Abstract 4383: Effects of inhibition of upregulated microRNAs in canine histiocytic sarcoma

Abstract

Abstract Histiocytic diseases encompass a spectrum of proliferative diseases in humans and dogs. While these orphan malignancies are rare in the human, histiocytic diseases are relatively frequent in certain breeds of dog. In the dog, these diseases range from benign histiocytoma to malignant histiocytic sarcoma (HS). Disseminated HS has a poor prognosis and lacks effective treatment options in both humans and dogs. The overall goal of this study is to unravel the mechanisms of tumorigenesis in histiocytic diseases and identify better treatments. Our studies have focused on microRNAs (miRNAs), which are master regulators of gene expression and may have a significant role in tumorigenesis in histiocytic diseases. MiRNA profiling of canine histiocytic diseases was conducted on cases of reactive histiocytosis, HS, and hemophagocytic HS. These samples were compared to normal canine histiocytes derived from peripheral blood or peritoneal fluid. Several miRNAs were identified to be upregulated in the disease samples and were selected for validation by qRT-PCR. From these results, two miRNA targets were selected for further evaluation. We are probing the significance of the upregulation of these miRNAs by inhibiting their function in canine HS cell lines using chemical miRNA inhibitors and sponge constructs designed to competitively bind the upregulated miRNAs, thus preventing them from acting on their targets. Our results to date indicate that inhibiting these miRNAs in the canine HS cell line, DH82, decreases growth rate by as much as 39%. Studies into other aspects of tumorigenicity potentially affected by the inhibition of these miRNAs are underway. Our preliminary data suggests these miRNAs themselves may be effective therapeutic targets for histiocytic diseases. Additionally, further analysis of the pathways regulated by these miRNAs may identify critical gene targets in HS tumorigenesis and thus increase our understanding of these malignancies and discover novel and effective therapies. Comparative studies have the potential to provide opportunities for advancement in these orphan malignancies, and in this case, improve clinical outcome in dogs and humans. Citation Format: Emmalena J. Gregory-Bryson, Maciej Parys, Matti Kiupel, Vilma Yuzbasiyan-Gurkan. Effects of inhibition of upregulated microRNAs in canine histiocytic sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2014-4383