Snail-modulated microRNA 493 forms a negative feedback loop with the insulin-like growth factor 1 receptor pathway and blocks tumorigenesis

Arathy S. Kumar, Sankar Jagadeeshan, Ravi Shankar Pitani, Vijayalakshmi Ramshankar, Kesavan Venkitasamy, Ganesh Venkatraman, Suresh K. Rayala

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Article numbere00510-16
JournalMolecular and Cellular Biology
Volume37
Issue number6
DOIs
StatePublished - 1 Jan 2017
Externally publishedYes

Keywords

  • Feedback loop
  • IGF1R
  • MiR-493
  • Nicotine, IGF1R
  • Snail

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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