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The microRNAs miR-449a and miR-424 suppress osteosarcoma by targeting cyclin A2 expression.

ABSTRACT: 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/G2 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.

SUBMITTER: Shekhar R

PROVIDER: S-EPMC6433048 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The microRNAs miR-449a and miR-424 suppress osteosarcoma by targeting cyclin A2 expression.

Shekhar Ritu R Priyanka Priyanka P Kumar Praveen P Ghosh Tanushree T Khan Md Muntaz MM Nagarajan Perumal P Saxena Sandeep S

The Journal of biological chemistry 20190124 12

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<sub>2</sub> phase cyclin, cyclin A2 (<i>CCNA2</i>), in a bipartite manner. We found that ...[more]

PMID: 30679313

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The microRNAs miR-449a and miR-424 suppress osteosarcoma by targeting cyclin A2 expression.

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The microRNAs miR-449a and miR-424 suppress osteosarcoma by targeting cyclin A2 expression.

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