MiR‐16‐1‐3p and miR‐16‐2‐3p possess strong tumor suppressive and antimetastatic properties in osteosarcoma

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‐16‐1‐3p and miR‐16‐2‐3p “passenger” strands, as well as the “lead” miR‐16‐5p strand, are frequently downregulated and possess strong tumor suppressive functions in human OS. Furthermore, we report different although strongly overlapping functions for miR‐16‐1‐3p and miR‐16‐2‐3p 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‐16‐1‐3p and miR‐16‐2‐3p in OS cells. Moreover, validation experiments identified FGFR2 as a direct target for miR‐16‐1‐3p and miR‐16‐2‐3p. Overall, our findings underscore the importance of passenger strand miRNAs, at least some, in osteosarcomagenesis. What's new? Disruptions in the expression of microRNAs contribute to the onset and progression of osteosarcoma. Here, the authors looked at miRNA‐16, which is downregulated in osteosarcoma. One strand of the miRNA is the guide strand, while the other, “passenger” strand, is preferentially degraded. miR‐16 originates from two different loci, and though both loci produce the same guide strand, they produce different passenger strands, miR‐16‐1‐3p and miR‐16‐2‐3p. All three microRNAs, the authors found, act as tumor suppressors and reduce metastasis in osteosarcoma. Boosting their expression sensitizes the cells to chemotherapy. The authors also identified FGFR2 as a target of miR‐16‐1‐3p and miR‐16‐2‐3p.