Kwok Zhi Hao, Zhang Bin, Chew Xiao Hong, Chan Jia Jia, Teh Velda, Yang Henry, Kappei Dennis, Tay Yvonne
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Cancer Res. 2021 Mar 1;81(5):1308-1320. doi: 10.1158/0008-5472.CAN-20-1406. Epub 2020 Nov 10.
Approximately half of all miRNA reside within intronic regions and are often cotranscribed with their host genes. However, most studies of intronic miRNA focus on individual miRNA, while conversely most studies of protein-coding and noncoding genes frequently ignore any intron-derived miRNA. We hypothesize that the individual components of such multigenic loci may play cooperative or competing roles in driving disease progression and that examining the combinatorial effect of these components would uncover deeper insights into their functional importance. To address this, we performed systematic analyses of intronic miRNA:host loci in colon cancer. The locus, comprising of a long noncoding RNA and multiple intronic miRNA, was highly upregulated in cancer, and cooperativity within this multicomponent locus promoted cancer growth. interacted with DHX9 and DICER and regulated A-to-I RNA editing and miRNA expression. These results show for the first time that a long noncoding RNA can regulate A-to-I RNA editing, further expanding the functional repertoire of long noncoding RNA. Intronic miR-374b and miR-545 inhibited tumor suppressors and to enhance proto-oncogenic PI3K-AKT signaling. Furthermore, intronic miR-421 may exert an autoregulatory effect on miR-374b and miR-545. Taken together, our data unveil the intricate interplay between intronic miRNA and their host transcripts in the modulation of key signaling pathways and disease progression, adding new perspectives to the functional landscape of multigenic loci. SIGNIFICANCE: This study illustrates the functional relationships between individual components of multigenic loci in regulating cancer progression..
大约一半的微小RNA（miRNA）位于内含子区域，并且常常与其宿主基因一起共转录。然而，大多数关于内含子miRNA的研究聚焦于单个miRNA，相反，大多数关于蛋白质编码基因和非编码基因的研究常常忽略任何源自内含子的miRNA。我们推测，这种多基因位点的各个组分可能在驱动疾病进展中发挥协同或竞争作用，并且研究这些组分的组合效应将揭示其功能重要性的更深入见解。为了解决这一问题，我们对结肠癌中的内含子miRNA：宿主基因座进行了系统分析。该基因座由一个长链非编码RNA和多个内含子miRNA组成，在癌症中高度上调，并且这个多组分基因座内的协同作用促进了癌症生长。它与DHX9和Dicer相互作用，并调节A到I的RNA编辑和miRNA表达。这些结果首次表明长链非编码RNA可以调节A到I的RNA编辑，进一步扩展了长链非编码RNA的功能范围。内含子miR-374b和miR-545抑制肿瘤抑制因子并增强原癌基因PI3K-AKT信号传导。此外，内含子miR-421可能对miR-374b和miR-545发挥自调节作用。综上所述，我们的数据揭示了内含子miRNA与其宿主转录本在关键信号通路调节和疾病进展中的复杂相互作用，为多基因位点的功能格局增添了新的视角。意义：本研究阐明了多基因位点的各个组分在调节癌症进展中的功能关系。
