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CXADR-Like Membrane Protein Regulates Colonic Epithelial Cell Proliferation and Prevents Tumor Growth.

Authors
  • Luissint, Anny-Claude1
  • Fan, Shuling1
  • Nishio, Hikaru2
  • Lerario, Antonio M3
  • Miranda, Jael1
  • Hilgarth, Roland S1
  • Cook, Jonas1
  • Nusrat, Asma4
  • Parkos, Charles A5
  • 1 Department of Pathology, University of Michigan, Ann Arbor, Michigan.
  • 2 Department of Pathology, Emory University, Atlanta, Georgia. , (Georgia)
  • 3 Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan.
  • 4 Department of Pathology, University of Michigan, Ann Arbor, Michigan. Electronic address: [email protected].
  • 5 Department of Pathology, University of Michigan, Ann Arbor, Michigan. Electronic address: [email protected].
Type
Published Article
Journal
Gastroenterology
Publication Date
Jan 01, 2024
Volume
166
Issue
1
Identifiers
DOI: 10.1053/j.gastro.2023.09.012
PMID: 37716376
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

CXADR-like membrane protein (CLMP) is structurally related to coxsackie and adenovirus receptor. Pathogenic variants in CLMP gene have been associated with congenital short bowel syndrome, implying a role for CLMP in intestinal development. However, the contribution of CLMP to regulating gut development and homeostasis is unknown. In this study, we investigated CLMP function in the colonic epithelium using complementary in vivo and in vitro approaches, including mice with inducible intestinal epithelial cell (IEC)-specific deletion of CLMP (ClmpΔIEC), intestinal organoids, IECs with overexpression, or loss of CLMP and RNA sequencing data from individuals with colorectal cancer. Loss of CLMP enhanced IEC proliferation and, conversely, CLMP overexpression reduced proliferation. Xenograft experiments revealed increased tumor growth in mice implanted with CLMP-deficient colonic tumor cells, and poor engraftment was observed with CLMP-overexpressing cells. ClmpΔIEC mice showed exacerbated tumor burden in an azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis model, and CLMP expression was reduced in human colorectal cancer samples. Mechanistic studies revealed that CLMP-dependent regulation of IEC proliferation is linked to signaling through mTOR-Akt-β-catenin pathways. These results reveal novel insights into CLMP function in the colonic epithelium, highlighting an important role in regulating IEC proliferation, suggesting tumor suppressive function in colon cancer. Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.

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