title: Snail-Modulated MicroRNA 493 Forms a Negative Feedback Loop with the Insulin-Like Growth Factor 1 Receptor Pathway and Blocks Tumorigenesis.
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.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: Arathy S
authors.initials: AS
authors.lastname: Kumar
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: Sankar
authors.initials: S
authors.lastname: Jagadeeshan
authors.affiliation: Department of Community Medicine, Sri Ramachandra University, Chennai, India.
authors.forename: Ravi Shankar
authors.initials: RS
authors.lastname: Pitani
authors.affiliation: Department of Preventive Oncology, Cancer Institute (WIA), Chennai, India.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ramshankar
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India.
authors.forename: Kesavan
authors.initials: K
authors.lastname: Venkitasamy
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Chennai, India ganeshv@sriramachandra.edu.in rayala@iitm.ac.in.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkatraman
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India ganeshv@sriramachandra.edu.in rayala@iitm.ac.in.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Rayala
mesh_terms: D000818:Animals; D001665:Binding Sites; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009538:Nicotine / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C555448:MIRN493 microRNA, human; D035683:MicroRNAs; D000071250:Snail Family Transcription Factors; D009538:Nicotine; D017526:Receptor, IGF Type 1
keywords: IGF1R; Snail; feedback loop; miR-493; nicotine