KPNA2 promotes osteosarcoma growth and metastasis in a c-Myc-dependent manner via the hedgehog /GLI1 signaling pathway

Abstract

Despite recent advances, the poor outcomes in osteosarcoma suggest that novel therapeutic targets are needed. Karyopherin alpha 2 (KPNA2) has been identified as a novel oncogene in many cancers. However, the function of KPNA2 in osteosarcoma and its relative mechanisms remain unclear. Herein, we reported that KPNA2 was highly expressed in osteosarcoma, which contributed to poor survival of patients. Knockdown of KPNA2 significantly suppressed osteosarcoma growth and metastasis in vitro and in vivo. Hedgehog/GLI1 was identified as the key effector pathway of KPNA2 in the study. Mechanistically, KPNA2 acts as a nuclear–cytoplasmic shuttle vehicle to transport c-Myc into the nucleus, where c-Myc binds to the promoter of GLI1 to trigger its expression. Besides, c-Myc can also transcriptionally regulate the expression of KPNA2, thus providing a positive feedback effect to amplify the pro-cancer signal further. In summary, our study revealed that KPNA2 promoted the growth and metastasis of osteosarcoma in a c-Myc-dependent manner via the hedgehog/GLI1 signaling pathway. Targeting KPNA2/c-Myc/GLI1 signal axis might provide a potential therapeutic target for the treatment of osteosarcoma.