HuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis.
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Authors
Lang, MichaelaBerry, David
Passecker, Katharina
Mesteri, Ildiko
Bhuju, Sabin
Ebner, Florian
Sedlyarov, Vitaly
Evstatiev, Rayko
Dammann, Kyle
Loy, Alexander
Kuzyk, Orest
Kovarik, Pavel
Khare, Vineeta
Beibel, Martin
Roma, Guglielmo
Meisner-Kober, Nicole
Gasche, Christoph
Issue Date
2017-05-01
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Show full item recordAbstract
HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3' untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia. Intraperitoneal injection of the HuR small-molecule inhibitor MS-444 in AOM/DSS mice, a model of IBD and inflammatory colon cancer, augmented DSS-induced weight loss and increased tumor multiplicity, size, and invasiveness. MS-444 treatment also abrogated tumor cell apoptosis and depleted tumor-associated eosinophils, accompanied by a decrease in IL18 and eotaxin-1. In contrast, HuR inhibition in APCMin mice, a model of FAP and colon cancer, diminished the number of small intestinal tumors generated. In this setting, fecal microbiota, evaluated by 16S rRNA gene amplicon sequencing, shifted to a state of reduced bacterial diversity, with an increased representation of Prevotella, Akkermansia, and Lachnospiraceae Taken together, our results indicate that HuR activation is an early event in FAP-adenoma but is not present in IBD-dysplasia. Furthermore, our results offer a preclinical proof of concept for HuR inhibition as an effective means of FAP chemoprevention, with caution advised in the setting of IBD. Cancer Res; 77(9); 2424-38. ©2017 AACR.Citation
Cancer Res. 2017 May 1;77(9):2424-2438. doi: 10.1158/0008-5472.CAN-15-1726. Epub 2017 Feb 20.Affiliation
ZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
American Association for Cancer ResearchJournal
Cancer ResearchPubMed ID
28428272Type
ArticleLanguage
enISSN
1538-7445ae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-15-1726
Scopus Count
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