title: The adult stem cell marker Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via Notch-1 and p21WAF1/CIP1.
abstract: The RNA-binding protein Musashi-1 has been proposed to maintain stem cell function during development and regenerative processes as a modulator of the Notch-1 signaling pathway. Musashi-1 expression is upregulated in endometrial carcinoma, however, its pathogenetic role in this tumor entity is unknown. Here we investigate the functional impact and mode of action of Musashi-1 on endometrial carcinoma cell behaviour in vitro. Aldehyde dehydrogenase-1 activity and side population (SP) measurement by Hoechst dye exclusion revealed that the Ishikawa endometrial carcinoma cell line contains a pool of putative cancer stem cells. Musashi-1 expression is 20.8-fold upregulated in SP+ compared to SP- and equally distributed between ALDH+ and ALDH- cell pools. siRNA-mediated knockdown of Musashi-1 mRNA expression lead to an altered expression of the signaling receptor Notch-1 and its downstream targets, the transcription factor Hes-1 and the cell cycle regulators p21(WAF1/CIP1)  and cyclin B1, as determined by Western blotting and quantitative real-time PCR. Flow cytometric and ELISA analyses revealed that Musashi-1-mediated modulation of these factors exerted an antiproliferative effect on the cell cycle, and increased apoptosis in endometrial carcinoma cells. We conclude that Ishikawa cells contain a subpopulation of cells with stem cell-like properties. Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via the stemness-related factors Notch-1, Hes-1 and p21(WAF1/CIP1) , thus emerging as a novel future target for endometrial carcinoma therapy.
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital, Münster, Germany. mgotte@uni-muenster.de
authors.forename: Martin
authors.initials: M
authors.lastname: Götte
authors.forename: Burkhard
authors.initials: B
authors.lastname: Greve
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kelsch
authors.forename: Heike
authors.initials: H
authors.lastname: Müller-Uthoff
authors.forename: Kristin
authors.initials: K
authors.lastname: Weiss
authors.forename: Behzad
authors.initials: B
authors.lastname: Kharabi Masouleh
authors.forename: Walter
authors.initials: W
authors.lastname: Sibrowski
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kiesel
authors.forename: Olaf
authors.initials: O
authors.lastname: Buchweitz
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C493956:CDKN1A protein, human; C491297:MSI1 protein, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human