Differential expression of miRNAs in primary canine appendicular osteosarcoma tissue and pulmonary metastases.

Abstract

Canine appendicular osteosarcoma (OSA) is a highly metastatic tumor in dogs. Mortality due to metastatic disease is common and frequently occurs within 1 year of diagnosis despite standard-of-care treatment. Treatment includes amputation for palliation and chemotherapy for metastatic disease. Current histologic grading schemes and biomarkers are poor at predicting clinical outcome. Novel prognostic and therapeutic markers are required to improve patient care. MicroRNAs (miRNAs) are small molecules expressed by all cells and released into bodily fluids. Studies in human and canine OSA cell lines, tissues from the primary site, and blood have demonstrated the role of miRNAs in metastatic progression of OSA and its prognostication. We sought to investigate the miRNA profile of primary OSA tissue and compare it to pulmonary metastases and normal lung tissue by real-time quantitative polymerase chain reaction (PCR). Multiple miRNA and multiple variable models were investigated in primary OSA tissue to predict clinical outcome. Thirteen miRNAs had similar expression between primary and metastatic OSA but were different from normal lung tissue. MiR-9-5p, miR-196a-5p, and miR-196b were expressed in metastatic OSA but lacked expression in almost all normal lung samples. In multiple variable models for overall survival and disease-free interval, only miRNAs were selected as significant variables. This study found miRNAs that are nearly exclusively expressed in metastatic pulmonary OSA and could serve as novel therapeutic targets. MiRNAs were also found to be important prognostic biomarkers in tissue and improved prognostic ability as miRNA signatures.