Role and regulation of miR-483 in cancer

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.