miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2
miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2
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DOI：
10.3390/ijms21072423
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发表时间：
2020-03
影响因子：
5.6
通讯作者：
L. Villanova;Chiara Barbini;Cristina Piccolo;Alessandra Boe;R. De Maria;M. Fiori
中科院分区：
文献类型：
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作者：
L. Villanova;Chiara Barbini;Cristina Piccolo;Alessandra Boe;R. De Maria;M. Fiori
microRNA是微小但在转录后水平上对基因表达具有强大调节作用的分子。致癌和抑癌microRNA的异常表达已被认为是人类癌症的共同特征。结直肠癌代表了发达国家的主要临床挑战，创新治疗方法的设计依赖于新生物靶点的鉴定。在这里，我们使用锁核酸（LNA）修饰的抗miR文库在结直肠癌细胞中进行功能筛选，以揭示推定的致癌microRNA，其抑制产生细胞毒性作用。我们鉴定了miR-1285- 3 p，并进一步探索其在商业细胞系和原代结直肠癌干细胞中的靶向作用，发现其诱导细胞周期停滞和凋亡。我们发现，DAPK 2，一种已知的肿瘤抑制因子，是一种新的miR-1285靶点，并介导miR-1285耗尽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一种新的致癌microRNA，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。
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.