title: IMP1 promotes tumor growth, dissemination and a tumor-initiating cell phenotype in colorectal cancer cell xenografts.
abstract: Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is a messenger RNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the blood. Furthermore, intestine-specific knockdown of Imp1 dramatically reduces tumor number in the Apc (Min/+) mouse model of intestinal tumorigenesis. In addition, IMP1 knockdown xenografts exhibit a reduced number of tumor cells entering the circulation, suggesting that IMP1 may directly modulate this early metastatic event. We further demonstrate that IMP1 overexpression decreases E-cadherin expression, promotes survival of single tumor cell-derived colonospheres and promotes enrichment and maintenance of a population of CD24+CD44+ cells, signifying that IMP1 overexpressing cells display evidence of loss of epithelial identity and enhancement of a tumor-initiating cell phenotype. Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hamilton
authors.forename: Felicite K
authors.initials: FK
authors.lastname: Noubissi
authors.forename: Prateek S
authors.initials: PS
authors.lastname: Katti
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hahn
authors.forename: Sonya R
authors.initials: SR
authors.lastname: Davey
authors.forename: Emma T
authors.initials: ET
authors.lastname: Lundsmith
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Spiegelman
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C579063:IMP1 protein, mouse; D016601:RNA-Binding Proteins; C045073:Cre recombinase; D019426:Integrases