Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer
Regulation of the adenomatous polyposis coli gene by the miR-135 family in colorectal cancer
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DOI：
10.1158/0008-5472.can-08-0951
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Agami, Reuven
中科院分区：
文献类型：
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作者：
Nagel, Remco;le Sage, Carlos;Agami, Reuven
大肠腺瘤性息肉病（APC）基因的失活是结直肠肿瘤发生的主要起始事件。APC中的大多数突变产生过早的终止密码子，导致失去β-连环蛋白结合位点的截短蛋白。无APC的β-连环蛋白刺激Wnt信号通路，导致靶基因的主动转录。在目前的研究中，我们描述了一种新的APC调节机制。我们表明miR-135 a & b靶向APC的3'非翻译区，抑制其表达，并诱导下游Writ途径活性。有趣的是，我们发现miR-135 a和b在结直肠腺瘤和癌中显著上调，这与低APC mRNA水平显著相关。无论APC的突变状态如何，这种遗传相互作用也在表达miR-135a&b的成熟癌细胞系中保留。因此，我们的研究结果揭示了一种miRNA介导的机制，用于控制APC表达和Writ通路活性，并表明其对结直肠癌发病机制的贡献。
Inactivation of the adenomatouspolyposis coli (APC) gene is a major initiating event in colorectal tumorigenesis. Most of the mutations in APC generate premature stop codons leading to truncated proteins that have lost beta-catenin binding sites. APC-free beta-catenin stimulates the Wnt signaling pathway, leading to active transcription of target genes. In the current study, we describe a novel mechanism for APC regulation. We show that miR-135a&b target the 3' untranslated region of APC, suppress its expression, and induce downstream Writ pathway activity. Interestingly, we find a considerable up-regulation of miR-135a&b in colorectal adenomas and carcinomas, which significantly correlated with low APC mRNA levels. This genetic interaction is also preserved in full-blown cancer cell lines expressing miR-135a&b, regardless of the mutational status of APC. Thus, our results uncover a miRNA-mediated mechanism for the control of APC expression and Writ pathway activity, and suggest its contribution to colorectal cancer pathogenesis.