<scp> <i>miRNA‐34c</i> </scp> Suppresses Osteosarcoma Progression In Vivo by Targeting Notch and <scp>E2F</scp>

Abstract

The expression of microRNAs (miRNAs) is dysregulated in many types of cancers including osteosarcoma (OS) due to genetic and epigenetic alterations. Among these, <i>miR-34c</i>, 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 <i>miR-34c</i> in OS progression using in vitro assays and <i>in vivo</i> genetic mouse models. We found that <i>miR-34c</i> 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 <i>miR-34c</i> increased survival in the osteoblast specific p53 mutant OS mouse model. We found that <i>miR-34c</i> regulates the transcription of several genes in Notch signaling (<i>NOTCH1</i>, <i>JAG1</i>, and <i>HEY2</i>) and in p53-mediated cell cycle and apoptosis (<i>CCNE2</i>, <i>E2F5</i>, <i>E2F2</i>, and <i>HDAC1</i>). 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 <i>miR-34c</i> that was identified in our transcriptome analysis, such as <i>E2F5</i> and <i>NOTCH1</i>. In conclusion, we demonstrate that <i>miR-34c</i> is a tumor suppressive miRNA in OS progression <i>in vivo</i>. In addition, we highlight the therapeutic potential of targeting <i>miR-34c</i> in OS. © 2022 The Authors. <i>JBMR Plus</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.