ADAR2 induces the differentiation of osteosarcoma cells by editing activity on IGFBP7: new implications for therapy

Osteosarcoma is a highly malignant bone tumor which primarily affects the juvenile population and is characterized by high rate of recurrence and metastasis. RNA editing has emerged as a key process in cancer progression. Herein, we investigated the role of RNA editing enzyme ADAR2 (Adenosine Deaminase Acting on RNA 2) in osteosarcoma. We demonstrated that ADAR2 expression increases during osteoblast differentiation and inversely correlates with the aggressiveness of osteosarcoma cells. Interestingly, the overexpression of ADAR2 in osteosarcoma cell lines reduces their tumoral properties and promotes their differentiation in osteoblast-like cells, as shown by gene expression analysis and mineralization assays. These results were also confirmed by in vivo experiments; indeed, intratibial injection of ADAR2-overexpressing osteosarcoma cells in NSG mice resulted in less aggressive tumors compared to mice injected with pEmpty or pInactive ADAR2 E/A vector-transfected cells. To elucidate the mechanisms by which ADAR2 overexpression induces osteogenic terminal differentiation of osteosarcoma cells, we performed RNA-seq analysis of Saos-2 cells and identified IGFBP7 (Insulin-like Growth Factor Binding Protein 7) as the most highly edited transcript in ADAR2-overexpressing cells. We showed that the editing activity of ADAR2 on IGFBP7 abolishes its proliferative effect on osteosarcoma cells and triggers terminal differentiation. Overall, our results indicate that ADAR2 acts as a tumor suppressor in osteosarcoma and may represent a novel therapeutic target for this aggressive pediatric tumor.