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

Autor:	Luissint AC; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Fan S; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Nishio H; Department of Pathology, Emory University, Atlanta, Georgia., Lerario AM; Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan., Miranda J; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Hilgarth RS; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Cook J; Department of Pathology, University of Michigan, Ann Arbor, Michigan., Nusrat A; Department of Pathology, University of Michigan, Ann Arbor, Michigan. Electronic address: anusrat@med.umich.edu., Parkos CA; Department of Pathology, University of Michigan, Ann Arbor, Michigan. Electronic address: cparkos@med.umich.edu.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2024 Jan; Vol. 166 (1), pp. 103-116.e9. Date of Electronic Publication: 2023 Sep 14.
DOI:	10.1053/j.gastro.2023.09.012
Abstrakt:	Background & Aims: 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. Methods: 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 (Clmp ΔIEC ), intestinal organoids, IECs with overexpression, or loss of CLMP and RNA sequencing data from individuals with colorectal cancer. Results: 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. Clmp ΔIEC 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. Conclusions: 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.)
Databáze:	MEDLINE
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