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NDRG 4, an early detection marker for colorectal cancer, is specifically expressed in enteric neurons
Author(s) -
Vaes N.,
Lentjes M. H. F. M.,
Gijbels M. J.,
Rademakers G.,
Daenen K. L.,
Boesmans W.,
Wouters K. A. D.,
Geuzens A.,
Qu X.,
Steinbusch H. P. J.,
Rutten B. P. F.,
Baldwin S. H.,
Sharkey K. A.,
Hofstra R. M. W.,
Engeland M.,
Vanden Berghe P.,
Melotte V.
Publication year - 2017
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13095
Subject(s) - enteric nervous system , interstitial cell of cajal , biology , in situ hybridization , immunofluorescence , western blot , immunohistochemistry , pathology , microbiology and biotechnology , immunology , gene expression , neuroscience , medicine , gene , antibody , biochemistry
Background Promoter methylation of N‐myc Downstream‐Regulated Gene 4 ( NDRG 4) in fecal DNA is an established early detection marker for colorectal cancer ( CRC ). Despite its connection to CRC , NDRG 4 is predominantly studied in brain and heart, with little to no knowledge about its expression or role in other organs. In this study, we aimed to determine the whole‐body expression of NDRG 4, with a focus on the intestinal tract. Methods We investigated NDRG 4 expression throughout the body by immunohistochemistry, Western Blotting and in situ mRNA hybridization using tissues from NDRG 4 wild‐type, heterozygous and knockout mice and humans. In addition, we explored cell‐specific expression of NDRG 4 in murine whole‐mount gut preparations using immunofluorescence and confocal microscopy. Key Results NDRG 4 is specifically expressed within nervous system structures throughout the body. In the intestinal tract of both mouse and man, NDRG 4 immunoreactivity was restricted to the enteric nervous system ( ENS ), where it labeled cell bodies of the myenteric and submucosal plexuses and interconnecting nerve fibers. More precisely, NDRG 4 expression was limited to neurons, as NDRG 4 always co‐localized with HuC/D (pan‐neuronal marker) but never with GFAP (an enteric glial cell marker). Furthermore, NDRG 4 was expressed in various neuropeptide Y positive neurons, but was only found in a minority (~10%) of neurons expressing neuronal nitric oxide synthase. Conclusions and Inferences NDRG 4 is exclusively expressed by central, peripheral and enteric neurons/nerves, suggesting a neuronal‐specific role of this protein. Our findings raise the question whether NDRG 4, via the ENS , an understudied component of the tumor microenvironment, supports CRC development and/or progression.