Abstract

Osteosarcoma (OS) is a bone malignancy mostly found in adolescents accounting for about 60% of malignant bone tumors. Despite the availability of limb-saving surgery, multiagent and dose-intensive chemotherapy, the survival rate is low for patients with axial OS and distant metastasis. Moreover, the etiology of OS has not been fully understood, greatly impeding the development of new treatments. Recently, circular RNAs (circRNAs) emerge as a new class of noncoding RNAs and are implicated in oncogenesis as a sponge for microRNAs. Here, we report the identification of circ-DNAH1, a novel cytoplasmic circRNA that is generated from exon 67 to 70 of DNAH1 (Dynein Axonemal Heavy Chain 1) and inhibits the OS progression. Circ-DNAH1 is downregulated in OS, and the lower levels of circ-DNAH1 are inversely correlated with survival rates. Functionally, overexpression of circ-DNAH1 inhibits the proliferation, migration and invasion of OS cells in vitro. Mechanistically, circ-DNAH1 sponges miR-663a, a microRNA that functions as an oncogene and promotes OS progression through EMP3 and MAPK/ERK signaling pathways. Moreover, overexpression of circ-DNAH1 reverses miR-663a-induced enhancement of cell proliferation, migration and invasion of OS cells. Furthermore, enforced expression of circ-DNAH1 suppresses OS growth and metastasis in vivo. Together, we have characterized a novel circular RNA, circ-DNAH1 that acts as a tumor suppressor in OS development and serves as an independent prognostic factor for OS patients.