Role of IRES-dependent translation of MYC in Colorectal Cancer

Anno
2018
Proponente Gianluca Canettieri - Professore Ordinario
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Abstract

Colorectal cancer (CRC) is a major cause of death from cancer worldwide. Several genes and pathways have been found mutated in CRC and most of them converge on the activation of MYC, thus making this oncogene an attractive therapeutic target. However, attempts to find direct MYC inhibitors have been disappointing, suggesting that alternative strategies, aimed at reducing MYC expression or activity are preferable options. One avenue is the inhibition of MYC translation, although the presence of an IRES region in its 5'UTR enables this oncogene to be translated also under non-permissive conditions and to escape from pharmacological inhibition. Thus, IRES-translation of MYC might represent a novel actionable target for CRC.
Our preliminary work has led to the identification of CNBP as a regulator of MYC IRES translation that is essential for the growth and survival of CRC.
The proposed project aims at elucidating the role of IRES-mediated translation of MYC and of its putative regulator CNBP in colorectal tumorigenesis and the therapeutic potential of their targeting.
We will address these issues with the following main tasks:
Task 1: We will define the pathophysiological relevance of IRES-dependent translation of MYC and the role of CNBP on colorectal tumorigenesis: we will delete by CRISPR-Cas9 approach the IRES region of MYC from CRC cells and study the consequences on tumor proliferation and viability in vitro and in vivo, in the presence or absence of CNBP.
Task 2: We will study the effect of CNBP ablation in the colorectal cancer mouse models APCMin/+: we will delete CNBP gene in the intestinal epithelium using our newly established CNBP loxP/loxP x villin CRE mouse model and cross these mice with APCMin/+.
Results of this project will inform us about an unprecedented mechanism of regulation of MYC translation and the consequences of its targeting in CRC.

ERC
LS3_5, LS1_10, LS4_6
Keywords:
BASI BIOLOGICHE DEL CANCRO, TRASDUZIONE DEI SEGNALI, MEDICINA MOLECOLARE, BIOLOGIA MOLECOLARE E INTERAZIONI, SEGNALAZIONE E INTERAZIONI CELLULARI

© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma