Cell Cycle-Targeting MicroRNAs as Therapeutic Tools Against Refractory Cancers [SW900 cells]

Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in nearly all human tumor types. To identify new approaches for interfering with cyclins/CDKs, we systematically searched for microRNAs (miRNAs) regulating these proteins. We uncovered a group of miRNAs that target nearly all cyclins and CDKs, and demonstrated that these miRNAs are very effective in shutting off cancer cell expansion. By profiling the response of over 120 human cancer cell lines representing 12 tumor types to these cell-cycle-targeting miRNAs, we identified miRNAs particularly effective against triple-negative breast cancers and KRAS-mutated cancers. We also derived expression-based algorithm that predicts response of primary tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we halted tumor progression in seven mouse xenograft models, including three highly aggressive and treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types. RNA-seq for SW900 cells transfected with 25 nM of miR-193a-3p mimic or 25 nM of negative miRNA control (Negative control #2, Ambion).

细胞周期蛋白（Cyclins）与细胞周期蛋白依赖性激酶（CDKs）在几乎所有人类肿瘤类型中均呈过度激活状态。为探寻干预细胞周期蛋白/CDKs的新策略，我们系统筛选了调控这类蛋白的微小RNA（miRNAs）。我们发现了一类可靶向几乎所有细胞周期蛋白与CDKs的miRNAs，并证实这类miRNAs可高效阻断癌细胞增殖。我们对覆盖12种肿瘤类型的120余株人类癌细胞系进行分析，检测其对这类靶向细胞周期的miRNAs的应答反应，最终筛选出对三阴性乳腺癌及KRAS突变型癌症尤为有效的miRNAs。我们还构建了基于表达谱的算法，可预测原发肿瘤对靶向细胞周期miRNAs的应答情况。通过系统性给药纳米颗粒递送的miRNAs，我们在7个小鼠异种移植模型中阻断了肿瘤进展，其中包括3株高侵袭性、治疗抵抗的患者来源肿瘤，且未对正常组织造成影响。本研究结果证实，靶向细胞周期的miRNAs可用于治疗难治性肿瘤类型。本数据集包含转染25 nM miR-193a-3p模拟物或25 nM阴性miRNA对照（阴性对照#2，Ambion公司）的SW900细胞的RNA测序数据。