MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer
MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer
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DOI：
10.1093/carcin/bgs161
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发表时间：
2012-08-01
期刊：
影响因子：
4.7
通讯作者：
Williams, Cecilia
中科院分区：
文献类型：
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作者：
Aydogdu, Eylem;Katchy, Anne;Williams, Cecilia
MicroRNAs （miRNAs）在干细胞生物学、分化和肿瘤发生中起着关键作用，作为潜在的乳腺癌治疗药物受到高度关注。然而，它们在正常乳腺分化和乳腺癌中的表达和功能仍有待阐明。为了确定哪些miRNA参与乳腺分化，我们使用两种不同的大规模方法，然后使用qPCR，深入研究了未分化的干细胞样小鼠乳腺细胞功能分化过程中miRNA的表达。在乳腺细胞多轮分化过程中，21种mirna的表达发生了显著变化。大多数，包括miR-200家族和已知的肿瘤抑制mirna，在分化过程中上调。只有四种mirna，包括oncomiR miR-17下调。通路分析表明，受调控的miRNA簇与干细胞分化、增殖和维持的主要通路之间存在复杂的相互作用。与人类乳腺癌肿瘤的比较显示，未分化的干细胞样阶段的基因图谱与预后不良的乳腺癌聚集在一起。在这些组中，一个共同的提名者是E2F途径，它在分化诱导的mirna靶向的基因中被过度代表。mirna的一个子集可以进一步区分人类非癌症和乳腺癌细胞系，miR-200a/miR-200b、miR-146b和miR-148a在三阴性乳腺癌细胞中特异性下调。我们发现miR-200a/miR-200b可以抑制未分化、非致瘤性乳腺细胞的上皮间充质转化(EMT)-特征性形态学变化。我们的研究提出EphA2是miR-200a新的重要靶基因。总之，我们提供了mirna如何参与乳腺细胞分化的证据数据，并指出它们在乳腺癌中的相关作用。
MicroRNAs (miRNAs) play pivotal roles in stem cell biology, differentiation and oncogenesis and are of high interest as potential breast cancer therapeutics. However, their expression and function during normal mammary differentiation and in breast cancer remain to be elucidated. In order to identify which miRNAs are involved in mammary differentiation, we thoroughly investigated miRNA expression during functional differentiation of undifferentiated, stem cell-like, murine mammary cells using two different large-scale approaches followed by qPCR. Significant changes in expression of 21 miRNAs were observed in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only four miRNAs, including oncomiR miR-17, were downregulated. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways involved in differentiation, proliferation and stem cell maintenance. Comparisons with human breast cancer tumors showed the gene profile from the undifferentiated, stem-like stage clustered with that of poor-prognosis breast cancer. A common nominator in these groups was the E2F pathway, which was overrepresented among genes targeted by the differentiation-induced miRNAs. A subset of miRNAs could further discriminate between human non-cancer and breast cancer cell lines, and miR-200a/miR-200b, miR-146b and miR-148a were specifically downregulated in triple-negative breast cancer cells. We show that miR-200a/miR-200b can inhibit epithelialmesenchymal transition (EMT)-characteristic morphological changes in undifferentiated, non-tumorigenic mammary cells. Our studies propose EphA2 as a novel and important target gene for miR-200a. In conclusion, we present evidentiary data on how miRNAs are involved in mammary cell differentiation and indicate their related roles in breast cancer.