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dc.contributor.authorLang, Michaela
dc.contributor.authorBerry, David
dc.contributor.authorPassecker, Katharina
dc.contributor.authorMesteri, Ildiko
dc.contributor.authorBhuju, Sabin
dc.contributor.authorEbner, Florian
dc.contributor.authorSedlyarov, Vitaly
dc.contributor.authorEvstatiev, Rayko
dc.contributor.authorDammann, Kyle
dc.contributor.authorLoy, Alexander
dc.contributor.authorKuzyk, Orest
dc.contributor.authorKovarik, Pavel
dc.contributor.authorKhare, Vineeta
dc.contributor.authorBeibel, Martin
dc.contributor.authorRoma, Guglielmo
dc.contributor.authorMeisner-Kober, Nicole
dc.contributor.authorGasche, Christoph
dc.date.accessioned2019-09-19T13:49:06Z
dc.date.available2019-09-19T13:49:06Z
dc.date.issued2017-05-01
dc.identifier.citationCancer Res. 2017 May 1;77(9):2424-2438. doi: 10.1158/0008-5472.CAN-15-1726. Epub 2017 Feb 20.en_US
dc.identifier.issn1538-7445
dc.identifier.pmid28428272
dc.identifier.doi10.1158/0008-5472.CAN-15-1726
dc.identifier.urihttp://hdl.handle.net/10033/621952
dc.description.abstractHuR 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.en_US
dc.language.isoenen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleHuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis.en_US
dc.typeArticleen_US
dc.contributor.departmentZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalCancer Researchen_US
refterms.dateFOA2019-09-19T13:49:06Z
dc.source.journaltitleCancer research


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