MicroRNA-214 Promotes Apoptosis in Canine Hemangiosarcoma by Targeting the COP1-p53 Axis.
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.
United Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan; Department of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan.
Kazuki
K
Heishima
United Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan; Department of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan.
Takashi
T
Mori
United Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan; Department of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan.
Hiroki
H
Sakai
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Gifu, Japan.
Nobuhiko
N
Sugito
Department of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan.
Mami
M
Murakami
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Gifu, Japan.
Nami
N
Yamada
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Gifu, Japan.
Yukihiro
Y
Akao
United Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu, Japan; Department of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Gifu, Japan.
Kohji
K
Maruo
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006394:Hemangiosarcoma / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D020413:3' Untranslated Regions; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53