ADAR1-Mediated Regulaton of Melanoma Invasion

The main RNA-editing enzyme, Adenosine Deaminase Acting on RNA-1 (ADAR1), is silenced in many metastatic tumors, including melanoma. We have recently shown that ADAR1 suppresses several cancer features, as its downregulation alters cell morphology, facilitates cell-cycle, proliferation, and dramatically enhances the tumorigenicity in-vivo. We further demonstrated that ADAR1 controls the expression of >100 microRNAs, which regulate hundreds of genes that account for the observed phenotype.

Cutaneous melanoma is a highly metastasizing neoplastic disease, and its malignant potential has been previously associated with integrin beta-3 (ITGB3) expression, a known oncogene, strongly linked to the acquisition of invasive properties of many tumors. However, only little is known about the regulation of ITGB3 expression in cancer cells. ITGB3 is upregulated during the transition from dysplastic nevi to tumorigenic melanomas, inversely to the substantial reduction in ADAR1 expression. We show in several cell lines that silencing of ADAR1 directly enhances melanoma cell invasiveness and ITGB3 expression. The enhanced invasion is corrected when ITGB3 is blocked with monoclonal antibodies. Experiments with a series of melanoma cell lines transfected with wild type or catalytically inactive ADAR1 mutants show that this phenomenon is independent of RNA-editing. Mechanistically, we found that ADAR1 controls ITGB3 expression both at the post transcriptional and transcriptional level, via miR-22 and PAX6 transcription factor, respectively, which are described here as direct regulators of ITGB3. The novel ADAR1-dependent and RNA-editing-independent regulation of invasion presented here, mediated by ITGB3, as well as the ADAR1-controlled regulation of ITGB3 expression, strongly points on a central involvement of ADAR1 in cancer progression and metastasis. These findings provide novel insights on the process of cancer development with potential implications for future translational medicine.