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      Schistosoma mansoni Egg–Secreted Antigens Activate Hepatocellular Carcinoma–Associated Transcription Factors c‐Jun and STAT3 in Hamster and Human Hepatocytes

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          Abstract

          Clinical data have provided evidence that schistosomiasis can promote hepatocellular carcinogenesis. c‐Jun and STAT3 are critical regulators of liver cancer development and progression. The aim of the present study was to investigate the hepatocellular activation of c‐Jun and STAT3 by Schistosoma mansoni infection. Expression and function of c‐Jun and STAT3 as well as proliferation and DNA repair were analyzed by western blotting, electrophoretic mobility‐shift assay, and immunohistochemistry in liver of S. mansoni–infected hamsters, Huh7 cells, primary hepatocytes, and human liver biopsies. Hepatocellular activation of c‐Jun was demonstrated by nuclear translocation of c‐Jun, enhanced phosphorylation (Ser73), and AP‐1/DNA‐binding in response to S. mansoni infection. Nuclear c‐Jun staining pattern around lodged eggs without ambient immune reaction, and directionally from granuloma to the central veins, suggested that substances released from schistosome eggs were responsible for the observed effects. In addition, hepatocytes with c‐Jun activation show cell activation and DNA double‐strand breaks. These findings from the hamster model were confirmed by analyses of human biopsies from patients with schistosomiasis. Cell culture experiments finally demonstrated that activation of c‐Jun and STAT3 as well as DNA repair were induced by an extract from schistosome eggs (soluble egg antigens) and culture supernatants of live schistosome egg (egg‐conditioned medium), and in particular by IPSE/alpha‐1, the major component secreted by live schistosome eggs. The permanent activation of hepatocellular carcinoma–associated proto‐oncogenes such as c‐Jun and associated transcription factors including STAT3 by substances released from tissue‐trapped schistosome eggs may be important factors contributing to the development of liver cancer in S. mansoni–infected patients. Therefore, identification and therapeutic targeting of the underlying pathways is a useful strategy to prevent schistosomiasis‐associated carcinogenesis.

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          DNA double-strand breaks: signaling, repair and the cancer connection.

          To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and post-transcriptional activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death. An inability to respond properly to, or to repair, DNA damage leads to genetic instability, which in turn may enhance the rate of cancer development. Indeed, it is becoming increasingly clear that deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most, if not all, human cancers. Here we describe recent progress in our understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation-the DNA double-strand break (DSB). Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.
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            Ubiquitous activation of Ras and Jak/Stat pathways in human HCC.

            Although the natural history and pathologic characteristics of human hepatocellular carcinoma (HCC) are well documented, the molecular pathogenesis of HCC remains poorly understood. Here, we define the role for Ras and Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathways in human HCC. Promoter and genomic status of Ras and Jak/Stat inhibitors were assessed in 80 HCCs by methylation-specific polymerase chain reaction and microsatellite analysis. Activation of Ras and Jak/Stat signaling pathways was determined by DNA sequencing, Western blot, and immunoprecipitation analysis. Suppression of Ras and Jak/Stat pathways in HCC cell lines was evaluated by viability and apoptosis assays. Activation of Ras and Jak/Stat pathways was enhanced in all HCCs when compared with nonneoplastic surrounding and normal livers coincidently with the suppression of at least 1 Ras (RASSF1A and/or NORE1A) and 2 Jak/Stat inhibitors (cytokine-inducible SH2-protein [CIS]; suppressor of cytokine signaling [SOCS]1, 2, 3; and SH2-containing phosphatases [SHP1]). HCC associated with cirrhosis showed significantly higher frequency of RASSF1A, CIS, and SOCS1 promoter methylation than HCC without cirrhosis (P < .002, P < .02, and P < .02, respectively). Furthermore, aberrant methylation of NORE1A and SOCS3 promoters was observed only in a subclass of HCC with poor survival, suggesting that inactivation of these 2 genes might be involved in HCC progression. Combined treatment of HCC cell lines with Ras and Jak/Stat inhibitors as well as with the demethylating agent zebularine induced a strong apoptotic response. These data demonstrate the ubiquitous activation of Ras and Jak/Stat pathways in HCC and suggest the potential use of Ras and Jak/Stat inhibitors and demethylating agents as therapeutic modality for human liver cancer.
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              Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139.

              Histone H2AX is a ubiquitous member of the H2A histone family that differs from the other H2A histones by the presence of an evolutionarily conserved C-terminal motif, -KKATQASQEY. The serine residue in this motif becomes rapidly phosphorylated in cells and animals when DNA double-stranded breaks are introduced into their chromatin by various physical and chemical means. In the present communication we show that this phosphorylated form of H2AX, referred to as gamma-H2AX, appears during apoptosis concurrently with the initial appearance of high molecular weight DNA fragments. gamma-H2AX forms before the appearance of internucleosomal DNA fragments and the externalization of phosphatidylserine to the outer membrane leaflet. gamma-H2AX formation is inhibited by N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and the inhibitor of caspase-activated DNase, and it is induced when DNase I and restriction enzymes are introduced into cells, suggesting that any apoptotic endonuclease is sufficient to induce gamma-H2AX formation. These results indicate that gamma-H2AX formation is an early chromatin modification following initiation of DNA fragmentation during apoptosis.
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                Author and article information

                Contributors
                elke.roeb@innere.med.uni-giessen.de
                Journal
                Hepatology
                Hepatology
                10.1002/(ISSN)1527-3350
                HEP
                Hepatology (Baltimore, Md.)
                John Wiley and Sons Inc. (Hoboken )
                0270-9139
                1527-3350
                12 February 2019
                August 2020
                : 72
                : 2 ( doiID: 10.1002/hep.v72.2 )
                : 626-641
                Affiliations
                [ 1 ] Department of Gastroenterology Justus‐Liebig‐University Giessen Germany
                [ 2 ] Institute of Parasitology BFS, Justus‐Liebig‐University Giessen Germany
                [ 3 ] Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry RWTH University Hospital Aachen Aachen Germany
                [ 4 ] Translational Gastrointestinal Pathology, Institute of Pathology University Hospital Heidelberg Heidelberg Germany
                [ 5 ] Experimental Pneumology, Priority Research Area Asthma & Allergy Research Center Borstel Parkallee, Borstel Germany
                [ 6 ] Institute for Medical Informatics Justus‐Liebig‐University Giessen Germany
                Author notes
                [*] [* ] Address Correspondence and Reprint Requests to:

                Elke Roeb, M.D., Department of Gastroenterology, Internal Medicine, Justus‐Liebig‐University Klinikstrasse 33, D‐35385 Giessen, Germany. E‐mail: elke.roeb@ 123456innere.med.uni-giessen.de . Tel: +49‐641‐985‐42337

                Author information
                http://orcid.org/0000-0003-3888-0931
                Article
                HEP30192
                10.1002/hep.30192
                7496692
                30053321
                f55a0ba9-435c-402e-878e-bdc4cca408d8
                © 2018 The Authors. H epatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 22 December 2017
                : 23 July 2018
                Page count
                Figures: 6, Tables: 1, Pages: 20, Words: 12476
                Funding
                Funded by: Von‐Behring‐Röntgen‐Stiftung
                Award ID: 60-0002
                Funded by: Gilead Sciences
                Award ID: support program infectiology 2017
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: RO957/10
                Funded by: University Hospital Giessen and Marburg
                Categories
                Original Article
                Original Articles
                Liver Biology/Pathobiology
                Custom metadata
                2.0
                August 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020

                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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