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      Aberrant methylation and silencing of the SPINT2 gene in high‐grade gliomas

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          Abstract

          Hepatocyte growth factor activator inhibitor type 2 ( HAI‐2), encoded by the SPINT2 gene, is a membrane‐anchored protein that inhibits proteases involved in the activation of hepatocyte growth factor ( HGF), a ligand of MET receptor. Epigenetic silencing of the SPINT2 gene has been reported in a human glioblastoma cell line (U87) and glioblastoma‐derived cancer stem cells. However, the incidence of SPINT2 methylation in tumor tissues obtained from glioma patients is unknown. In this study, we analyzed the methylation status of the SPINT2 gene of eight human glioblastoma cell lines and surgically resected glioma tissues of different grades ( II, III, and IV) by bisulfite sequence analysis and methylation‐specific PCR. Most glioblastoma lines (7/8) showed methylation of the SPINT2 gene with a significantly reduced level of SPINT2 mRNA compared to cultured astrocytes and normal brain tissues. However, all glioblastoma lines expressed mRNA for HGF activator ( HGFAC ), a target protease of HAI‐2/ SPINT2. Forced expression of SPINT2 reduced MET phosphorylation of U87 glioblastoma cells both in vitro and in intracranial xenografts in nude mice. Methylation‐specific PCR analysis of the resected glioma tissues indicated notable methylation of the SPINT2 gene in 33.3% (2/6), 71.4% (10/14), and 74.3% (26/35) of grade II, III, and IV gliomas, respectively. Analysis of RNA sequencing data in a public database indicated an increased HGFAC / SPINT2 expression ratio in high‐grade compared to low‐grade gliomas ( =  .01). In summary, aberrant methylation of the SPINT2 gene is frequently observed in high‐grade gliomas and might confer MET signaling in the glioma cells.

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          Most cited references 28

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          Gene methylation in gastric cancer.

          Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.
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            Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor.

            Hepatocyte growth factor (HGF) activator is a serine protease that is produced and secreted by the liver and circulates in the blood as an inactive zymogen. In response to tissue injury, the HGF activator zymogen is converted to the active form by limited proteolysis. The activated HGF activator converts an inactive single chain precursor of HGF to a biologically active heterodimer in injured tissue. The activated HGF may be involved in the regeneration of the injured tissue. In this study, we purified an inhibitor of HGF activator from the conditioned medium of a human MKN45 stomach carcinoma cell line and molecularly cloned its cDNA. The sequence of the cDNA revealed that the inhibitor has two well defined Kunitz domains, suggesting that the inhibitor is a member of the Kunitz family of serine protease inhibitors. The sequence also showed that the primary translation product of the inhibitor has a hydrophobic sequence at the COOH-terminal region. Inhibitory activity toward HGF activator was detected in the membrane fraction as well as in the conditioned medium of MKN45 cells. These results suggest that the inhibitor may be produced as a membrane-associated form and secreted by the producing cells as a proteolytically truncated form.
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              Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues

              Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activator (HGFA) and matriptase are the most potent activators. Increased activities of both proteases have been observed in various cancers. HGFA is synthesized mainly by the liver and secreted as an inactive pro-form. In cancer tissues, pro-HGFA is likely activated by thrombin and/or human kallikrein 1-related peptidase (KLK)-4 and KLK-5. Matriptase is a type II transmembrane serine protease that is expressed by most epithelial cells and is also synthesized as an inactive zymogen. Matriptase activation is likely to be mediated by autoactivation or by other trypsin-like proteases. Recent studies revealed that matriptase autoactivation is promoted by an acidic environment. Given the mildly acidic extracellular environment of solid tumors, matriptase activation may, thus, be accelerated in the tumor microenvironment. HGFA and matriptase activities are regulated by HGFA inhibitor (HAI)-1 (HAI-1) and/or HAI-2 in the pericellular microenvironment. HAIs may have an important role in cancer cell biology by regulating HGF/SF-activating proteases.
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                Author and article information

                Contributors
                mejina@med.miyazaki-u.ac.jp
                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                16 August 2018
                September 2018
                : 109
                : 9 ( doiID: 10.1111/cas.2018.109.issue-9 )
                : 2970-2979
                Affiliations
                [ 1 ] Section of Oncopathology and Regenerative Biology Department of Pathology Faculty of Medicine University of Miyazaki Miyazaki Japan
                [ 2 ] Department of Molecular Pathology Yamaguchi University Graduate School of Medicine Ube Japan
                [ 3 ] Section of Neurosurgery Department of Clinical Neuroscience Faculty of Medicine University of Miyazaki Miyazaki Japan
                Author notes
                [* ] Correspondence: Hiroaki Kataoka, Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, JapanEmail: ( mejina@ 123456med.miyazaki-u.ac.jp ).
                Article
                CAS13732
                10.1111/cas.13732
                6125435
                29987920
                © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 5, Tables: 2, Pages: 10, Words: 5759
                Product
                Funding
                Funded by: Miyazaki University Hospital
                Funded by: Japan Society for the Promotion of Science KAKENHI
                Award ID: 16H05175
                Award ID: 17K08764
                Categories
                Original Article
                Original Articles
                Pathology
                Custom metadata
                2.0
                cas13732
                September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.7.1 mode:remove_FC converted:06.09.2018

                Oncology & Radiotherapy

                gene methylation, glioma, hai‐2, hgf activator, spint2

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