miR-126 modulates the PI3K/Akt pathway in breast cancer cells

Dysregulation of miRNA expression profiles occurs in several human malignancies and, depending on mRNAs targeted by the specific miRNA, they can exert either promoting or suppressive effects on cancer cells. We have previously shown that physiological delivery of platelet miR-126 induces cellular effects in breast cancer cells, including cell cycle arrest, inhibition of migration and sensitivity to cisplatin. Here, we went further insight by investigating potential miR-126 molecular targets. We identified two strictly related miR-126 direct targets, that are the regulatory subunit p85α of PI3K (PI3KR1) and the downstream kinase Akt2. Indeed, both genes contain specific sequences targeted by miR126 in their 3’UTRs and, moreover, an inverse correlation between miR-126 levels and expression of the two target genes can be established in different BC cell lines. miR-126-mediated down-regulation of PI3KR1 and Akt2 leads to inhibition of migration, through modulation of cytoskeletal regulatory genes and, thus, cytoskeleton actin remodelling. In particular, we found that the presence of miR-126 promotes accumulation of inactive phospho-cofilin involved in actin filament depolymerization. Notably, accumulation is not related to enhanced activity of specific kinases (ROCK2/LIMK1), but instead to inhibition of the Slingshot protein phosphatase 1 (SSH1). Our results, together with literature data reporting other proteins of the PI3K/Akt signalling cascade directly targeted by miR-126, indicate that miR126 exerts tumour suppressor activity, by specifically controlling events downstream this cascade and involved in cancer biology. This finding suggests that modulation of miR-126 levels may be an useful tool in multimodal therapeutic approaches in cancer patients.