Snail-Modulated MicroRNA 493 Forms a Negative Feedback Loop with the Insulin-Like Growth Factor 1 Receptor Pathway and Blocks Tumorigenesis.

Autor:	Kumar AS; Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India., Jagadeeshan S; Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India., Pitani RS; Department of Community Medicine, Sri Ramachandra University, Chennai, India., Ramshankar V; Department of Preventive Oncology, Cancer Institute (WIA), Chennai, India., Venkitasamy K; Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India., Venkatraman G; Department of Human Genetics, Sri Ramachandra University, Chennai, India ganeshv@sriramachandra.edu.in rayala@iitm.ac.in., Rayala SK; Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, India ganeshv@sriramachandra.edu.in rayala@iitm.ac.in.
Jazyk:	angličtina
Zdroj:	Molecular and cellular biology [Mol Cell Biol] 2017 Mar 01; Vol. 37 (6). Date of Electronic Publication: 2017 Mar 01 (Print Publication: 2017).
DOI:	10.1128/MCB.00510-16
Abstrakt:	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. (Copyright © 2017 American Society for Microbiology.)
Databáze:	MEDLINE
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