECK) and ecotropic viral integration site 5 (EVI5) were identified as the direct and functional targets of miR-135b in HCC. Furthermore, we observed that heat shock transcription factor 1 (HSF1) directly activated miR-135b expression, consequently enhancing HCC cell motility and invasiveness. The newly identified HSF1/miR-135b/RECK&EVI5 axis provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.
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20
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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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Yeh HH, Tseng YF, Hsu YC, Lan SH, Wu SY, Raghavaraju G, Cheng DE, Lee YR, Chang TY, Chow NH, Hung WC, Liu HS. Ras induces experimental lung metastasis through up-regulation of RbAp46 to suppress RECK promoter activity. BMC Cancer 2015; 15:172. [PMID: 25885317 PMCID: PMC4377201 DOI: 10.1186/s12885-015-1155-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 03/02/2015] [Indexed: 12/30/2022] Open
Abstract
Background Mutant Ras plays multiple functions in tumorigenesis including tumor formation and metastasis. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a metastasis inhibitor gene, suppresses matrix metalloproteinase (MMP) activity in the metastatic cascade. Clarifying the relationship between Ras and RECK and understanding the underlying molecular mechanism may lead to the development of better treatment for Ras-related tumors. Methods Suppression subtractive hybridization PCR (SSH PCR) was conducted to identify Ha-rasval12 up-regulated genes in bladder cancer cells. Stable cell lines of human breast cancer (MCF-7-ras) and mouse NIH3T3 fibroblasts (7–4) harboring the inducible Ha-rasval12 oncogene, which could be induced by isopropylthio-β-D-galactoside (IPTG), were used to clarify the relationship between Ras and the up-regulated genes. Chromatin immunoprecipitation (ChIP) assay, DNA affinity precipitation assay (DAPA) and RECK reporter gene assay were utilized to confirm the complex formation and binding with promoters. Results Retinoblastoma binding protein-7 (RbAp46) was identified and confirmed as a Ha-rasval12 up-regulated gene. RbAp46 could bind with histone deacetylase (HDAC1) and Sp1, followed by binding to RECK promoter at the Sp1 site resulting in repression of RECK expression. High expression of Ras protein accompanied with high RbAp46 and low RECK expression were detected in 75% (3/4) of the clinical bladder cancer tumor tissues compared to the adjacent normal parts. Ras induced RbAp46 expression increases invasion of the bladder cancer T24 cells and MMP-9 activity was increased, which was confirmed by specific lentiviral shRNAs inhibitors against Ras and RbAp46. Similarly, knockdown of RbAp46 expression in the stable NIH3T3 cells “7-4” by shRNA decreased Ras-related lung metastasis using a xenograft nude mice model. Conclusions We confirmed that RbAp46 is a Ha-rasval12 up-regulated gene and binds with HDAC1 and Sp1. Furthermore, RbAp46 binds to the RECK promoter at the Sp1 site via recruitment by Sp1. RECK is subsequently activated, leading to increased MMP9 activity, which may lead to increased metastasis in vivo. Our findings of Ras upregulation of RbAp46 may lead to revealing a novel mechanism of Ras-related tumor cell metastasis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1155-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hsuan-Heng Yeh
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan. .,Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
| | - Yu-Fen Tseng
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.
| | - Yu-Chiao Hsu
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.
| | - Sheng-Hui Lan
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan. .,Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
| | - Shan-Ying Wu
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan. .,Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
| | - Giri Raghavaraju
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.
| | - Da-En Cheng
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan.
| | - Ying-Ray Lee
- Department of Medical Research, Chiayi Christian Hospital, Chiayi, Taiwan.
| | - Tsuey-Yu Chang
- Department of Parasitology, National Cheng Kung University, Tainan, Taiwan.
| | - Nan-Haw Chow
- Department of Pathology, National Cheng Kung University, Tainan, Taiwan.
| | - Wen-Chun Hung
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan. .,National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
| | - Hsiao-Sheng Liu
- Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan. .,Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan. .,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
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Beishline K, Azizkhan-Clifford J. Sp1 and the 'hallmarks of cancer'. FEBS J 2015; 282:224-58. [PMID: 25393971 DOI: 10.1111/febs.13148] [Citation(s) in RCA: 396] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 09/26/2014] [Accepted: 11/10/2014] [Indexed: 12/19/2022]
Abstract
For many years, transcription factor Sp1 was viewed as a basal transcription factor and relegated to a role in the regulation of so-called housekeeping genes. Identification of Sp1's role in recruiting the general transcription machinery in the absence of a TATA box increased its importance in gene regulation, particularly in light of recent estimates that the majority of mammalian genes lack a TATA box. In this review, we briefly consider the history of Sp1, the founding member of the Sp family of transcription factors. We review the evidence suggesting that Sp1 is highly regulated by post-translational modifications that positively and negatively affect the activity of Sp1 on a wide array of genes. Sp1 is over-expressed in many cancers and is associated with poor prognosis. Targeting Sp1 in cancer treatment has been suggested; however, our review of the literature on the role of Sp1 in the regulation of genes that contribute to the 'hallmarks of cancer' illustrates the extreme complexity of Sp1 functions. Sp1 both activates and suppresses the expression of a number of essential oncogenes and tumor suppressors, as well as genes involved in essential cellular functions, including proliferation, differentiation, the DNA damage response, apoptosis, senescence and angiogenesis. Sp1 is also implicated in inflammation and genomic instability, as well as epigenetic silencing. Given the apparently opposing effects of Sp1, a more complete understanding of the function of Sp1 in cancer is required to validate its potential as a therapeutic target.
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Affiliation(s)
- Kate Beishline
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
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Zhou XQ, Huang SY, Zhang DS, Zhang SZ, Li WG, Chen ZW, Wu HW. Effects of 5-aza-2'deoxycytidine on RECK gene expression and tumor invasion in salivary adenoid cystic carcinoma. ACTA ACUST UNITED AC 2014; 48:254-60. [PMID: 25517920 PMCID: PMC4381946 DOI: 10.1590/1414-431x20144102] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 10/13/2014] [Indexed: 11/22/2022]
Abstract
Reversion-inducing cysteine-rich protein with kazal motifs (RECK), a
novel tumor suppressor gene that negatively regulates matrix metalloproteinases
(MMPs), is expressed in various normal human tissues but downregulated in several
types of human tumors. The molecular mechanism for this downregulation and its
biological significance in salivary adenoid cystic carcinoma (SACC) are unclear. In
the present study, we investigated the effects of a DNA methyltransferase (DNMT)
inhibitor, 5-aza-2′deoxycytidine (5-aza-dC), on the methylation status of the
RECK gene and tumor invasion in SACC cell lines.
Methylation-specific PCR (MSP), Western blot analysis, and quantitative real-time PCR
were used to investigate the methylation status of the RECK gene and
expression of RECK mRNA and protein in SACC cell lines. The invasive ability of SACC
cells was examined by the Transwell migration assay. Promoter methylation was only
found in the ACC-M cell line. Treatment of ACC-M cells with 5-aza-dC partially
reversed the hypermethylation status of the RECK gene and
significantly enhanced the expression of mRNA and protein, and 5-aza-dC significantly
suppressed ACC-M cell invasive ability. Our findings showed that 5-aza-dC inhibited
cancer cell invasion through the reversal of RECK gene
hypermethylation, which might be a promising chemotherapy approach in SACC
treatment.
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Affiliation(s)
- X Q Zhou
- Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, China
| | - S Y Huang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, China
| | - D S Zhang
- Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, China
| | - S Z Zhang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, China
| | - W G Li
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, China
| | - Z W Chen
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, China
| | - H W Wu
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, China
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24
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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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25
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Yuki K, Yoshida Y, Inagaki R, Hiai H, Noda M. E-cadherin-downregulation and RECK-upregulation are coupled in the non-malignant epithelial cell line MCF10A but not in multiple carcinoma-derived cell lines. Sci Rep 2014; 4:4568. [PMID: 24691523 PMCID: PMC3972504 DOI: 10.1038/srep04568] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 03/17/2014] [Indexed: 01/06/2023] Open
Abstract
Expression of a mesenchymal phenotype is often associated with invasive/metastatic behaviors of carcinoma cells. Acquisition of a mesenchymal phenotype by a carcinoma cell is known as epithelial-mesenchymal transition (EMT). The membrane-anchored matrix metalloproteinase-regulator RECK is abundant in normal mesenchymal cells. In aggressive carcinomas, however, RECK expression is often downregulated. This apparent paradox prompted us to clarify the relationship between EMT and RECK. We found that TGFβ-induced E-cadherin downregulation, a hallmark of EMT, is accompanied by RECK-upregulation in a non-tumorigenic epithelial cell line (MCF10A). In contrast, the loss of E-cadherin expression is uncoupled from RECK-upregulation in carcinoma-derived cell lines (MCF7, MDA-MB-231, and A549). When RECK was artificially expressed in A549 cells, it showed little effect on EMT but elevated the level of integrin α5 and attenuated cell proliferation and migration. These findings implicate RECK in the regulation of proliferation and migration of normal epithelial cells after EMT and suggest how the uncoupling between EMT and RECK-upregulation impacts on the fates and behaviors of carcinoma cells.
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Affiliation(s)
- Kanako Yuki
- 1] Department of Molecular Oncology, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] Laboratory for Malignancy Control Research, Medical Innovation Center, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoko Yoshida
- Laboratory for Malignancy Control Research, Medical Innovation Center, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Ryosaku Inagaki
- Genomic Research Laboratories Research Division, Dainippon Sumitomo Pharma Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka-shi, Osaka 554-0022, Japan
| | - Hiroshi Hiai
- Laboratory for Malignancy Control Research, Medical Innovation Center, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Makoto Noda
- 1] Department of Molecular Oncology, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] Laboratory for Malignancy Control Research, Medical Innovation Center, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] Global COE Program, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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26
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Zhou X, Huang S, Jiang L, Zhang S, Li W, Chen Z, Zhang D. Expression of RECK and MMP-2 in salivary adenoid cystic carcinoma: Correlation with tumor progression and patient prognosis. Oncol Lett 2014; 7:1549-1555. [PMID: 24765174 PMCID: PMC3997680 DOI: 10.3892/ol.2014.1906] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 01/15/2014] [Indexed: 11/25/2022] Open
Abstract
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol-anchored glycoprotein, inhibits the enzymatic activities of certain matrix metalloproteinases (MMPs). RECK has been studied in numerous human tumors, but the expression of RECK in salivary adenoid cystic carcinoma (SACC), and its correlation with patient prognosis, has never been investigated thus far. In the present study, the expression of RECK and MMP-2 was evaluated in two ACC cell lines and in 83 patients with SACC. The results of quantitative polymerase chain reaction and western blot analysis revealed that the ACC-2 and ACC-M cell lines expressed RECK and MMP-2 mRNA and protein. The immunohistochemical staining in the patients demonstrated that positive expression of RECK and MMP-2 was observed in 21/83 (25.3%) and 69/83 (83.1%) cases, respectively, and that RECK expression was significantly associated with the tumor-node-metastasis stage, histological grade and perineural invasion of patients with SACC (P<0.05). Furthermore, there was a significant association between the positive expression of RECK and that of MMP-2 (P<0.0001). Univariate and multivariate analyses confirmed that a lack of RECK expression was an independent and significant factor for the prediction of a poor prognosis. In conclusion, RECK is a promising prognostic marker and potential therapeutic agent in SACC.
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Affiliation(s)
- Xiaoqing Zhou
- Department of Oral and Maxillofacial Surgery, First People's Hospital of Jining, Jining, Shandong 272111, P.R. China
| | - Shengyun Huang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Licheng Jiang
- Department of Oral and Maxillofacial Surgery, Liaocheng Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Shizhou Zhang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Wengang Li
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhanwei Chen
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Dongsheng Zhang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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27
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Qi Q, Lu N, Li C, Zhao J, Liu W, You Q, Guo Q. Involvement of RECK in gambogic acid induced anti-invasive effect in A549 human lung carcinoma cells. Mol Carcinog 2014; 54 Suppl 1:E13-25. [PMID: 24532189 DOI: 10.1002/mc.22138] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 01/06/2014] [Accepted: 01/22/2014] [Indexed: 02/06/2023]
Abstract
Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been demonstrated possessing anti-metastatic activity in vitro and in vivo. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein negatively regulating matrix metalloproteinases (MMPs), plays an important role in tumor invasion and metastasis. The present study investigates the regulatory effect of GA on RECK expression and the role of RECK in GA-induced anti-invasion in A549 human lung cancer cells. Our results showed that GA dose-dependently inhibited cell invasion and suppressed A549 experimental lung metastasis in vivo, which was attributed to RECK up-regulation at both protein and mRNA levels. With small interference RNA (siRNA) blocking RECK expression, we found inhibition of RECK decreased the GA-induced inhibition of MMP-2/9, which was in consistent with the attenuated anti-invasive effect of GA. Further study indicated that GA effectively suppressed Histone deacetylase (HDAC) 1/specificity protein (Sp) 1 binding and Sp1 phosphorylation associating with Extracellular signal-regulated kinases (ERK) signaling blocking, leading to RECK up-regulation. Taken together, these data demonstrate that RECK contributes to GA's anti-invasive activity and provide new evidence for GA being served as a therapeutic candidate for cancer metastasis.
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Affiliation(s)
- Qi Qi
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China.,Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Na Lu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Chenglin Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jie Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Wei Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Qidong You
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
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28
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Guo J, Zou L. Correlation of RECK with matrix metalloproteinase-2 in regulation of trophoblast invasion of early pregnancy. ACTA ACUST UNITED AC 2014; 26:738-40. [PMID: 17357505 DOI: 10.1007/s11596-006-0631-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
To study the role of the reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) gene and matrix metalloproteinase-2 (MMP-2) in the regulation of trophoblast invasion of early pregnancy. Immunohistochemistry, Western blot and gelatin zymography were used to detect the RECK protein expression localization, expression level and MMP-2 activation level in the placental tissues harvested from 52 normal pregnant women (27 in the early pregnancy, 25 in the term pregnancy). Immunohistochemistry showed that RECK expression was found both in villous tissues of early pregnancy group and term pregnancy group and was mainly observed in cell membrane and cytoplasm of cytotrophoblasts and syncytiotrophoblasts. RECK expression increased with gestational time. RECK expression of early pregnancy group was significantly lower than that of term pregnancy group (P<0.05). RECK expression was significantly lower in cellular column (CC) with invasion ability. Western blot showed that the RECK protein expression in early pregnancy group was significantly lower than that in term pregnancy (P<0.05). The optical density values of RECK protein expression in early pregnancy group and term pregnancy group were 1.35-0.14 and 2.68+/-0.26, respectively, while MMP-2 activation ratio was contrary to RECK protein expression and decreased with the gestation time (P<0.01). The MMP-2 activation ratios of early pregnancy group and term pregnancy group were 0.46 +/- 0.05 and 0.10+/-0.02, respectively. The expression of the tumor inhibitory gene RECK was positively related with the invasion ability of trophoblasts, while the invasion gene MMP-2 was negatively related with the ability. The interaction between RECK and MMP-2 may play an important role in the regulation of the trophoblast invasion in early pregnancy.
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Affiliation(s)
- Junhong Guo
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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29
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Siddesha JM, Valente AJ, Yoshida T, Sakamuri SSVP, Delafontaine P, Iba H, Noda M, Chandrasekar B. Docosahexaenoic acid reverses angiotensin II-induced RECK suppression and cardiac fibroblast migration. Cell Signal 2014; 26:933-41. [PMID: 24447911 DOI: 10.1016/j.cellsig.2014.01.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 01/08/2014] [Indexed: 01/08/2023]
Abstract
The omega-3 polyunsaturated fatty acids (ω-3 fatty acids) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been reported to inhibit or delay the progression of cardiovascular diseases, including myocardial fibrosis. Recently we reported that angiotensin II (Ang II) promotes cardiac fibroblast (CF) migration by suppressing the MMP regulator reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), through a mechanism dependent on AT1, ERK, and Sp1. Here we investigated the role of miR-21 in Ang II-mediated RECK suppression, and determined whether the ω-3 fatty acids reverse these effects. Ang II induced miR-21 expression in primary mouse cardiac fibroblasts (CFs) via ERK-dependent AP-1 and STAT3 activation, and while a miR-21 inhibitor reversed Ang II-induced RECK suppression, a miR-21 mimic inhibited both RECK expression and Ang II-induced CF migration. Moreover, Ang II suppressed the pro-apoptotic PTEN, and the ERK negative regulator Sprouty homologue 1 (SPRY1), but induced the metalloendopeptidase MMP2, all in a manner that was miR-21-dependent. Further, forced expression of PTEN inhibited Akt phosphorylation, Sp1 activation, and MMP2 induction. Notably, while both EPA and DHA reversed Ang II-mediated RECK suppression, DHA appeared to be more effective, and reversed Ang II-induced miR-21 expression, RECK suppression, MMP2 induction, and CF migration. These results indicate that Ang II-induced CF migration is differentially regulated by miR-21-mediated MMP induction and RECK suppression, and that DHA has the potential to upregulate RECK, and therefore may exert potential beneficial effects in cardiac fibrosis.
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Affiliation(s)
- Jalahalli M Siddesha
- Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, United States; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Anthony J Valente
- Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX 78229, United States
| | - Tadashi Yoshida
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Siva S V P Sakamuri
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Patrice Delafontaine
- Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Hideo Iba
- Department of Microbiology and Immunology, University of Tokyo, Tokyo 108-8639, Japan
| | - Makoto Noda
- Department of 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, United States; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, United States.
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30
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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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31
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Mao X, Liu L, Zhang B, Zhang D. Reversion-inducing cysteine-rich protein with Kazal motifs gene expression and its clinical significance in peripheral T-cell lymphoma. Oncol Lett 2013; 5:1867-1871. [PMID: 23833658 PMCID: PMC3700891 DOI: 10.3892/ol.2013.1306] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 04/12/2013] [Indexed: 11/12/2022] Open
Abstract
The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene was originally identified as a transformation suppressor gene that is widely expressed in normal tissues. In tumor tissues, RECK expression levels are significantly reduced, and the downregulation of RECK has been implicated in tumors that are more aggressive with a poor prognosis. In the present study, RECK expression in peripheral T-cell lymphoma (PTCL; n=82) was examined using immunohistochemistry, and its correlation with clinicopathological factors was analyzed. According to the proportion of positively-stained cells and the staining intensity (SI), the patients were categorized into RECK-negative or RECK-positive groups. RECK expression was observed in 30 of the 82 patients (36.6%). The 3-year survival rate of the patients with RECK-positive tumors (65.5%) was significantly high compared with that of the patients with RECK-negative tumors (20.3%; P=0.046). Reduced RECK expression was found to be significantly correlated with extranodal lymphomatous involvement (P=0.012). The survival analysis showed that RECK-negative expression was an independent and significant factor for predicting a poor prognosis. RECK status is a useful prognostic factor for assessing the biological behavior in PTCL.
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Affiliation(s)
- Xia Mao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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32
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Ahn MY, Kang DO, Na YJ, Yoon S, Choi WS, Kang KW, Chung HY, Jung JH, Min DS, Kim HS. Histone deacetylase inhibitor, apicidin, inhibits human ovarian cancer cell migration via class II histone deacetylase 4 silencing. Cancer Lett 2012; 325:189-199. [PMID: 22781396 DOI: 10.1016/j.canlet.2012.06.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Revised: 06/27/2012] [Accepted: 06/30/2012] [Indexed: 01/05/2023]
Abstract
This study examined the molecular mechanisms of apicidin in the modulation of human ovarian cancer SKOV-3 cells invasion and migration. Apicidin markedly decreased histone deacetylase 4 (HDAC4) expression and blocked cell migration and invasion. Cell migration was inhibited via down-regulation of matrix metalloproteinase-2 (MMP-2) and up-regulation of RECK in the HDAC4-blocked SKOV-3 cells. Apicidin significantly suppressed the binding of HDAC4 to Sp1 binding elements of the RECK promoter via repression of HDAC4. In an in vivo model, apicidin suppressed the growth of transplanted SKOV-3 cells by down-regulating HDAC4 and MMP-2. Apicidin may potentially be used as an anti-cancer agent for inhibition of cancer cell migration and invasion through the repression of MMP-2 which is related to the reduction of HDAC4.
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Affiliation(s)
- Mee Young Ahn
- Department of Oral & Maxillofacial Pathology, College of Dentistry, Wonkwang Bone Regeneration Institute, Daejeon Dental Hospital, Wonkwang University, Republic of Korea
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33
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Reis ST, Leite KRM, Piovesan LF, Pontes-Junior J, Viana NI, Abe DK, Crippa A, Moura CM, Adonias SP, Srougi M, Dall'Oglio MF. Increased expression of MMP-9 and IL-8 are correlated with poor prognosis of Bladder Cancer. BMC Urol 2012; 12:18. [PMID: 22695075 PMCID: PMC3424138 DOI: 10.1186/1471-2490-12-18] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 06/13/2012] [Indexed: 12/22/2022] Open
Abstract
Background Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their inhibitors. The purpose of this study was to investigate whether the expression of MMP-9, MMP-2 and its specific inhibitors, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis in Bladder Cancer (BC). Methods MMP-9, MMP-2 and its specific inhibitors expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in fresh-frozen malignant tissue collected from 40 patients with BC submitted to transurethral resection of bladder. The control group consisted of normal bladder tissue from five patients who had undergone retropubic prostatectomy to treat benign prostatic hyperplasia. Results MMP-9 was overexpressed in 59.0 % of patients, and MMP-2, TIMP-1, TIMP-2, MMP-14, RECK and IL-8 was underexpressed in most of the patients. Regarding prognostic parameters we observed that high-grade tumors exhibited significantly higher levels of MMP-9 and IL-8 (p = 0.012, p = 0.003). Invasive tumors (pT1-pT2) had higher expression levels of MMP-9 than superficial tumors (pTa) (p = 0.026). The same was noted for IL-8 that was more expressed by invasive tumors (p = 0.015, p = 0.048). Most importantly tumor recurrence was related with higher levels of both MMP-9 (p = 0.003) and IL-8 (p = 0.005). Conclusion We have demonstrated that the overexpression of MMP-9 and higher expression of IL-8 are related to unfavorable prognostic factors of urothelial bladder cancer and tumor recurrence and may be useful in the follow up of the patients.
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Chung TT, Yeh CB, Li YC, Su SC, Chien MH, Yang SF, Hsieh YH. Effect of RECK gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features. PLoS One 2012; 7:e33517. [PMID: 22428065 PMCID: PMC3299798 DOI: 10.1371/journal.pone.0033517] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 02/10/2012] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) down-regulation has been confirmed in numerous human cancers and is clinically associated with metastasis. This study investigates the potential associations of RECK single-nucleotide polymorphisms (SNPs) with hepatocellular carcinoma (HCC) susceptibility and its clinicopathologic characteristics. METHODOLOGY/PRINCIPAL FINDINGS A total of 135 HCC cancer patients and 501 cancer-free controls were analyzed for four RECK SNPs (rs10814325, rs16932912, rs11788747, and rs10972727) using real-time PCR and PCR-RFLP genotyping analysis. After adjusting for other co-variants, the individuals carrying RECK promoter rs10814325 inheriting at least one C allele had a 1.85-fold [95% confidence interval (CI), 1.03-3.36] risk of developing HCC compared to TT wild type carriers. The HCC patients, who carried rs11788747 with at least one G allele, had a higher distant metastasis risk than wild type probands. CONCLUSIONS RECK gene polymorphisms might be a risk factor increasing HCC susceptibility and distant metastasis in Taiwan.
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Affiliation(s)
- Tsung-Te Chung
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Otolaryngology, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Chao-Bin Yeh
- Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yi-Ching Li
- Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan
| | - Shih-Chi Su
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ming-Hsien Chien
- Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yi-Hsien Hsieh
- Department of Biochemistry, School of Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
- * E-mail:
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Prendergast A, Linbo TH, Swarts T, Ungos JM, McGraw HF, Krispin S, Weinstein BM, Raible DW. The metalloproteinase inhibitor Reck is essential for zebrafish DRG development. Development 2012; 139:1141-52. [PMID: 22296847 DOI: 10.1242/dev.072439] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The neural crest is a migratory, multipotent cell lineage that contributes to myriad tissues, including sensory neurons and glia of the dorsal root ganglia (DRG). To identify genes affecting cell fate specification in neural crest, we performed a forward genetic screen for mutations causing DRG deficiencies in zebrafish. This screen yielded a mutant lacking all DRG, which we named sensory deprived (sdp). We identified a total of four alleles of sdp, all of which possess lesions in the gene coding for reversion-inducing cysteine-rich protein containing Kazal motifs (Reck). Reck is an inhibitor of metalloproteinases previously shown to regulate cell motility. We found reck function to be both necessary for DRG formation and sufficient to rescue the sdp phenotype. reck is expressed in neural crest cells and is required in a cell-autonomous fashion for appropriate sensory neuron formation. In the absence of reck function, sensory neuron precursors fail to migrate to the position of the DRG, suggesting that this molecule is crucial for proper migration and differentiation.
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Affiliation(s)
- Andrew Prendergast
- Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA 98195-7420, USA
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Liu X, Wang W, Chen J, Chen C, Zhou J, Cao L. Expression of reversion-inducing cysteine-rich protein with kazal motifs and matrix metalloproteinase 9 in middle ear squamous cell carcinoma. ORL J Otorhinolaryngol Relat Spec 2011; 74:16-21. [PMID: 22178867 DOI: 10.1159/000334243] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Accepted: 10/04/2011] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Reversion-inducing cysteine-rich protein with kazal motifs (RECK) may negatively regulate matrix metalloproteinase 9 (MMP9) activity and suppress tumor invasion and metastasis. The aim of this study was to investigate whether RECK and MMP were involved in regulating middle ear carcinoma invasion and metastasis. METHODS RECK and MMP9 were measured in 30 middle ear squamous cell carcinoma tissues and 20 adjacent normal external ear canal skin tissues using immunohistochemical analysis. RESULTS The positive rate of RECK expression in the middle ear squamous cell carcinoma was much lower than that in the normal external ear canal skin. In contrast, the positive rate of MMP9 expression was higher in middle ear squamous cell carcinoma tissue than that in normal external ear canal skin tissue. The expressions of RECK and MMP9 were correlated with the histological grade and tumor stage, but not with patient age or gender. CONCLUSIONS RECK and MMP9 are involved in middle ear squamous cell carcinoma and may serve as markers to evaluate progression and metastasis.
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Affiliation(s)
- Xiang Liu
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
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Involvement of the SKP2-p27(KIP1) pathway in suppression of cancer cell proliferation by RECK. Oncogene 2011; 31:4128-38. [PMID: 22158033 DOI: 10.1038/onc.2011.570] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in cancers; in some cases, a significant correlation between the level of residual RECK in resected tumors and patient survival has been noted. Furthermore, restoration of RECK expression in certain cancer-derived cell lines results in reduced tumorigenicity. Here we report that acute RECK expression in colon carcinoma cells results in cell cycle-arrest accompanied by downregulation of a ubiquitin ligase component, S-phase kinase-associated protein 2 (SKP2), and upregulation of its substrate, p27(KIP1). Our data indicate that RECK-induced growth suppression is at least partially dependent on p27, and that RECK and type I collagen share similar effects on the SKP2-p27 pathway. Importantly, in patients with lung, colorectal and bladder cancers, the RECK/SKP2 ratio is high in normal tissues and lower in the cancer tissues. These findings reveal a novel molecular pathway linking cell-cycle progression to RECK downregulation, extracellular matrix degradation and SKP2 upregulation, and suggest that treatment regimens that induce RECK expression could be promising cancer therapies.
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Murai R, Yoshida Y, Muraguchi T, Nishimoto E, Morioka Y, Kitayama H, Kondoh S, Kawazoe Y, Hiraoka M, Uesugi M, Noda M. A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs. Oncotarget 2011; 1:252-64. [PMID: 21304177 DOI: 10.18632/oncotarget.100802] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS(12V) oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics.
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Affiliation(s)
- Ryuya Murai
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Japan
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Wittschieber D, Stenzinger A, Klauschen F, Stephan C, Jung K, Erbersdobler A, Rabien A. Decreased RECK and Increased EMMPRIN expression in urothelial carcinoma of the bladder are associated with tumor aggressiveness. Pathobiology 2011; 78:123-31. [PMID: 21613799 DOI: 10.1159/000323563] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 12/10/2010] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Urothelial bladder carcinomas show a divergent biological behavior, which significantly complicates risk stratification and clinical management. The MMP repressor RECK and the MMP activator EMMPRIN regulate the invasive potential by metalloproteinase-induced stromal degradation. Data on RECK in urothelial bladder cancer are lacking and information on EMMPRIN is sparse. This study aims to investigate the expression of RECK and EMMPRIN in urothelial carcinoma of the bladder and to correlate these findings with clinicopathological parameters. METHODS Our study included 127 specimens of urothelial carcinomas derived from 103 patients who underwent either TUR-B or cystectomy. Immunohistochemical expression analysis was performed for RECK, EMMPRIN, MMP-2, MMP-9 and MMP-14. Expression levels were graded for staining intensity and correlated with pT stage and WHO tumor grade. RESULTS Invasive (≥pT1) as well as WHO high-grade urothelial carcinomas showed a statistically significant and stepwise downregulation of RECK (p < 0.001) and concomitant upregulation of EMMPRIN (p < 0.001) compared to non-invasive and WHO low-grade tumors. No correlation was observed for the MMPs investigated. CONCLUSION Decreased RECK and increased EMMPRIN expression are associated with increasing stage and grade. Both proteins may serve as molecular marker for the distinction between potentially invasive (≥pT1) and non-invasive tumors (≤pTa).
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Affiliation(s)
- Daniel Wittschieber
- Institute of Pathology, Charité University Hospital, Berlin, Germany. d.wittschieber @ gmx.de
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Namwat N, Puetkasichonpasutha J, Loilome W, Yongvanit P, Techasen A, Puapairoj A, Sripa B, Tassaneeyakul W, Khuntikeo N, Wongkham S. Downregulation of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is associated with enhanced expression of matrix metalloproteinases and cholangiocarcinoma metastases. J Gastroenterol 2011; 46:664-75. [PMID: 21076843 DOI: 10.1007/s00535-010-0345-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2010] [Accepted: 10/25/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND Reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) has been implicated in the attenuation of tumor metastasis by negatively regulating metalloproteinase (MMP) levels. RECK gene expression is downregulated in many solid tumors, with this downregulation being associated with poor prognosis. This study evaluated the role of RECK in cholangiocarcinoma (CCA). METHODS The expression of RECK, MMP-2, and MMP-9 in paraffin sections of hamster and human CCA specimens was analyzed by immunohistochemistry. Functional analysis of RECK was performed in RECK small interfering (si) RNA knockdown CCA cell lines. The effect of aspirin on RECK status and function was evaluated using Western blotting, gelatin zymography, invasion and proliferation assays, and PhosphoELISArray analysis of Ras downstream mediators. RESULTS Hamster tissues showed high RECK expression in hyperplastic biliary duct epithelia, low RECK expression in precancerous lesions, and no RECK expression in CCA. In human specimens, RECK was highly expressed in normal biliary cells, whereas intrahepatic CCA showed low levels of expression. Downregulation of RECK was correlated with tumor metastasis (P < 0.01) and shorter patient survival (P < 0.02). RECK expression levels were inversely correlated with MMP-2 and MMP-9 expression (P < 0.05). SiRNA RECK-depleted M139 CCA cells exhibited increased MMP-2/-9 gelatinase activities and invasiveness. Aspirin (500 μM) demonstrated myriad effects in human CCA cell lines, including growth suppression, reduced phosphorylation of Akt/Erk/c-Jun, elevation of RECK expression, inhibition of MMP-2/MMP-9 activity, and enhanced invasiveness. CONCLUSIONS RECK functions as a metastasis suppressor in CCA; upregulation of RECK expression could provide a potential therapy to improve the prognosis of this type of cancer.
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Affiliation(s)
- N Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
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Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling. Oncogene 2010; 30:737-50. [PMID: 20890302 DOI: 10.1038/onc.2010.448] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19(Arf), Trp53 and p21(Cdkn1a). In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19(Arf), Trp53, p21(Cdkn1a) and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling.
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Wang H, Imamura Y, Ishibashi R, Chandana EPS, Yamamoto M, Noda M. The Reck tumor suppressor protein alleviates tissue damage and promotes functional recovery after transient cerebral ischemia in mice. J Neurochem 2010; 115:385-98. [PMID: 20796170 DOI: 10.1111/j.1471-4159.2010.06933.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The extracellular matrix (ECM) is important for both structural integrity and functions of the brain. Matrix metalloproteinases (MMPs) play major roles in ECM-remodeling under both physiological and pathological conditions. Reversion-inducing cysteine-rich protein with Kazal motifs (Reck) is a membrane-anchored MMP-regulator implicated in coordinated regulation of pericellular proteolysis. Although patho-physiological importance of MMPs and another group of MMP-regulators, tissue inhibitor of metalloproteinases, in brain ischemia has been demonstrated, little is known about the role of Reck in this process. In this study, we found that Reck is up-regulated in hippocampus and penumbra of subventricular zone after transient cerebral ischemia in mice. Most of the Reck-positive cells found at day 2 after ischemia are positive for Nestin as well as Ki67 and localized to the CA2 region of the hippocampus. At day 7 after ischemia, the Reck-positive cells increased in number, extended processes, expressed the reactive astrocyte marker GFAP and the neuronal marker NF200, and were widely distributed in the hippocampus. In the mutant mice carrying single functional Reck allele (Reck+/-), tissue damage and cell death after cerebral ischemia were augmented, the recovery of long-term potentiation in the hippocampus was compromised, NR2C subunit of NMDA receptor was up-regulated, gelatinolytic activity of MMPs were up-regulated and laminin-immunoreactivity was reduced. Our data implicate Reck in protection of ECM/tissue integrity and promotion of functional recovery in the brain after transient cerebral ischemia.
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Affiliation(s)
- Huan Wang
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
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Li Y, Zhang Y, Zheng Q. Expression of RECK gene and MMP-9 in hilar cholangiocarcinoma and its clinical significance. ACTA ACUST UNITED AC 2010; 25:552-4. [PMID: 16463672 DOI: 10.1007/bf02896015] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
In order to study the expression of transformation suppressor gene RECK and MMP-9 in hilar cholangiocarcinomas and its clinical significance, and explore the roles of RECK gene in metastasis and invasion of hilar cholangiocarcinoma, the expression levels of RECK, and MMP-9 mRNA were detected by using reverse transcription-polymerase reaction in 42 paraffin-embedded samples of hilar cholangiocarcinomas and 10 samples of benign bile duct diseases. The results showed that in hilar cholangiocarcinoma tissues, the expression of RECK gene was 0.235 +/- 0.062, significantly lower than in normal bile duct tissues (0.533 +/- 0.024, P < 0.05). In hilar cholangiocarcinoma tissues, the expression of MMP-9 (0.528 +/- 0.039) was significantly higher than in the normal tissues (0.311 +/- 0.032, P < 0.05). The expression of RECK gene was closely related to the intrahepatic and surrounding organs invasion (P < 0.05). It was concluded that RECK gene could inhibit the expression of MMP-9 in hilar cholangiocarcinomas and closely correlated with the biological behaviors. The abnormal expression of RECK gene might be one of the molecular mechanisms of hilar cholangiocarcinoma metastasis.
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Affiliation(s)
- Yiqing Li
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Murai R, Yoshida Y, Muraguchi T, Nishimoto E, Morioka Y, Kitayama H, Kondoh S, Kawazoe Y, Hiraoka M, Uesugi M, Noda M. A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs. Oncotarget 2010; 1:252-264. [PMID: 21304177 PMCID: PMC3248105 DOI: 10.18632/oncotarget.136] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Accepted: 07/20/2010] [Indexed: 11/25/2022] Open
Abstract
The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS(12V) oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics.
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Affiliation(s)
- Ryuya Murai
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoko Yoshida
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Teruyuki Muraguchi
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Emi Nishimoto
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoko Morioka
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Global COE Program, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Hitoshi Kitayama
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Global COE Program, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Shinae Kondoh
- Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoshinori Kawazoe
- Institutes for Chemical Research, Institute for Integrated Cell-Material Sciences, and Global COE Program, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Masahiro Hiraoka
- Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Global COE Program, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Motonari Uesugi
- Institutes for Chemical Research, Institute for Integrated Cell-Material Sciences, and Global COE Program, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Makoto Noda
- Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Global COE Program, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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Noda M, Takahashi C, Matsuzaki T, Kitayama H. What we learn from transformation suppressor genes: lessons from RECK. Future Oncol 2010; 6:1105-16. [DOI: 10.2217/fon.10.80] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Expression cloning is a powerful approach to finding genes that induce appreciable changes in cultured cells. One way to use this technique in cancer research is to isolate cDNAs that induce flat reversion in transformed cells. Such screening, however, is inherently artificial, and therefore requires independent validation of the clinical relevance of isolated genes. Studies of the mechanisms of actions, physiological functions and mechanisms of regulation of these genes at various levels may enrich our knowledge of cancer biology and supplement our toolbox in developing new cancer diagnoses and therapies. In this article we discuss the promise, limitations and recent innovations in this approach, taking one transformation suppressor gene, RECK, as an example.
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Affiliation(s)
| | - Chiaki Takahashi
- Division of Oncology & Molecular Biology, Center for Cancer & Stem Cell Research, Cancer Research Institute, Kanazawa University, Kakuma-cho, Kanazawa 920-1192, Japan
| | - Tomoko Matsuzaki
- Department of Molecular Oncology & Global COE Program, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Hitoshi Kitayama
- Department of Molecular Oncology & Global COE Program, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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Jeon HW, Lee YM. Inhibition of Histone Deacetylase Attenuates Hypoxia-Induced Migration and Invasion of Cancer Cells via the Restoration of RECK Expression. Mol Cancer Ther 2010; 9:1361-70. [DOI: 10.1158/1535-7163.mct-09-0717] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Miki T, Shamma A, Kitajima S, Takegami Y, Noda M, Nakashima Y, Watanabe KI, Takahashi C. The β1-Integrin–Dependent Function of RECK in Physiologic and Tumor Angiogenesis. Mol Cancer Res 2010; 8:665-76. [DOI: 10.1158/1541-7786.mcr-09-0351] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Kimura T, Okada A, Yatabe T, Okubo M, Toyama Y, Noda M, Okada Y. RECK is up-regulated and involved in chondrocyte cloning in human osteoarthritic cartilage. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 176:2858-67. [PMID: 20395433 DOI: 10.2353/ajpath.2010.091003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored matrix metalloproteinase regulator, but its functions in cartilage are not fully understood. The aim of the present study was to examine the expression and functions of RECK in human osteoarthritic (OA) cartilage. Quantitative RT-PCR indicated that the expression level of RECK is significantly higher in OA cartilage than in normal cartilage. By immunohistochemical analysis, RECK was localized to chondrocytes in OA cartilage, and the immunoreactivity directly correlated with the Mankin score and degree of chondrocyte cloning and proliferation. In cultured OA chondrocytes, RECK was expressed on the cell surface by glycosylphosphatidylinositol anchoring. The expression was stimulated by insulin-like growth factor-1 and suppressed by interleukin-1 and tumor necrosis factor-alpha. Down-regulation of RECK by small interfering RNA showed reduced spreading and smaller focal adhesions in the chondrocytes. Chondrocyte migration in a monolayer wounding assay was increased by down-regulation of RECK and inhibited by RECK overexpression in an matrix metalloproteinase activity-dependent manner. On the other hand, chondrocyte proliferation was suppressed by RECK silencing, and this was associated with reduced phosphorylation of focal adhesion kinase and extracellular signal-regulated kinase, whereas the proliferation was enhanced by RECK overexpression. These data are the first to demonstrate that RECK is up-regulated in human OA cartilage and suggest that RECK plays a role in chondrocyte cloning probably through suppression and promotion of chondrocyte migration and proliferation, respectively.
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Affiliation(s)
- Tokuhiro Kimura
- Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan
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de Oliveira Demarchi ACC, Zambuzzi WF, Paiva KBS, da Silva-Valenzuela MDG, Nunes FD, de Cássia Sávio Figueira R, Sasahara RM, Demasi MAA, Winnischofer SMB, Sogayar MC, Granjeiro JM. Development of secondary palate requires strict regulation of ECM remodeling: sequential distribution of RECK, MMP-2, MMP-3, and MMP-9. Cell Tissue Res 2010; 340:61-69. [PMID: 20165883 DOI: 10.1007/s00441-010-0931-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2009] [Accepted: 01/15/2010] [Indexed: 11/29/2022]
Abstract
We have evaluated RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), MMP-2 (matrix metalloproteinase-2), MMP-3, and MMP-9 involvement during palate development in mice by using various techniques. Immunohistochemical features revealed the distribution of RECK, MMP-2, and MMP-3 in the mesenchymal tissue and in the midline epithelial seam at embryonic day 13 (E13), MMPs-2, -3, and -9 being particularly expressed at E14 and E14.5. In contrast, RECK was weakly immunostained at these times. Involvement of MMPs was validated by measuring not only their protein expression, but also their activity (zymograms). In situ hybridization signal (ISH) for RECK transcript was distributed in mesenchymal and epithelial regions within palatal shelves at all periods evaluated. Importantly, the results from ISH analysis were in accord with those obtained by real-time polymerase chain reaction. The expression of RECK was found to be temporally regulated, which suggested possible roles in palatal ontogeny. Taken together, our results clearly show that remodeling of the extracellular matrix is finely modulated during secondary palate development and occurs in a sequential manner.
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Abstract
AIM: To investigate the relation between RECK methylation and clinicopathological characteristics of gastric cancer patients and evaluate the role of RECK methylation in peritoneal metastasis of gastric cancer.
METHODS: Methylation of RECK gene in 40 paired samples of gastric cancer and its corresponding adjacent normal mucosa, lymph nodes and peritoneal irrigation fluid was detected by methylation-specific polymerase chain reaction.
RESULTS: Aberrant methylation of RECK gene was detected in 27.5% (11/40) of the adjacent normal mucosa samples, in 47.5% (19/40) of gastric cancer samples, in 57.1% (12/21) of the lymph node samples, and in 35% (14/40) of peritoneal irrigation fluid samples, respectively, with a significant difference between the adjacent normal mucosa and lymph node samples (P = 0.023). Presence of RECK methylation in the primary tumor samples was significantly correlated with tumor invasion (P = 0.023). The accuracy of RECK methylation in peritoneal lavage fluid samples for the diagnosis of peritoneal metastasis of gastric cancer was 72.5% (26/40), with a sensitivity of 66.7% (6/9) and a specificity of 74.2% (23/31).
CONCLUSION: Aberrant methylation of RECK gene may provide useful information for the early diagnosis and treatment of peritoneal metastasis of gastric cancer.
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