Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer.
Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer.
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DOI：
10.1186/bcr2839
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发表时间：
2011-03-04
期刊：
影响因子：
--
通讯作者：
Rosenberg CL
中科院分区：
文献类型：
--
作者：
Hannafon BN;Sebastiani P;de las Morenas A;Lu J;Rosenberg CL
微小RNA（miRNA）是一类短的非编码RNA，它们对基因表达起负调控作用，可能在浸润性乳腺癌中起因果作用。由于浸润性疾病的许多基因异常在早期阶段即可检测到，我们假设miRNA表达失调以及基因表达的预测变化在早期乳腺肿瘤中也可能存在。
通过实时定量聚合酶链反应测定法对365种miRNA进行表达谱分析，并结合激光捕获显微切割技术，获得了来自乳房缩小成形术（RM）的正常乳腺上皮（n = 9）以及组织学正常上皮（HN）和导管原位癌（DCIS）成对样本（n = 16）的上皮特异性miRNA表达特征。为了确定miRNA如何控制共同失调的mRNA的表达，我们还在相同的成对HN和DCIS样本中进行了基因表达微阵列分析，并将其与miRNA靶点预测相结合。我们通过调节MCF7细胞中miRNA的表达水平进一步验证了几个靶点对，并测量了靶点mRNA和蛋白质的表达。
35种miRNA在RM、HN和DCIS之间异常表达。29种miRNA和420种mRNA在HN和DCIS之间异常表达。将这两个数据集与miRNA靶点预测相结合，我们确定了两个已确定的靶点对（miR - 195：CCND1和miR - 21：NFIB），并测试了几个新的miRNA：mRNA靶点对。在DCIS中表达下调的假定肿瘤抑制因子miR - 125b的过表达抑制了MEMO1的表达，MEMO1是ErbB2驱动的细胞运动所必需的（也是miR - 125b的一个靶点），以及NRIP1/RIP140的表达，NRIP1/RIP140调节雌激素受体的转录活性。在DCIS中高度过表达的假定致癌miRNA miR - 182和miR - 183的敲低增加了染色质框同源物7（CBX7）（其调节E - 钙黏蛋白表达）、DOK4、NMT2和EGR1的表达。通过敲低miR - 182表达增加CBX7，反过来又正向调节E - 钙黏蛋白的表达，E - 钙黏蛋白是一种参与维持正常上皮细胞形态的关键蛋白质，在肿瘤进展过程中通常会丢失。
这些数据提供了正常乳腺上皮和浸润前乳腺癌的首个miRNA表达谱。此外，我们证明了改变的miRNA表达能够调节表征这些早期癌症的基因表达变化。我们得出结论，miRNA失调可能在早期乳腺癌的发展中起重要作用。
microRNA (miRNA) are short, noncoding RNA that negatively regulate gene expression and may play a causal role in invasive breast cancer. Since many genetic aberrations of invasive disease are detectable in early stages, we hypothesized that miRNA expression dysregulation and the predicted changes in gene expression might also be found in early breast neoplasias. Expression profiling of 365 miRNA by real-time quantitative polymerase chain reaction assay was combined with laser capture microdissection to obtain an epithelium-specific miRNA expression signature of normal breast epithelium from reduction mammoplasty (RM) (n = 9) and of paired samples of histologically normal epithelium (HN) and ductal carcinoma in situ (DCIS) (n = 16). To determine how miRNA may control the expression of codysregulated mRNA, we also performed gene expression microarray analysis in the same paired HN and DCIS samples and integrated this with miRNA target prediction. We further validated several target pairs by modulating the expression levels of miRNA in MCF7 cells and measured the expression of target mRNA and proteins. Thirty-five miRNA were aberrantly expressed between RM, HN and DCIS. Twenty-nine miRNA and 420 mRNA were aberrantly expressed between HN and DCIS. Combining these two data sets with miRNA target prediction, we identified two established target pairs (miR-195:CCND1 and miR-21:NFIB) and tested several novel miRNA:mRNA target pairs. Overexpression of the putative tumor suppressor miR-125b, which is underexpressed in DCIS, repressed the expression of MEMO1, which is required for ErbB2-driven cell motility (also a target of miR-125b), and NRIP1/RIP140, which modulates the transcriptional activity of the estrogen receptor. Knockdown of the putative oncogenic miRNA miR-182 and miR-183, both highly overexpressed in DCIS, increased the expression of chromobox homolog 7 (CBX7) (which regulates E-cadherin expression), DOK4, NMT2 and EGR1. Augmentation of CBX7 by knockdown of miR-182 expression, in turn, positively regulated the expression of E-cadherin, a key protein involved in maintaining normal epithelial cell morphology, which is commonly lost during neoplastic progression. These data provide the first miRNA expression profile of normal breast epithelium and of preinvasive breast carcinoma. Further, we demonstrate that altered miRNA expression can modulate gene expression changes that characterize these early cancers. We conclude that miRNA dysregulation likely plays a substantial role in early breast cancer development.
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影响因子：
8.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Itoh, S;Lemay, S;Abe, J
通讯作者：
Abe, J
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
5
作者：
Hui, Angela B. Y.;Shi, Wei;Liu, Fei-Fei
通讯作者：
Liu, Fei-Fei
影响因子：
11.2
作者：
Federico, Antonella;Pallante, Pierlorenzo;Fusco, Alfredo
通讯作者：
Fusco, Alfredo