The LIN28B-IMP1 post-transcriptional regulon has opposing effects on oncogenic signaling in the intestine

Aim: RNA binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood.Method: Here we describe a novel interplay between RBPsLIN28B and IMP1 in intestinal epithelial cells. Ribosome-profiling and RNA-sequencing identifies IMP1 as a principle nodefor gene expression regulation downstream of LIN28B.Results: In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild type or LIN28B-overexpressing mice enhancesthe regenerative response to irradiation.Conclusions: Together, our data provide new evidence for the opposing effects of the LIN28B-IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.

研究目的：RNA结合蛋白（RNA binding proteins, RBPs）在发育与恶性转化过程中广泛表达，但其在上皮稳态中的机制性作用，或是作为肿瘤起始与进展的驱动因子的相关机制，目前仍未完全阐明。
研究方法：本研究阐明了肠道上皮细胞中RNA结合蛋白LIN28B与IMP1之间的新型相互作用。通过核糖体谱分析（ribosome-profiling）与RNA测序（RNA-sequencing），我们鉴定出IMP1是LIN28B下游基因表达调控的核心节点。
研究结果：体外与体内实验数据表明，上皮细胞中IMP1缺失会上调WNT靶基因的表达，并增强LIN28B介导的肠道肿瘤发生进程；而在体内独立过表达IMP1可逆转该效应。此外，在野生型或LIN28B过表达小鼠中敲除IMP1，可增强其受辐照后的再生应答能力。
研究结论：综上，本研究数据为LIN28B-IMP1轴对经典WNT信号通路的转录后调控发挥相反效应提供了新的实验证据，其研究发现对肠道稳态维持、组织再生及肿瘤发生领域具有重要参考意义。