MicroRNA Profiling and MicroRNA-Based Treatment of Canine Cancers
The goals of this study are to identify important canine miRNAs that can be used to improve cancer diagnosis and treatment in the dog.
MicroRNAs (miRNAs) are small non-protein coding RNAs that have been implicated in humans as having a fundamental role in cancer initiation and progression. Osteosarcoma (OSA) is the most common bone tumor in dogs, and although breeds such as Rottweilers and Greyhounds are at higher risk for developing OSA, the understanding of its molecular etiology is limited.
In this study, we determined that canine OSA possess a unique miRNA expression signature distinct from that found in normal canine osteoblasts and that these dysregulated miRNAs contribute to OSA pathogenesis and progression. Notably, we identified 84 miRNAs that were expressed significantly higher or lower in OSA cells compared to normal osteoblasts (bone cells). Several of these miRNAs, have previously been identified as having a role in a variety of human cancers, including miR-155 and mir-21. Particularly interesting was the identification of miR-9 as being highly expressed in primary OSA tumors. This miRNA was simultaneously identified by us as being highly expressed in aggressive canine mast cell tumors (primary tumors that metastasized) compared to mast cell tumors that did not metastasize.
We then focused our efforts on understanding the role of miR-9 in canine OSA. To do this we developed methods to alter the expression (levels) of miR-9 in normal osteoblasts and in OSA cells in vitro. We were able to show that by increasing expression of miR-9 in OSA cells that we increased their invasive properties, a key biological feature in the metastatic process. Based on these findings, our laboratory is continuing to explore the consequences and functions of miR-9 dysregulation in OSA and other canine cancers.
This work has resulted in the development by our laboratory of a genetically engineered mouse where miR-9 can be overexpressed in selected specific cell types (e.g. osteoblasts) in vivo. By understanding miR-9 functions in OSA more fully, we should be able to develop strategies for effectively targeting miR-9 therapeutically, for example with “antagomiRs” that have been chemically modified, or by developing nanoparticle antagomiRs to inhibit miR-9 in vivo. These goals will form the basis of our subsequent proposal to the AKC-CHF.
Co-sponsored with the AKC Canine Health Foundation, Grant Number: 00790
William C. Kisseberth, DVM, PhD
Ohio State University