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      Gankyrin Contributes to Tumorigenesis and Chemoresistance in Sporadic Colorectal Cancer

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          Abstract

          Background: Although Gankyrin is overexpressed in many malignancies, the role of Gankyrin for tumorigenesis and chemoresistance remains to be elucidated in sporadic colorectal cancer (CRC). Aims: We investigate whether Gankyrin affects Adenomatous polyposis coli ( Apc) inactivation-induced tumorigenesis and therapeutic response to anti-angiogenic agents. Methods: Epithelial cell-specific APC and/or Gankyrin-deficient mice were used. The patients with metastatic CRC ( n = 53) who were enrolled in this study underwent resection of primary cancer followed by systemic chemotherapy containing bevacizumab. We determined whether gene expression in CRC tissues before chemotherapy is associated with radiological responses. Results: Deletion of Gankyrin in epithelial cell reduced the expression of c-Myc, a critical mediator of the APC signaling pathway, and interleukin-6. Gankyrin deficiency decreased the expression of Bmi1, a downstream molecule of c-Myc, and the activity of V-Akt murine thymoma viral oncogene homolog and extracellular signal-regulated protein kinase, leading to reduced Apc inactivation-induced tumorigenesis. Of 53 patients, 38 (72%) had increased Gankyrin expression in tumor cells. The enhanced Gankyrin expression in tumor cells was associated with unfavorable progression-free survival (log-rank test p = 0.026). Conclusion: Gankyrin in epithelial cell contributes to the development of sporadic CRC and the expression could serve as a biomarker to predict therapeutic response in patients with metastatic CRC.

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          Author and article information

          Journal
          DIG
          Digestion
          10.1159/issn.0012-2823
          Digestion
          S. Karger AG
          0012-2823
          1421-9867
          2019
          October 2019
          04 December 2018
          : 100
          : 3
          : 192-200
          Affiliations
          [_a] aDepartment of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
          [_b] bDepartment of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
          Author notes
          *Toshiharu Sakurai, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511 (Japan), E-Mail sakurai@med.kindai.ac.jp
          Author information
          https://orcid.org/0000-0001-5407-7925
          Article
          494969 Digestion 2019;100:192–200
          10.1159/000494969
          30513515
          70db4f6f-588a-4c7a-9ab0-28e26ecbaaa9
          © 2018 S. Karger AG, Basel

          Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

          History
          : 22 May 2018
          : 23 October 2018
          Page count
          Figures: 4, Tables: 1, Pages: 9
          Categories
          Original Paper

          Oncology & Radiotherapy,Gastroenterology & Hepatology,Surgery,Nutrition & Dietetics,Internal medicine
          Interleukin-6,V-Akt murine thymoma viral oncogene homolog,c-Myc,Bmi1,Bevacizumab,Extracellular signal-regulated protein kinase

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