State Key Lab of Reproductive Medicine, and Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing 210029, China.
J Mol Cell Biol. 2013 Feb;5(1):3-13. doi: 10.1093/jmcb/mjs049. Epub 2012 Aug 29.
Dysregulation of microRNAs is a common feature in human cancers, including breast cancer (BC). Here we describe the epigenetic regulation of miR-148a and miR-152 and their impact on BC cells. Due to the hypermethylation of CpG island, the expression levels of both miR-148a and miR-152 (miR-148a/152) are decreased in BC tissues and cells. DNMT1, the DNA methyltransferase 1 for the maintenance methylation, is aberrantly up-regulated in BC and its overexpression is responsible for hypermethylation of miR-148a and miR-152 promoters. Intriguingly, we found that DNMT1 expression, which is one of the targets of miR-148a/152, is inversely correlated with the expression levels of miR-148a/152 in BC tissues. Those results lead us to propose a negative feedback regulatory loop between miR-148a/152 and DNMT1 in BC. More importantly, we demonstrate that IGF-IR and IRS1, often overexpressed in BC, are two novel targets of miR-148a/152. Overexpression of miR-148a or miR-152 significantly inhibits BC cell proliferation, colony formation, and tumor angiogenesis via targeting IGF-IR and IRS1 and suppressing their downstream AKT and MAPK/ERK signaling pathways. Our results suggest a novel miR-148a/152-DNMT1 regulatory circuit and reveal that miR-148a and miR-152 act as tumor suppressors by targeting IGF-IR and IRS1, and that restoration of miR-148a/152 expression may provide a strategy for therapeutic application to treat BC patients.
miRNAs 的失调是人类癌症（包括乳腺癌）的一个常见特征。在这里，我们描述了 miR-148a 和 miR-152 的表观遗传调控及其对乳腺癌细胞的影响。由于 CpG 岛的超甲基化，miR-148a 和 miR-152（miR-148a/152）在乳腺癌组织和细胞中的表达水平降低。DNMT1 是维持甲基化的 DNA 甲基转移酶 1，在乳腺癌中异常上调，其过表达导致 miR-148a 和 miR-152 启动子的超甲基化。有趣的是，我们发现，DNMT1 表达是 miR-148a/152 的靶标之一，与乳腺癌组织中 miR-148a/152 的表达水平呈负相关。这些结果使我们提出了 miR-148a/152 和 DNMT1 之间在乳腺癌中的负反馈调节环。更重要的是，我们证明 IGF-IR 和 IRS1 在乳腺癌中经常过表达，是 miR-148a/152 的两个新靶标。过表达 miR-148a 或 miR-152 通过靶向 IGF-IR 和 IRS1 及其下游 AKT 和 MAPK/ERK 信号通路，显著抑制乳腺癌细胞增殖、集落形成和肿瘤血管生成。我们的结果表明了一个新的 miR-148a/152-DNMT1 调控回路，并揭示了 miR-148a 和 miR-152 通过靶向 IGF-IR 和 IRS1 发挥肿瘤抑制作用，恢复 miR-148a/152 的表达可能为治疗乳腺癌患者提供一种治疗应用策略。
