Institute of General Pathology, Catholic University of the Sacred Heart and Gemelli Polyclinic, Rome, Italy.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Cell Death Dis. 2018 Jan 19;9(2):49. doi: 10.1038/s41419-017-0080-x.
Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs' expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo.
治疗肺癌是一个未满足的需求，因为它占全球癌症死亡人数的大多数。新疗法的发展促使人们寻找潜在的靶点。miRNA 的表达在癌症中经常失调，其调节已被提议作为一种成功的策略来干扰肿瘤细胞的生长和扩散。我们最近报道了一种无偏见的高内涵方法，用于鉴定非小细胞肺癌 (NSCLC) 中调节细胞增殖和肿瘤发生的 miRNA。在这里，我们研究了 miR-663 在 NSCLC 生物学中的致癌作用，并分析了 miR-663 靶向治疗的潜力。我们发现，miR-663 通过表达两个新的直接靶标 PUMA/BBC3 和 BTG2 来调节细胞凋亡，通过控制线粒体外膜通透性 (MOMP)。具体来说，在 miR-663 敲低后，BH3 仅蛋白 PUMA/BBC3 直接激活线粒体去极化和细胞死亡，而 BTG2 的积累通过触发 p53 线粒体定位进一步增强这种效应。此外，我们还表明，miR-663 的耗竭足以在 NSCLC 细胞中引发细胞死亡，并在体内损害肿瘤生长。
