title: Intestinal epithelial HuR modulates distinct pathways of proliferation and apoptosis and attenuates small intestinal and colonic tumor development.
abstract: HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur (IKO) mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of Apc(min/+) mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a three-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis, and decreased expression of transcripts encoding antiapoptotic HuR target RNAs. Similarly, Hur(IKO) mice subjected to an inflammatory colon carcinogenesis protocol [azoxymethane and dextran sodium sulfate (AOM-DSS) administration] exhibited a two-fold decrease in tumor burden. Hur(IKO) mice showed no change in ileal Asbt expression, fecal bile acid excretion, or enterohepatic pool size that might explain the phenotype. Moreover, none of the HuR targets identified in Apc(min/+)Hur(IKO) were altered in AOM-DSS-treated Hur(IKO) mice, the latter of which exhibited increased apoptosis of colonic epithelial cells, where elevation of a unique set of HuR-targeted proapoptotic factors was documented. Taken together, our results promote the concept of epithelial HuR as a contextual modifier of proapoptotic gene expression in intestinal cancers, acting independently of bile acid metabolism to promote cancer. In the small intestine, epithelial HuR promotes expression of prosurvival transcripts that support Wnt-dependent tumorigenesis, whereas in the large intestine epithelial HuR indirectly downregulates certain proapoptotic RNAs to attenuate colitis-associated cancer. Cancer Res; 74(18); 5322-35. ©2014 AACR.
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Antonina
authors.initials: A
authors.lastname: Giammanco
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Valerie
authors.initials: V
authors.lastname: Blanc
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Grace
authors.initials: G
authors.lastname: Montenegro
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Coen
authors.initials: C
authors.lastname: Klos
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Susan
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Jianyang
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, New York.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, New York, New York.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Ilke
authors.initials: I
authors.lastname: Nalbantoglu
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.
authors.forename: Sekhar
authors.initials: S
authors.lastname: Dharmarajan
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri. nod@dom.wustl.edu.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D051959:ELAV Proteins
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