microrna-135b promotes cancer progression acting as a downstream effector of oncogenic pathways in...
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Oral Plenary Abstracts
www.thelancet.com 17
Published OnlineFebruary 27, 2013
Institute of Cancer Sciences, University of Glasgow. Glasgow, UK (N Valeri, C Braconi); Comprehensive Cancer Center, Ohio State University, Columbus, USA (P Gasparini, F Lovat, G Nuovo, W Frankel, J Groden, C M Croce); Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, USA (J Hart, P K Vogt); Departments of Pharmacology and Pathology, University California at San Diego, San Diego, USA (S Grivennikov, M Karin); and Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy (G Lanza, R Gafa)
Correspondence to: Nicola Valeri, Institute of Cancer Sciences, Beatson Labs, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, [email protected]
microRNA-135b promotes cancer progression acting as a downstream eff ector of oncogenic pathways in colon cancerNicola Valeri, Chiara Braconi, Pierluigi Gasparini, Jonathan Hart, Sergei Grivennikov, Francesca Lovat, Giovanni Lanza, Roberta Gafa, Gerard Nuovo, Wendy Frankel, Joanna Groden, Peter K Vogt, Michael Karin, Carlo M Croce
Abstract Background microRNAs (miRs) are small non-coding RNAs often deregulated in colorectal cancer. We aimed to identify miRs with a driver role in carcinogenesis altered by similar mechanisms in both human and mouse colorectal cancer. The goal was to use colorectal cancer mouse models for the preclinical development of anti-miRs as therapeutics.
Methods Azoximetane/dextran-sulphate (AOM/DSS) treated mice were used to study infl ammation-associated colorectal cancer and CDX2P-NLS Cre;Apc+/loxP (CPC;Apc) mice were used to study sporadic APC-related colorectal cancer. Human infl ammatory bowel disease associated (n=15) colorectal cancer and sporadic (n=62) colorectal cancer with their matched normal tissues were used for miR expression analysis. miR and gene expression profi ling was assessed by nCounter technology. Anti-miR-135b probes for in-vivo studies were synthesised by Girindus.
Findings miR profi ling from AOM/DSS and CPC;Apc colorectal cancer showed that miR-135b is one of the most upregulated miR in both models. miR-135b was overexpressed in human infl ammatory bowel disease and sporadic colorectal cancer and was associated with poor survival. Molecular studies in mouse embryo fi broblast and human colorectal cancer cell lines defi ned APC/β-catenin and SRC-PI3K as key pathways in miR-135b activation. miR-135b up-regulation resulted in reduced apoptosis and increased cell growth due to the downregulation of TGFRB2, DAPK1, APC, and FIH. miR-135b silencing in vivo reduced tumour multiplicity and tumour load in the AOM/DSS colorectal cancer model. Mice treated with anti-miR-135b showed well-diff erentiated tumours with an acinar pattern whereas tumours in the control groups showed poor diff erentiation and adenomatous pattern. Tumours in mice treated with anti-miR-135b showed reduced proliferation and increased apoptosis.
Interpretation Our data suggest that miR-135b is a key molecule whose activation is downstream of driver genes frequently mutated in colorectal cancer. The in-vivo silencing of miR-135b shows preclinical effi cacy with low toxicity and represents the fi rst in-vivo study for use of anti-miRs in treatment of colorectal cancer.
Funding University of Glasgow.