RRC ID 78448
Author Nakata T, Shimizu H, Nagata S, Ito G, Fujii S, Suzuki K, Kawamoto A, Ishibashi F, Kuno R, Anzai S, Murano T, Mizutani T, Oshima S, Tsuchiya K, Nakamura T, Hozumi K, Watanabe M, Okamoto R.
Title Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors.
Journal Biochem Biophys Res Commun
Abstract Ligand-dependent activation of Notch signaling is required to maintain the stem-cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5+ve cells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors. In vitro studies using tumor-derived organoids confirmed the intrinsic Notch activity-dependent growth of tumor cells. Surprisingly, the targeted deletion of Jag1 but not RBPJ in LGR5+ve tumor-initiating cells resulted in the silencing of Hes1 expression, disruption of the tumor stem cell niche, and dramatic reduction in the proliferation activity of APC-deficient intestinal tumors in vivo. Thus, our results highlight the importance of ligand-dependent non-canonical Notch signaling in the proliferation and maintenance of the tumor stem cell niche in APC-deficient intestinal adenomas.
Volume 482(4)
Pages 1296-1303
Published 2017-1-22
DOI 10.1016/j.bbrc.2016.12.031
PII S0006-291X(16)32075-7
PMID 27939883
MeSH Adenoma / metabolism Adenomatous Polyposis Coli Protein / genetics* Animals Cell Proliferation Epidermal Growth Factor / metabolism Gene Deletion Gene Expression Regulation, Neoplastic Gene Silencing Intestinal Neoplasms / metabolism* Jagged-1 Protein / genetics* Ligands Mice Microscopy, Fluorescence Neoplastic Stem Cells / cytology Receptors, G-Protein-Coupled / metabolism Receptors, Notch / metabolism* Signal Transduction Stem Cells / cytology*
Mice RBRC01872