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Role and regulation of miR-483 in cancer

Veronese, Angelo (2012) Role and regulation of miR-483 in cancer. PhD Thesis , Università degli studi di Ferrara.

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    Abstract

    The hsa-mir-483 locus is located at chromosome 11p15.5 within intron 2 of the IGF2 locus. Because of its location, de-regulated in Wilms’ tumor and other neoplasia, I hypothesized that this microRNA had a potential role in tumors. By analyzing 19 Wilms’ tumors, I proved that miR-483-3p is indeed over-expressed in 100% of the cases and a co-regulation with the over-expression of IGF2 was found. However, several other types of common adult cancers exhibit high or even extremely high levels of miR-483-3p expression without IGF2 over-expression. Indeed, independently from IGF2, the expression of the miR-483-3p could also be induced by the oncoprotein β-catenin through a novel interaction with the basic Helix-Loop-Helix protein upstream stimulatory transcription factor 1 (USF1). I also show that β-catenin itself is a target of miR-483-3p, triggering a negative regulative loop that becomes ineffective in cells harbouring activating mutations of β-catenin pathway. The potential oncogenic role of miR-483-3p was supported by the findings that its ectopic expression protects cells from apoptosis and, conversely, its inhibition increase the level of apoptosis. To understand the mechanisms of its action, I investigated potential gene targets. Among these, an important pro-apoptotic protein, Puma, were inhibited by miR-483-3p. My results indicate that miR-483-3p functions as an anti-apoptotic oncogene, coordinately over-expressed with IGF2 in Wilms’ tumors or induced by β-catenin activation in other tumor types.

    Item Type:Thesis (PhD Thesis)
    Date:8 March 2012
    Tutor:Croce, Carlo Maria
    Coordinator:Cuneo, Antonio
    Institution:Università degli studi di Ferrara
    PhD:XXIV Anno 2009 > FARMACOLOGIA E ONCOLOGIA MOLECOLARE
    Divisions:Dipartimento > Medicina clinica e sperimentale
    Subjects:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
    Uncontrolled Keywords:microRNA, cancer, CTNNB1, miR-483
    Deposited on:13 Feb 2013 15:04

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