MiR-16-1* and miR-16-2* possess strong tumor suppressive and anti-metastatic properties in osteosarcoma.

Abstract

Osteosarcoma (OS) is an aggressive malignancy affecting mostly children and adolescents. MicroRNAs (miRNAs) play important roles in OS development and progression. Here we found that miR-16-1* and miR-16-2* \"passenger\" strands as well as the \"lead\" miR-16 strand possess strong tumor suppressive functions in human OS. We report different although strongly overlapping functions for miR-16-1* and miR-16-2* in OS cells. Ectopic expression of these miRNAs affected primary tumor growth, metastasis seeding, and chemoresistance and invasiveness of human OS cells. Loss-of-function experiments verified tumor suppressive functions of these miRNAs at endogenous levels of expression. Using RNA immunoprecipitation (RIP) assays, we identify direct targets of miR-16-1* and miR-16-2* in OS cells. Furthermore, validation experiments identified FGFR2 as a direct target for miR-16-1* and miR-16-2*. Overall, our findings underscore the importance of passenger strand miRNAs in osteosarcomagenesis.\n\nNovelty and ImpactOsteosarcoma (OS) can be a fatal disease. MicroRNAs (miRNAs) play crucial roles in osteosarcomagenesis. In this study, we identify miR-16-1* and miR-16-2* as strong tumor suppressors and anti-metastatic genes in OS. This is the first report demonstrating tumor suppressive functions of passenger strands of these miRNAs in OS. Given that MIR-16-1 is located in 13q14 region that is commonly deleted in several human malignancies, our findings shed light on oncogenic mechanisms triggered by 13q14 deletion.