Abstract
Osteosarcoma is the most common malignant bone tumor in children, adolescents, and young adults. This pleiomorphic tumor depends on new blood vessel development, also known as angiogenesis, for tumor growth and metastasis. Therefore, it’s of utmost importance to identify the key genes and pathways that regulate this pro-metastatic process in order to develop more efficient therapies. Here, we have shown that the RNA-binding protein AUF1 positively regulates the expression of the pro-angiogenic factor VEGF-A and its positive regulator HIF-1alpha through direct binding and stabilization of their mRNAs. This effect is mediated through the seeding sequence of the AUF1 protein in the VEGF-A and HIF-1alpha 3’UTR sequences. As a consequence, the expression of the 3 genes was highly correlative in various osteosarcoma cell lines, and AUF1 enhanced the pro-angiogenic capabilities of osteosarcoma cells both in vitro and in vivo. Indeed, while inhibition of AUF1 using specific siRNA suppressed the pro-angiogenic effects of osteosarcoma cells, ectopic expression of AUF1 enhanced the pro-angiogenic effect in a VEGF-A-dependent manner. Therefore, in the era of targeted therapy, anti-angiogenic therapies targeting AUF1 could provide effective methods for treating osteosarcoma.
Highlights
Osteosarcoma is the most common primary bone malignancy in children and young adults
To shed light on the role of AUF1 in the regulation of the pro-angiogenic capabilities of osteosarcoma cells, we first assessed the levels of the AUF1 and Vascular endothelial growth factor-A (VEGF-A) mRNAs in various osteosarcoma cell lines by quantitative RT-PCR
While down-regulation of AUF1 abolished the pro-angiogenic potential of osteosarcoma cells, ectopic expression of AUF1 enhanced this capacity in a VEGF-A-dependent manner
Summary
Osteosarcoma is the most common primary bone malignancy in children and young adults These aggressive tumors commonly metastasize and are highly resistant for the newly devised poly-chemotherapy regimens. AUF1 (AU binding factor 1), known as heterogenous nuclear ribonucleoprotein D (hnRNPD), has four isoforms (37, 40, 42, and 45 kDa), which result from alternative splicing of a single pre-mRNA [7] These isoforms have various affinity for target transcripts, and p37 exhibits the strongest affinity [7, 8]. We present clear evidence that AUF1 is highly expressed in the aggressive osteosarcoma cell lines, and positively regulates the expression and secretion of the pro-angiogenic factor VEGF-A and its regulator HIF-1α. AUF1 enhances the pro-angiogenic capabilities of osteosarcoma cells in vitro and in vivo
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