MicroRNA-214 Promotes Apoptosis in Canine Hemangiosarcoma by Targeting the COP1-p53 Axis

• Published in: PloS one Vol. 10; no. 9; p. e0137361
• Main Authors: Heishima, Kazuki, Mori, Takashi, Sakai, Hiroki, Sugito, Nobuhiko, Murakami, Mami, Yamada, Nami, Akao, Yukihiro, Maruo, Kohji
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.09.2015; Public Library of Science (PLoS)
• Subjects: 3' Untranslated Regions - genetics; Analysis; Angiogenesis; Angiosarcoma; Animals; Apoptosis; Apoptosis - genetics; Biotechnology; Cancer therapies; Cell activation; Cell Cycle; Cell Division; Cell Line, Tumor; Dog Diseases - genetics; Dog Diseases - metabolism; Dog Diseases - pathology; Dogs; Drug development; Endothelial cells; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genes, Reporter; Genetic aspects; Hemangiosarcoma - genetics; Hemangiosarcoma - metabolism; Hemangiosarcoma - veterinary; Information science; Kinases; Liver cancer; Male; Medical prognosis; Metastasis; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - physiology; miRNA; Molecular Targeted Therapy; Mutation; Neoplasm Proteins - physiology; Oncology; p53 Protein; Restoration; Ribonucleic acid; RNA; RNA Interference; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Neoplasm - genetics; RNA, Neoplasm - physiology; RNA, Small Interfering - genetics; Transcription activation; Transfection; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - physiology; Tumorigenesis; Tumors; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0137361

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.