Nowicki-Osuch Karol, Li Yaoyong, Challinor Mairi, Gerrard David T, Hanley Neil A, Sharrocks Andrew D
School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
PLoS One. 2017 Jul 21;12(7):e0181902. doi: 10.1371/journal.pone.0181902. eCollection 2017.
Long non-coding RNAs are being increasingly recognised as important molecules involved in regulating a diverse array of biological functions. For example, many long non-coding RNAs have been associated with tumourigenesis and in this context their molecular functions often involves impacting on chromatin and transcriptional control processes. One important cellular control system that is often deregulated in cancer cells is the ERK MAP kinase pathway. Here we have investigated whether ERK pathway signaling in response to EGF stimulation, leads to changes in the production of long non-coding RNAs. We identify several different classes of EGF pathway-regulated lncRNAs. We focus on one of the inducible lincRNAs, EGF inducible long intergenic non-coding RNA 1 (EINCR1). EINCR1 is predominantly nuclear and shows delayed activation kinetics compared to other immediate-early EGF-inducible genes. In humans it is expressed in a tissue-specific manner and is mainly confined to the heart but it exhibits little evolutionary conservation. Importantly, in several cancers EINCR1 shows elevated expression levels which correlate with poor survival in lung adenocarcinoma patients. In the context of lung adenocarcinomas, EINCR1 expression is anti-correlated with the expression of several protein coding EGF-regulated genes. A potential functional connection is demonstrated as EINCR1 overexpression is shown to reduce the expression of EGF-regulated protein coding genes including FOS and FOSB.
长链非编码RNA越来越被认为是参与调节多种生物学功能的重要分子。例如,许多长链非编码RNA与肿瘤发生有关,在这种情况下,它们的分子功能通常涉及影响染色质和转录控制过程。癌细胞中经常失调的一个重要细胞控制系统是ERK MAP激酶途径。在这里,我们研究了响应EGF刺激的ERK途径信号传导是否会导致长链非编码RNA产生的变化。我们鉴定了几类不同的受EGF途径调节的lncRNA。我们重点研究了一种可诱导的lincRNA,即EGF诱导的长链基因间非编码RNA 1(EINCR1)。EINCR1主要位于细胞核中,与其他早期立即受EGF诱导的基因相比,其激活动力学延迟。在人类中,它以组织特异性方式表达,主要局限于心脏,但进化保守性较低。重要的是,在几种癌症中,EINCR1表达水平升高,这与肺腺癌患者的不良生存率相关。在肺腺癌的背景下,EINCR1表达与几种蛋白质编码的受EGF调节的基因的表达呈负相关。EINCR1过表达被证明会降低包括FOS和FOSB在内的受EGF调节的蛋白质编码基因的表达,这表明它们之间存在潜在的功能联系。