Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Biochem Biophys Res Commun. 2013 Feb 15;431(3):617-22. doi: 10.1016/j.bbrc.2012.12.083. Epub 2012 Dec 27.
In human epithelial cancers, the microRNA (miRNA) mir-30d is amplified with high frequency and serves as a critical oncomir by regulating metastasis, apoptosis, proliferation, and differentiation. Autophagy, a degradation pathway for long-lived protein and organelles, regulates the survival and death of many cell types. Increasing evidence suggests that autophagy plays an important function in epithelial tumor initiation and progression. Using a combined bioinformatics approach, gene set enrichment analysis, and miRNA target prediction, we found that mir-30d might regulate multiple genes in the autophagy pathway including BECN1, BNIP3L, ATG12, ATG5, and ATG2. Our further functional experiments demonstrated that the expression of these core proteins in the autophagy pathway was directly suppressed by mir-30d in cancer cells. Finally, we showed that mir-30d regulated the autophagy process by inhibiting autophagosome formation and LC3B-I conversion to LC3B-II. Taken together, our results provide evidence that the oncomir mir-30d impairs the autophagy process by targeting multiple genes in the autophagy pathway. This result will contribute to understanding the molecular mechanism of mir-30d in tumorigenesis and developing novel cancer therapy strategy.
在人类上皮性癌症中，微 RNA（miRNA）mir-30d 高频扩增，通过调节转移、凋亡、增殖和分化，充当关键的致癌 miRNA。自噬是一种长寿命蛋白和细胞器的降解途径，调节许多细胞类型的存活和死亡。越来越多的证据表明，自噬在上皮性肿瘤的发生和发展中起着重要作用。我们采用了一种组合的生物信息学方法、基因集富集分析和 miRNA 靶标预测，发现 mir-30d 可能调节自噬途径中的多个基因，包括 BECN1、BNIP3L、ATG12、ATG5 和 ATG2。我们进一步的功能实验表明，mir-30d 在癌细胞中直接抑制自噬途径中这些核心蛋白的表达。最后，我们表明 mir-30d 通过抑制自噬体形成和 LC3B-I 向 LC3B-II 的转化来调节自噬过程。总之，我们的研究结果为致癌 miRNA mir-30d 通过靶向自噬途径中的多个基因来破坏自噬过程提供了证据。这一结果将有助于理解 mir-30d 在肿瘤发生中的分子机制，并为开发新的癌症治疗策略做出贡献。
