Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1.
Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1.
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DOI：
10.1158/1541-7786.mcr-15-0456
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Rottapel R
中科院分区：
文献类型：
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作者：
Kent OA;Mendell JT;Rottapel R
激活KRAS突变几乎普遍存在于胰腺癌中，发生在超过95%的临床病例中。微小RNA（miRNA）是一种小型非编码RNA，通过结合靶mRNA 3 'UTR内的序列来调节基因表达。miRNA在癌症发病机制中的不可或缺的作用是公认的;然而，miRNA在KRAS介导的肿瘤发生中的作用的特征很差。在此证明miR-31的表达与致癌KRAS的表达和MAPK途径的活性偶联。miR-31在患者来源的异种移植物和一组携带激活KRAS突变的胰腺癌和结肠直肠癌细胞中高度表达。miR-31宿主基因是与miR-31表达相关的大的非编码RNA，并且使得能够鉴定推定的miR-31启动子。使用荧光素酶报告基因，发现最小的RAS响应性miR-31启动子依赖于突变型KRAS和转录因子ELK 1的表达来驱动稳健的荧光素酶活性。此外，ELK 1以MAPK依赖性方式与内源性miR-31启动子直接相互作用。通过调节miR-31靶基因RASA 1激活RhoA，增强miR-31的表达显著增强了多种胰腺癌细胞的侵袭和迁移。重要的是，RASA 1表型的急性敲除通过增加RhoA活化来加强miR-31对胰腺癌细胞迁移行为的表达。
Activating KRAS mutations are nearly ubiquitous in pancreatic cancer occurring in more than 95% of clinical cases. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding sequences within the 3′UTRs of target mRNAs. An integral role for miRNAs in cancer pathogenesis is well established; however, the role of miRNAs in KRAS-mediated tumorigenesis is poorly characterized. Here it is demonstrated that expression of miR-31 is coupled to expression of oncogenic KRAS and activity of the MAPK pathway. MiR-31 is highly expressed in patient derived xenografts and a panel of pancreatic and colorectal cancer cells harboring activating KRAS mutations. The miR-31 host gene is a large non-coding RNA that correlates with miR-31 expression and enabled identification of the putative miR-31 promoter. Using luciferase reporters, a minimal RAS responsive miR-31 promoter was found to drive robust luciferase activity dependent on expression of mutant KRAS and the transcription factor ELK1. Furthermore, ELK1 interacts directly with the endogenous miR-31 promoter in a MAPK-dependent manner. Expression of enforced miR-31 significantly enhanced invasion and migration of multiple pancreatic cancer cells resulting from activation of RhoA through regulation of the miR-31 target gene RASA1. Importantly, acute knockdown of RASA1 phenocopied enforced miR-31 expression on the migratory behavior of pancreatic cancer cells through increased RhoA activation.