Fiori M E, Barbini C, Haas T L, Marroncelli N, Patrizii M, Biffoni M, De Maria R
1] Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy [2] Regina Elena National Cancer Institute, Rome, Italy.
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Cell Death Differ. 2014 May;21(5):774-82. doi: 10.1038/cdd.2014.6. Epub 2014 Jan 31.
Lung cancer is the leading cause of tumor-related death. The lack of effective treatments urges the development of new therapeutic approaches able to selectively kill cancer cells. The connection between aberrant microRNA (miRNA - miR) expression and tumor progression suggests a new strategy to fight cancer by interfering with miRNA function. In this regard, LNAs (locked nucleic acids) have proven to be very promising candidates for miRNA neutralization. Here, we employed an LNA-based anti-miR library in a functional screening to identify putative oncogenic miRNAs in non-small-cell lung cancer (NSCLC). By screening NIH-H460 and A549 cells, miR-197 was identified as a new functional oncomiR, whose downregulation induces p53-dependent lung cancer cell apoptosis and impairs the capacity to establish tumor xenografts in immunodeficient mice. We further identified the two BH3-only proteins NOXA and BMF as new miR-197 targets responsible for induction of apoptosis in p53 wild-type cells, delineating miR-197 as a key survival factor in NSCLC. Thus, we propose the inhibition of miR-197 as a novel therapeutic approach against lung cancer.
肺癌是肿瘤相关死亡的主要原因。缺乏有效的治疗方法促使人们开发能够选择性杀死癌细胞的新治疗方法。异常微小RNA（miRNA - miR）表达与肿瘤进展之间的联系提示了一种通过干扰miRNA功能来对抗癌症的新策略。在这方面，锁核酸（LNA）已被证明是用于中和miRNA的非常有前景的候选物。在此，我们在功能筛选中使用基于LNA的抗miR文库来鉴定非小细胞肺癌（NSCLC）中假定的致癌miRNA。通过筛选NIH-H460和A549细胞，miR-197被鉴定为一种新的功能性致癌miR，其下调诱导p53依赖性肺癌细胞凋亡，并损害在免疫缺陷小鼠中建立肿瘤异种移植物的能力。我们进一步鉴定了仅含BH3结构域的两种蛋白NOXA和BMF作为负责在p53野生型细胞中诱导凋亡的新miR-197靶点，将miR-197描绘为NSCLC中的关键生存因子。因此，我们提出抑制miR-197作为一种针对肺癌的新型治疗方法。
