Bladder cancer represents a disease associated with significant morbidity and mortality. MiR-21 has been found to have oncogenic activity in multiple cancers, including bladder cancer, whereas inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in bladder cancer and evaluate the effects of i.v. and i.p. administration of a novel miR-21 chemical inhibitor in vivo. LNA miR-21 reduced the oncogenic potential of bladder cancer cells, whereas 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 bladder cancer 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 bladder cancer cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21–induced oncogenic effects in bladder cancer. Integrative analysis of human bladder cancer tumors and a large panel of human bladder cancer 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 bladder cancer cell growth. Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A–ERK network in mice. Mol Cancer Ther; 17(7); 1430–40. ©2018 AACR.

中文翻译：

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MKAD-21 抑制膀胱癌中 miR-21/PPP2R2A/ERK 分子网络的致癌活性

膀胱癌代表一种与显着发病率和死亡率相关的疾病。已发现 MiR-21 在多种癌症（包括膀胱癌）中具有致癌活性，而抑制其表达可抑制肿瘤生长。在这里，我们检查了膀胱癌中受 miR-21 调节的分子网络，并评估了 iv 和 ip 体内新型 miR-21 化学抑制剂的影响。LNA miR-21 降低了膀胱癌细胞的致癌潜力，而 MKAD-21 化学修饰的反义寡核苷酸针对 miR-21 剂量依赖性地阻断了异种移植物的生长。LNA miR-21 的静脉内给药比 ip 给药更有效地抑制肿瘤生长。在一组 28 个膀胱癌系中整合计算和转录组学分析揭示了与 miR-21 水平相关的 15 个基因特征。蛋白磷酸酶 2 调节亚基 Balpha (PPP2R2A) 是这 15 个基因之一，并通过实验验证为新型 miR-21 直接靶基因。基因网络和分子分析表明，PPP2R2A 是 ERK 通路激活和膀胱癌细胞增殖的有效负调节因子。重要的是，我们表明 PPP2R2A 作为 miR-21 诱导的膀胱癌致癌作用的介质。对人膀胱癌肿瘤和一大组人膀胱癌细胞系的综合分析揭示了一种与 miR-21 水平相关的新型 15 基因特征。重要的，我们提供的证据表明 PPP2R2A 代表了一个新的 miR-21 直接靶标和 ERK 通路和膀胱癌细胞生长的调节剂。此外，静脉注射 MKAD-21 抑制剂可通过调节小鼠的 PPP2R2A-ERK 网络有效抑制肿瘤生长。摩尔癌症治疗; 17(7); 1430-40。©2018 AACR。