突变型KRAS(G12C)三维肺癌球体中的转座元件RNA失调

Transposable element RNA dysregulation in mutant KRAS(G12C) 3D lung cancer spheroids.

作者信息

Carrillo David, Reggiardo Roman E, Lim John, Mantalas Gary, Peddu Vikas, Kim Daniel H

机构信息

Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.

Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA.

出版信息

bioRxiv. 2023 Feb 28:2023.02.27.530369. doi: 10.1101/2023.02.27.530369.

DOI:10.1101/2023.02.27.530369

PMID:36909578

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10002638/

Abstract

Mutant KRAS regulates transposable element (TE) RNA and interferon-stimulated gene (ISG) expression, but it remains unclear whether diverse mutations in KRAS affect different TE RNAs throughout the genome. We analyzed the transcriptomes of 3D human lung cancer spheroids that harbor KRAS(G12C) mutations to determine the landscape of TE RNAs regulated by mutant KRAS(G12C). We found that KRAS(G12C) signaling is required for the expression of LINE- and LTR-derived TE RNAs that are distinct from TE RNAs previously shown to be regulated by mutant KRAS(G12D) or KRAS(G12V). Moreover, KRAS(G12C) inhibition specifically upregulates SINE-derived TE RNAs from the youngest Alu subfamily AluY. Our results reveal that TE RNA dysregulation in KRAS-driven lung cancer cells is mutation-dependent, while also highlighting a subset of young, Alu-derived TE RNAs that are coordinately activated with innate immunity genes upon KRAS(G12C) inhibition.

摘要

突变型KRAS调节转座元件（TE）RNA和干扰素刺激基因（ISG）的表达，但尚不清楚KRAS中的不同突变是否会影响整个基因组中不同的TE RNA。我们分析了携带KRAS（G12C）突变的三维人肺癌球体的转录组，以确定由突变型KRAS（G12C）调节的TE RNA的情况。我们发现，KRAS（G12C）信号传导对于LINE和LTR衍生的TE RNA的表达是必需的，这些TE RNA与先前显示受突变型KRAS（G12D）或KRAS（G12V）调节的TE RNA不同。此外，KRAS（G12C）抑制特异性地上调了来自最年轻的Alu亚家族AluY的SINE衍生的TE RNA。我们的结果表明，KRAS驱动的肺癌细胞中TE RNA的失调是突变依赖性的，同时也突出了一部分年轻的、Alu衍生的TE RNA，它们在KRAS（G12C）抑制时与先天免疫基因协同激活。