MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatoma-derived growth factor in human hepatoma
| Autor: | Chia-Hao Huang, Sen-Yung Hsieh, Ming-Chin Yu, Ta-Sen Yeh, Yun-Shien Lee, Yin-Jing Tien, Chih-Jen Wen, Tsung-Chieh Shih, Tzu-Chen Yen |
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| Rok vydání: | 2012 |
| Předmět: |
Carcinoma
Hepatocellular Angiogenesis Down-Regulation Mice Nude Kaplan-Meier Estimate Biology Neovascularization Mice chemistry.chemical_compound Downregulation and upregulation Cell Line Tumor Paracrine Communication Human Umbilical Vein Endothelial Cells medicine Animals Humans miR-214 Tube formation Neovascularization Pathologic Hepatology Liver Neoplasms Hepatoma-derived growth factor Prognosis Gene Expression Regulation Neoplastic Vascular endothelial growth factor MicroRNAs HEK293 Cells chemistry Case-Control Studies Disease Progression Cancer research Intercellular Signaling Peptides and Proteins Ectopic expression Neoplasm Recurrence Local medicine.symptom Neoplasm Transplantation |
| Zdroj: | Journal of Hepatology. 57:584-591 |
| ISSN: | 0168-8278 |
| DOI: | 10.1016/j.jhep.2012.04.031 |
| Popis: | Background & Aims Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We elucidated the biological and clinical significance of miR-214 downregulation in HCC. Methods MicroRNAs deregulated in HCC were identified using array-based microRNA profiling. A luciferase reporter assay confirmed target association between miR-214 and the hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays validated the roles of miR-214/HDGF in angiogenesis. Results miR-214 downregulation was associated with higher tumor recurrence and worse clinical outcomes. Ectopic expression of miR-214 suppressed xenograft tumor growth and microvascularity of the tumors and their surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis disclosed HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, suppression of HDGF expression or ectopic expression of miR-214 in the donor HCC cells. The angiogenic activity of the conditioned media, lost by ectopic expression of miR-214 in the donor cells, was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214. Conclusions A novel role of microRNA in tumorigenesis is identified. Downregulation of miR-214 contributes to the unusual hypervascularity of HCC via activation of the HDGF paracrine pathway for tumor angiogenesis. |
| Databáze: | OpenAIRE |
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