Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.
Int J Mol Sci. 2020 Mar 31;21(7):2423. doi: 10.3390/ijms21072423.
MicroRNAs are tiny but powerful regulators of gene expression at the post-transcriptional level. Aberrant expression of oncogenic and tumor-suppressor microRNAs has been recognized as a common feature of human cancers. Colorectal cancer represents a major clinical challenge in the developed world and the design of innovative therapeutic approaches relies on the identification of novel biological targets. Here, we perform a functional screening in colorectal cancer cells using a library of locked nucleic acid (LNA)-modified anti-miRs in order to unveil putative oncogenic microRNAs whose inhibition yields a cytotoxic effect. We identify miR-1285-3p and further explore the effect of its targeting in both commercial cell lines and primary colorectal cancer stem cells, finding induction of cell cycle arrest and apoptosis. We show that DAPK2, a known tumor-suppressor, is a novel miR-1285 target and mediates both the anti-proliferative and the pro-apoptotic effects of miR-1285 depletion. Altogether, our findings uncover a novel oncogenic microRNA in colorectal cancer and lay the foundation for further studies aiming at the development of possible therapeutic strategies based on miR-1285 targeting.
微小 RNA 是在后转录水平上调控基因表达的微小但强大的调节因子。致癌和肿瘤抑制微小 RNA 的异常表达已被认为是人类癌症的共同特征。结直肠癌在发达国家是一个主要的临床挑战，创新治疗方法的设计依赖于新的生物靶标的识别。在这里，我们使用锁定核酸 (LNA) 修饰的抗微小 RNA 文库在结直肠癌细胞中进行功能筛选，以揭示可能的致癌微小 RNA，其抑制作用产生细胞毒性。我们鉴定出 miR-1285-3p，并进一步探索其在商业细胞系和原发性结直肠肿瘤干细胞中的靶向作用，发现诱导细胞周期停滞和细胞凋亡。我们表明，DAPK2 是一种已知的肿瘤抑制因子，是 miR-1285 的一个新的靶标，介导 miR-1285 耗竭的抗增殖和促凋亡作用。总之，我们的研究结果揭示了结直肠癌中的一种新型致癌微小 RNA，并为进一步研究基于 miR-1285 靶向的可能治疗策略奠定了基础。
