title: The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial-Mesenchymal Transition in Breast Cancer.
abstract: Epithelial-to-mesenchymal transition (EMT) is a core process underlying cell movement during embryonic development and morphogenesis. Cancer cells hijack this developmental program to execute a multi-step cascade, leading to tumorigenesis and metastasis. CD133 (PROM1), a marker of cancer stem cells, has been shown to facilitate EMT in various cancers, but the regulatory networks controlling CD133 gene expression and function in cancer remain incompletely delineated. In this study, we show that a ribonucleoprotein complex including the long noncoding RNA MALAT1 and the RNA-binding protein HuR (ELAVL1) binds the CD133 promoter region to regulate its expression. In luminal nonmetastatic MCF-7 breast cancer cells, HuR silencing was sufficient to upregulate N-cadherin (CDH2) and CD133 along with a migratory and mesenchymal-like phenotype. Furthermore, we found that in the basal-like metastatic cell line MDA-MB-231 and primary triple-negative breast cancer tumor cells, the repressor complex was absent from the CD133-regulatory region, but was present in the MCF-7 and primary ER+ tumor cells. The absence of the complex from basal-like cells was attributed to diminished expression of MALAT1, which, when overexpressed, dampened CD133 levels. In conclusion, our findings suggest that the failure of a repressive complex to form or stabilize in breast cancer promotes CD133 upregulation and an EMT-like program, providing new mechanistic insights underlying the control of prometastatic processes. Cancer Res; 76(9); 2626-36. ©2016 AACR.
authors.affiliation: Laboratory of Genomic Screening, Center for Integrative Biology, University of Trento, Trento, Italy. Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy. elisa.latorre@unimi.it alessandro.provenzani@unitn.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Latorre
authors.affiliation: Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Stephana
authors.initials: S
authors.lastname: Carelli
authors.affiliation: Laboratory of Transcriptional Networks, Center for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Raimondi
authors.affiliation: Laboratory of Genomic Screening, Center for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: D'Agostino
authors.affiliation: Laboratory of Genomic Screening, Center for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Castiglioni
authors.affiliation: Laboratory of Genomic Screening, Center for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zucal
authors.affiliation: San Paolo Hospital, Milan, Italy.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Moro
authors.affiliation: San Paolo Hospital, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Luciani
authors.affiliation: Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy. San Paolo Hospital, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ghilardi
authors.affiliation: Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy. San Paolo Hospital, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Monti
authors.affiliation: Laboratory of Transcriptional Networks, Center for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.affiliation: Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giulio
authors.affiliation: Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gorio
authors.affiliation: Laboratory of Genomic Screening, Center for Integrative Biology, University of Trento, Trento, Italy. elisa.latorre@unimi.it alessandro.provenzani@unitn.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Provenzani
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism*
chemical_list: C571163:CD33 protein, human; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C557041:MALAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D063268:Sialic Acid Binding Ig-like Lectin 3