MKAD-21 suppresses the oncogenic activity of the miR-21/PPP2R2A/ERK molecular network in bladder cancer

Bladder cancer (BC) represents a disease associated with significant morbidity and mortality. MicroRNA-21 (MiR-21) has been found to have oncogenic activity in multiple cancers, including BC, while inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in BC and evaluate the effects of intravenous (I.V.) and intraperitoneal (I.P.) administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of BC cells, while the MKAD-21 chemically-modified antisense oligo against miR-21, dose-dependently blocked xenograft growth. I.V. administration of LNA miR-21 was more effective in suppressing tumor growth than was I.P. administration. Integration of computational and transcriptomic analyses in a panel of 28 BC lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and BC cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21-induced oncogenic effects in BC. Integrative analysis of human BC tumors and a large panel of human BC cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and BC cell growth. Furthermore, I.V. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A-ERK network in mice.

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