Abstract
MicroRNA-214 regulates both angiogenic function in endothelial cells and apoptosis in various cancers. However, the regulation and function of miR-214 is unclear in canine hemangiosarcoma, which is a spontaneous model of human angiosarcoma. The expression and functional roles of miR-214 in canine hemangiosarcoma were presently explored by performing miRNA TaqMan qRT-PCR and transfecting cells with synthetic microRNA. Here, we report that miR-214 was significantly down-regulated in the cell lines used and in clinical samples of canine hemangiosarcoma. Restoration of miR-214 expression reduced cell growth and induced apoptosis in canine hemangiosarcoma cell lines through transcriptional activation of p53-regulated genes although miR-214 had a slight effect of growth inhibition on normal endothelial cells. We identified COP1, which is a critical negative regulator of p53, as a novel direct target of miR-214. COP1 was overexpressed and the specific COP1 knockdown induced apoptosis through transcriptional activation of p53-regulated genes as well as did miR-214-transfection in HSA cell lines. Furthermore, p53 knockdown abolished the miR-214-COP1-mediated apoptosis; thus, miR-214 and COP1 regulated apoptosis through controlling p53 in HSA. In conclusion, miR-214 functioned as a tumor suppressor in canine hemangiosarcoma by inducing apoptosis through recovering the function of p53. miR-214 down-regulation and COP1 overexpression is likely to contribute to tumorigenesis of HSA. Therefore, targeting miR-214-COP1-p53 axis would possibly be a novel effective strategy for treatment of canine hemangiosarcoma and capable of being applied to the development of novel therapeutics for human angiosarcoma.
Highlights
Neoplastic endothelial proliferative diseases such as human angiosarcoma (AS) and canine hemangiosarcoma (HSA) are serious diseases for both humans and dogs
We first assessed the expression levels of miR-214 in HSA cell lines established from diverse primary sites (JuB2 from hepatic HSA, Re12 from atrial HSA, and Ud6 from splenic HSA) and in normal primary EC (CnAOEC) by performing miRNA TaqMan quantitative RT-PCR (qRT-PCR)
We found that miR-214 was significantly down-regulated in all HSA cell lines tested regardless of the primary sites of origin of the cell lines (Fig 1A)
Summary
Neoplastic endothelial proliferative diseases such as human angiosarcoma (AS) and canine hemangiosarcoma (HSA) are serious diseases for both humans and dogs. AS has not been well studied compared to the other major tumors because of its low incidence; i.e., it accounts for only 1.8% of soft-tissue sarcomas [8]. HSA, a canine malignant endothelial neoplasm, shares many features with AS in terms of malignant behaviors such as the low survival rate and frequent metastasis. Unlike in the case of AS, HSA is relatively common, accounting for approximately 20% of all canine soft-tissue sarcomas [10]. The most common primary site of HSA is the spleen, HSA occurs in various organs such as liver, right atrium of heart and skin with much higher incidence than that in humans [11]. Domestic dogs share environmental factors with humans and develop HSA spontaneously with high incidence. The direct translation of results from HSA to AS study should be careful because only a few comparisons between these sarcomas have been made at the cell signaling level, the study of HSA have potential to provide a powerful model for AS
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