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Muscle-invasive and metastatic bladder cancer have an extremely poor 5-year survival rate of 5%. In comparison, all other bladder cancers (BCs) have a 5-year survival rate of 77%. This striking contrast indicates that one of the therapeutic kernels for bladder cancer is to elucidate the molecular mechanisms underlying its invasiveness and metastasis. In the current study, we demonstrated that maternally expressed gene 3 (MEG3) is significantly downregulated in human invasive bladder cancers in comparison to non-invasive bladder cancers, and that ectopic expression of MEG3 dramatically inhibits the invasiveness of human bladder cancer cells. Consistently, ectopic expression of MEG3 also attenuates metastatic ability of T24T cells, a cell line derived from T24 cells, in the lungs of nude mice. Our mechanistic studies reveal that MEG3, as a ceRNA, inhibits the invasiveness of human bladder cancer cells via negative regulation of c-Myc by competing with PHLPP2 mRNA for miR-27a. These findings not only provide a novel insight into understanding the mechanisms behind the MEG3 inhibition of bladder cancer cell invasion, but also reveal the potential for use of MEG3 as a tool for the prevention and therapy of invasive bladder cancer.

MEG3, as a Competing Endogenous RNA, Binds with miR-27a to Promote PHLPP2 Protein Translation and Impairs Bladder Cancer Invasion