The microRNAs miR-449a and miR-424 suppress osteosarcoma by targeting cyclin A2 expression
| Autor: | Praveen Kumar, Tanushree Ghosh, Md. Muntaz Khan, Ritu Shekhar, Perumal Nagarajan, Priyanka Priyanka, Sandeep Saxena |
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| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
G2 Phase 0301 basic medicine Tumor suppressor gene Down-Regulation Bone Neoplasms Mice SCID Biology medicine.disease_cause Biochemistry Cell Line S Phase Mice 03 medical and health sciences Mice Inbred NOD Cell Line Tumor microRNA medicine Animals Humans Gene Regulatory Networks Gene Regulation RNA Messenger 3' Untranslated Regions Molecular Biology Cell Proliferation Cyclin Osteosarcoma 030102 biochemistry & molecular biology G1 Phase Cell Biology Cell cycle medicine.disease Disease Models Animal MicroRNAs 030104 developmental biology Cancer research Ectopic expression Carcinogenesis Cyclin A2 |
| Zdroj: | Journal of Biological Chemistry. 294:4381-4400 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.005778 |
| Popis: | MicroRNAs of the miR-16 and miR-34 families have been reported to inhibit cell cycle progression, and their loss has been linked to oncogenic transformation. Utilizing a high-throughput, genome-wide screen for miRNAs and mRNAs that are differentially regulated in osteosarcoma (OS) cell lines, we report that miR-449a and miR-424, belonging to the miR-34 and miR-16 families, respectively, target the major S/G(2) phase cyclin, cyclin A2 (CCNA2), in a bipartite manner. We found that the 3′-UTR of CCNA2 is recognized by miR-449a, whereas the CCNA2 coding region is targeted by miR-424. Of note, we observed loss of both miR-449a and miR-424 in OS, resulting in derepression of CCNA2 and appearance of aggressive cancer phenotypes. Ectopic expression of miR-449a and miR-424 significantly decreased cyclin A2 levels and inhibited proliferation rate, migratory potential, and colony-forming ability of OS cells. To further probe the roles of miR-449a and miR-424 in OS, we developed an OS mouse model by intraosseous injection of U2OS cells into the tibia bone of NOD-scid mice, which indicated that miR-449a and miR-424 co-expression suppresses tumor growth. On the basis of this discovery, we analyzed the gene expression of human OS biopsy samples, revealing that miR-449a and miR-424 are both down-regulated, whereas cyclin A2 is significantly up-regulated in these OS samples. In summary, the findings in our study highlight that cyclin A2 repression by miRNAs of the miR-16 and miR-34 families is lost in aggressive OS. |
| Databáze: | OpenAIRE |
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