Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells

doi:10.1074/jbc.M702806200

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Papers In Press, published online ahead of print September 7, 2007
J. Biol. Chem, 10.1074/jbc.M702806200
Submitted on April 3, 2007
Revised on September 7, 2007
Accepted on September 7, 2007

Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells

Bin Shi, Laura Sepp-Lorenzino, Marco Prisco, Peter Linsley, Tiziana deAngelis, and Renato Baserga

Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107

Corresponding Author: b_lupo{at}mail.jci.tju.edu

The insulin receptor substrate-1 (IRS-1), a docking protein for both the type 1 insulin-like growth factor receptor (IGF-IR) and the insulin receptor, is known to send a mitogenic, anti-apoptotic and anti-differentiation signal. Several micro RNAs (miRs) are suggested by the database as possible candidates for targeting IRS-1. We show here that one of the miRs predicted by the database, miR145, whether transfected as a synthetic oligonucleotide or expressed from a plasmid, causes down-regulation of IRS-1 in human colon cancer cells. IRS-1 mRNA is not decreased by miR145, while it is down-regulated by an siRNA targeting IRS-1. Targeting of the IRS-1 3’UTR by miR145 was confirmed using a reporter gene (luciferase) expressing the miR145 binding sites of the IRS-1 3’ UTR. In agreement with the role of IRS-1 in cell proliferation, we show that treatment of human colon cancer cells with miR145 causes growth arrest comparable to the use of an siRNA against IRS-1. Taken together, these results identify miR145 as a micro RNA that down-regulates the IRS-1 protein, and inhibits the growth of human cancer cells.

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