Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents and young adults. The essential mechanisms underlying osteosarcomagenesis and progression continue to be obscure. MicroRNAs (miRNAs) have far-reaching effects on the cellular biology of development and cancer. We recently reported that unique miRNA signatures associate with the pathogenesis and progression of OS. Of particular interest, we found that higher expression of miR-27a is associated with clinical metastatic disease. We report here that overexpression of miR-27a/miR-27a*, a microRNA pair derived from a single precursor, promotes pulmonary OS metastases formation. By contrast, sequestering miR-27a/miR-27a* by sponge technology suppressed OS cells invasion and metastases formation. miR-27a/miR-27a* directly repressed CBFA2T3 expression among other target genes. We demonstrated that CBFA2T3 is downregulated in majority of OS samples and its over expression significantly attenuated OS metastatic process mediated by miR-27a/miR-27a* underscoring CBFA2T3 functions as a tumor suppressor in OS. These findings establish that miR-27a/miR-27a* pair plays a significant role in OS metastasis and proposes it as a potential diagnostic and therapeutic target in managing OS metastases.
Highlights
Bone and joints cancer is the third cause of cancer death in childhood and adolescence
We report here that overexpression of miR-27a/miR-27a*, a microRNA pair derived from a single precursor, promotes pulmonary OS metastases formation
We demonstrated that CBFA2T3 is downregulated in majority of OS samples and its over expression significantly attenuated OS metastatic process mediated by miR-27a/miR27a* underscoring CBFA2T3 functions as a tumor suppressor in OS
Summary
Bone and joints cancer is the third cause of cancer death in childhood and adolescence. Osteosarcoma (OS) is the major type of bone and joint cancer [1]. Significant improvement in overall survival of OS patients was achieved after implementation of relatively effective chemotherapy in 1970s, but a third of patients still die during 5 years after diagnosis [2]. Overall 5 years survival drops even further to about 30% for OS patients with metastases at diagnosis [3]. Improvements in therapy of OS patients, those with the metastatic disease are needed. Advances in OS treatment are inconceivable without better understanding of molecular mechanisms of osteosarcomagenesis and, especially, metastatic processes in this kind of cancer
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