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Snail-modulated microRNA 493 forms a negative feedback loop with the insulin-like growth factor 1 receptor pathway and blocks tumorigenesis
Published in American Society for Microbiology
2017
PMID: 27956702
Volume: 37
   
Issue: 6
Abstract
In this study, we have identified one microRNA, microRNA 493 (miR-493), which could simultaneously and directly regulate multiple genes downstream of the insulin-like growth factor 1 receptor (IGF1R) pathway, including IGF1R, by binding with complementary sequences in the 3' untranslated region (UTR) of mRNAs of IGF1R, insulin receptor substrate 1 (IRS1), and mitogen-activated protein kinase 1 (MAPK1), thereby potentiating their inhibitory function at multiple levels in development and progression of cancers. This binding was further confirmed by pulldown of miR with AGO-2 antibody. Further, results from head and neck samples showed that miR-493 levels were significantly downregulated in tumors, with a concomitant increase in the expression of IGF1R and key downstream effectors. Functional studies from miR-493 overexpression cells and nude-mouse models revealed the tumor suppressor functions of miR-493. Regulation studies revealed that Snail binds to the miR-493 promoter and represses it. We found the existence of a dynamic negative feedback loop in the regulation of IGF1R and miR-493 mediated via Snail. Our study showed that nicotine treatment significantly decreases the levels of miR-493-with a concomitant increase in the levels of Snail-an indication of progression of cells toward tumorigenesis, reestablishing the role of tobacco as a major risk factor for head and neck cancers and elucidating the mechanism behind nicotine-mediated tumorigenesis. © 2017 American Society for Microbiology. All Rights Reserved.
About the journal
JournalMolecular and Cellular Biology
PublisherAmerican Society for Microbiology
ISSN02707306
Open AccessYes
Concepts (88)
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    AGO 2 ANTIBODY
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    Antineoplastic agent
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    ARGONAUTE 2 PROTEIN
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    Glycogen synthase kinase 3beta
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    Immunoglobulin enhancer binding protein
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    INSULIN RECEPTOR SUBSTRATE 1
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    Messenger rna
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    Microrna
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    MICRORNA 493
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    MITOGEN ACTIVATED PROTEIN KINASE 1
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    Nicotine
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    PROTEIN ANTIBODY
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    Protein kinase b
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    Small interfering rna
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    SOMATOMEDIN C RECEPTOR
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    STAT3 PROTEIN
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    TRANSCRIPTION FACTOR SNAIL
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    Unclassified drug
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    UVOMORULIN
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    VIMENTIN
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    VINCULIN
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    MIRN493 MICRORNA, HUMAN
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    SOMATOMEDIN C RECEPTOR
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    TRANSCRIPTION FACTOR SNAIL
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    3' UNTRANSLATED REGION
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    Animal experiment
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    Animal model
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    Animal tissue
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    Article
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    CANCER GROWTH
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    Cancer inhibition
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    CARCINOGENESIS
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    Controlled study
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    Down regulation
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    Epithelial mesenchymal transition
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    Fetus
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    Gene expression regulation
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    Gene overexpression
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    Gene repression
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    Head and neck cancer
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    HEAD AND NECK CANCER CELL LINE
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    Human
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    Human cell
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    Human tissue
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    Male
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    Mouse
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    Negative feedback
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    Nonhuman
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    Normal human
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    Priority journal
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    Promoter region
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    PROTEIN RNA BINDING
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    Signal transduction
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    Transcription regulation
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    Tumor microenvironment
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    TUMOR SUPPRESSOR GENE
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    Animal
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    Binding site
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    Biological model
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    Cell proliferation
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    Drug effects
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    Drug screening
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    Genetics
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    Head and neck tumor
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    Kinetics
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    Metabolism
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    Nude mouse
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    Pathology
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    Physiological feedback
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    Tumor cell line
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    TUMOR SUPPRESSOR GENE
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    Animals
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    Binding sites
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    CARCINOGENESIS
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    Cell line, tumor
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    Down-regulation
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    Epithelial-mesenchymal transition
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    Feedback, physiological
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    GENE EXPRESSION REGULATION, NEOPLASTIC
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    GENES, TUMOR SUPPRESSOR
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    HEAD AND NECK NEOPLASMS
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    Humans
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    Mice, nude
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    Micrornas
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    Models, biological
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    RECEPTOR, IGF TYPE 1
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    SNAIL FAMILY TRANSCRIPTION FACTORS
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    XENOGRAFT MODEL ANTITUMOR ASSAYS