Meta-analysis of transcripts in colon adenocarcinoma patient tissues led to the identification of a DNA damage responsive miR signature called DNA damage sensitive miRs (DDSMs). DDSMs were experimentally validated in the cancerous colon tissues obtained from an independent cohort of colon cancer patients and in multiple cellular systems with high levels of endogenous DNA damage. All the tested DDSMs were transcriptionally upregulated by a common intestine-specific transcription factor, CDX2. Reciprocally, DDSMs were repressed via the recruitment of HDAC1/2-containing complexes onto the CDX2 promoter. These miRs downregulated multiple key targets in the DNA damage response (DDR) pathway, namely BRCA1, ATM, Chk1 (also known as CHEK1) and RNF8. CDX2 directly regulated the DDSMs, which led to increased tumor volume and metastasis in multiple preclinical models. In colon cancer patient tissues, the DDSMs negatively correlated with BRCA1 levels, were associated with decreased probability of survival and thereby could be used as a prognostic biomarker. This article has an associated First Person interview with the first author of the paper.

中文翻译：

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CDX2 诱导性 microRNA 通过靶向多种 DNA 损伤反应途径因子来维持结肠癌。

对结肠腺癌患者组织中转录本的荟萃分析导致鉴定出 DNA 损伤响应性 miR 特征，称为 DNA 损伤敏感 miR (DDSM)。DDSM 在从独立的结肠癌患者队列中获得的癌性结肠组织以及具有高水平内源性 DNA 损伤的多个细胞系统中进行了实验验证。所有测试的 DDSM 均通过常见的肠道特异性转录因子 CDX2 进行转录上调。相反，DDSM 通过将含有 HDAC1/2 的复合物募集到 CDX2 启动子上而受到抑制。这些 miR 下调 DNA 损伤反应 (DDR) 通路中的多个关键靶标，即 BRCA1、ATM、Chk1（也称为 CHEK1）和 RNF8。CDX2 直接调节 DDSM，导致多种临床前模型中肿瘤体积增加和转移。在结肠癌患者组织中，DDSM 与 BRCA1 水平呈负相关，与生存概率降低相关，因此可用作预后生物标志物。本文有对该论文第一作者的相关第一人称采访。