miR-23a promotes the transition from indolent to invasive colorectal cancer.
miR-23a promotes the transition from indolent to invasive colorectal cancer.
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DOI：
10.1158/2159-8290.cd-11-0267
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发表时间：
2012-06
期刊：
影响因子：
28.2
通讯作者：
Lipkin SM
中科院分区：
文献类型：
--
作者：
Jahid S;Sun J;Edwards RA;Dizon D;Panarelli NC;Milsom JW;Sikandar SS;Gümüs ZH;Lipkin SM
结直肠癌（CRC）是一种典型的肿瘤，在其进化过程中经历了多个不同的阶段。为了了解从惰性到侵袭性疾病转变的调节机制，我们从Apc和DNA错配修复（MMR）突变小鼠模型中分析了非侵袭性腺瘤和侵袭性腺癌的体细胞拷贝数变化。我们在小鼠8号染色体上发现了一个编码microRNAs (mirnas) 23a和27a的重复扩增子。miRs-23a和27a水平在小鼠肠腺癌、来自I/II期CRC患者的原发肿瘤以及人类CRC细胞系和癌症干细胞中上调。在功能上，miR-23a促进结直肠癌细胞和干细胞的迁移和侵袭，而miR- 27a主要促进增殖。我们通过计算和实验验证了转移抑制因子1 （MTSS1）是miR-23a的直接靶点，同样验证了泛素连接酶FBXW7是miR-27a的直接靶点。对CRC患者微阵列数据集中计算预测的靶基因的分析与miR-23a的作用一致，但与miR-27a的作用不一致，特别是在侵袭性CRC中。
Colorectal cancer (CRC) is a classic example of a tumor that progresses through multiple distinct stages in its evolution. To understand the mechanisms regulating the transition from indolent to invasive disease, we profiled somatic copy number alterations in non-invasive adenomas and invasive adenocarcinomas from Apc and DNA mismatch repair (MMR) mutant mouse models. We identified a recurrent amplicon on mouse chromosome 8 that encodes microRNAs (miRs) 23a and 27a. miRs-23a and 27a levels are upregulated in mouse intestinal adenocarcinomas, primary tumors from stage I/II CRC patients, as well as in human CRC cell lines and cancer stem cells. Functionally, miR-23a promotes CRC cells and stem cells migration and invasion, while miR- 27a primarily promotes proliferation. We computationally and experimentally validated that Metastasis Suppressor 1 (MTSS1) is a direct miR-23a target and similarly validated that the ubiquitin ligase FBXW7 is a direct miR-27a target. Analyses of computationally predicted target genes in CRC patient microarray datasets are consistent with a role for miR-23a, but not miR-27a, specifically in invasive CRC.