Phd in INNOVATIVE TECHNOLOGIES IN DISEASES OF
SKELETON, SKIN AND ORO-CRANIOFACIAL DISTRICT

Thesis title: Understanding the role of ADAR2 in bone formation and osteosarcoma progression

Osteosarcoma is a highly malignant bone tumor primarily affecting the juvenile population, with a high rate of recurrence and metastasis. RNA editing was described to play a main role in cancer development. The most common RNA editing mechanism in human converts Adenosine residues to Inosine into double-stranded RNA, for hydrolytic deamination through the action of ADARs (Adenosine Deaminase Agents on RNA) enzymes. There are three ADAR enzymes (ADAR1, ADAR2 and ADAR3) exerting a relevant impact on cell biology; however, the role of ADAR2 editing in bone pathophysiology has not been deeply investigated. Our results suggest that ADAR2 has a key role in osteogenic differentiation of mesenchymal stem cells. Moreover, we observed that ADAR2 expression is lower in osteosarcoma cells compared to osteoblasts and that its levels inversely correlated to the aggressiveness of tumor cells. We demonstrated that the overexpression of ADAR2 in osteosarcoma cells reduces proliferation, migration and invasion of tumor cells, stimulating their osteogenic differentiation in osteoblast-like cells, leading also to an increased chemotherapy susceptibility. Consistent with the in vitro data, ADAR2 overexpression reduces tumorigenicity and metastatic ability of osteosarcoma cells intratibially injected in nude mice. To identify the mechanisms by which ADAR2 overexpression exerts its antitumor role, we investigated the editing activity by deep-seq analysis of ADAR2 overexpressing osteosarcoma cells that revealed a significant editing of COPA, IGFBP7 and COG3 transcripts, identifying a possible mechanism by which ADAR2 regulate osteogenic differentiation by IGFBP7. Our results demonstrated that the overexpression of ADAR2 exerts an onco-suppressor activity both in vitro and in vivo, representing a novel therapeutic target for this pediatric tumour.