Suppresses Osteosarcoma Progression In Vivo by Targeting Notch and E2F.

The expression of microRNAs (miRNAs) is dysregulated in many types of cancers including osteosarcoma (OS) due to genetic and epigenetic alterations. Among these, , an effector of tumor suppressor P53 and an upstream negative regulator of Notch signaling in osteoblast differentiation, is dysregulated in OS. Here, we demonstrated a tumor suppressive role of in OS progression using in vitro assays and genetic mouse models. We found that inhibits the proliferation and the invasion of metastatic OS cells, which resulted in reduction of the tumor burden and increased overall survival in an orthotopic xenograft model. Moreover, the osteoblast-specific overexpression of increased survival in the osteoblast specific p53 mutant OS mouse model. We found that regulates the transcription of several genes in Notch signaling (, , and ) and in p53-mediated cell cycle and apoptosis (, , , and ). More interestingly, we found that the metastatic-free survival probability was increased among a patient cohort from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) OS, which has lower expression of direct targets of that was identified in our transcriptome analysis, such as and . In conclusion, we demonstrate that is a tumor suppressive miRNA in OS progression . In addition, we highlight the therapeutic potential of targeting in OS. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.