Abstract
BackgroundOsteosarcoma (OSA) is the most common bone tumor in children and dogs; however, no substantial improvement in clinical outcome has occurred in either species over the past 30 years. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and play a fundamental role in cancer. The purpose of this study was to investigate the potential contribution of miR-34a loss to the biology of canine OSA, a well-established spontaneous model of the human disease.Methodology and principal findingsRT-qPCR demonstrated that miR-34a expression levels were significantly reduced in primary canine OSA tumors and canine OSA cell lines as compared to normal canine osteoblasts. In canine OSA cell lines stably transduced with empty vector or pre-miR-34a lentiviral constructs, overexpression of miR-34a inhibited cellular invasion and migration but had no effect on cell proliferation or cell cycle distribution. Transcriptional profiling of canine OSA8 cells possessing enforced miR-34a expression demonstrated dysregulation of numerous genes, including significant down-regulation of multiple putative targets of miR-34a. Moreover, gene ontology analysis of down-regulated miR-34a target genes showed enrichment of several biological processes related to cell invasion and motility. Lastly, we validated changes in miR-34a putative target gene expression, including decreased expression of KLF4, SEM3A, and VEGFA transcripts in canine OSA cells overexpressing miR-34a and identified KLF4 and VEGFA as direct target genes of miR-34a. Concordant with these data, primary canine OSA tumor tissues demonstrated increased expression levels of putative miR-34a target genes.ConclusionsThese data demonstrate that miR-34a contributes to invasion and migration in canine OSA cells and suggest that loss of miR-34a may promote a pattern of gene expression contributing to the metastatic phenotype in canine OSA.
Highlights
Osteosarcoma (OSA) is the most common form of malignant bone cancer in dogs and children, the incidence of disease in the canine population is approximately ten times higher than that in people [1,2,3]
These data demonstrate that miR-34a contributes to invasion and migration in canine OSA cells and suggest that loss of miR-34a may promote a pattern of gene expression contributing to the metastatic phenotype in canine OSA
We previously reported a miRNA expression signature that was associated with canine OSA using the nanoString nCounter platform, including down-regulation of miR-34a in primary canine OSA tumors
Summary
Osteosarcoma (OSA) is the most common form of malignant bone cancer in dogs and children, the incidence of disease in the canine population is approximately ten times higher than that in people [1,2,3] Both clinical and molecular evidence suggest that canine OSA exhibits a similar biology to its human counterpart including anatomic location, presence of early microscopic metastatic disease at diagnosis, development of chemotherapy-resistant metastases, altered expression/activation of several proteins (e.g. Met, PTEN, STAT3), and p53 inactivation, among others [2, 4]. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level through either mRNA cleavage and/or translational repression Their functions extend to both physiological and pathological conditions, including cell fate specification, cell death, development, metabolism, and cancer [13, 14]. The purpose of this study was to investigate the potential contribution of miR-34a loss to the biology of canine OSA, a well-established spontaneous model of the human disease.
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