ADAR1 regulates melanoma cell invasiveness by controlling beta3-integrin via microRNA-30 family members.

Melanoma cells utilize multiple mechanisms to exit the primary tumor mass, invade the surroundings and subsequently distant tissues. We have previously reported that the expression of the RNA editing enzyme ADAR1 (adenosine deaminase acting on RNA) is downregulated in metastatic melanoma, which facilitates proliferation and invasion. Here we show that ADAR1 controls melanoma invasiveness by regulating ITGB3 expression via miR-30a and miR-30d. ADAR1 overexpression or knockdown leads to an increase or decrease, respectively, in the expression of both microRNAs. The effect is independent of RNA-editing. Dual luciferase assays show that both microRNAs directly regulate the expression of the ITGB3 integrin. Overexpression of the miR-30a or miR-30d lead to a decrease in ITGB3 and a resultant decreased invasive and metastatic capacities. Neutralization of the endogenous miR-30a or miR-30d leads to the opposite effect. The microRNAs regulate ITGB3 levels probably through a post-transcriptional effect, as both mRNA and protein levels of ITGB3 are affected. These results further expand our knowledge on the ADAR1-ITGB3 network and its central role in acquisition of the invasive phenotype of metastatic melanoma.