Complex patterns of altered MicroRNA expression during the adenoma-adenocarcinoma sequence for microsatellite-stable colorectal cancer.
Complex patterns of altered MicroRNA expression during the adenoma-adenocarcinoma sequence for microsatellite-stable colorectal cancer.
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DOI：
10.1158/1078-0432.ccr-11-1452
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发表时间：
2011-12-01
期刊：
影响因子：
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通讯作者：
Hamilton SR
中科院分区：
文献类型：
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作者：
Bartley AN;Yao H;Barkoh BA;Ivan C;Mishra BM;Rashid A;Calin GA;Luthra R;Hamilton SR
MicroRNAs是调节基因表达的短非编码rna，在大多数肿瘤（包括结直肠腺癌）中表达过高或过低。MicroRNAs是潜在的生物标志物和治疗靶点和药物，但在众所周知的腺瘤-腺癌序列的进展过程中，microRNAome改变的信息有限，可用于指导其使用。我们通过芯片分析在69个匹配的微卫星稳定腺癌、邻近的前体腺瘤（包括高级别和低级别不典型增生区域）和非肿瘤性粘膜样本中分析了866个人类microrna。我们发现230个microrna在进展过程中显著表达差异，包括19个以前未报道的。改变的microrna聚集成早期（I型）和晚期（II型）差异表达的两种主要模式。在β-catenin的主要核定位之前，从粘膜到低级别非典型增生（IA亚型）的早期阶段改变的数量最多（n = 108），包括36个在整个序列中持续差异表达到腺癌的microrna。20个microrna间歇性改变（亚型IB）， 6个microrna短暂改变（亚型IC）。相比之下，33个microrna在晚期高级别发育不良和腺癌（亚型IIA）中发生改变，63个microrna仅在腺癌（亚型IIB）中发生改变。在12个分子通路中发现了高度改变的microrna的预测靶标，包括导致低级别发育不良的Wnt信号通路。β-catenin的表达与下调的microrna相关。我们的研究结果表明，许多microrna在导致结直肠腺癌的分子事件序列中发挥作用，特别是早期事件。在进展过程中，microRNAome改变的时间模式和复杂性将影响microRNAs在临床中的疗效。
MicroRNAs are short noncoding RNAs that regulate gene expression and are over- or under-expressed in most tumors, including colorectal adenocarcinoma. MicroRNAs are potential biomarkers and therapeutic targets and agents, but limited information on microRNAome alterations during progression in the well-known adenoma-adenocarcinoma sequence is available to guide their usage. We profiled 866 human microRNAs by microarray analysis in 69 matched specimens of microsatellite-stable adenocarcinomas, adjoining precursor adenomas including areas of high- and low-grade dysplasia, and nonneoplastic mucosa. We found 230 microRNAs that were significantly differentially expressed during progression, including 19 not reported previously. Altered microRNAs clustered into two major patterns of early (type I) and late (type II) differential expression. The largest number (n = 108) was altered at the earliest step from mucosa to low-grade dysplasia (subtype IA) prior to major nuclear localization of β-catenin, including 36 microRNAs that had persistent differential expression throughout the entire sequence to adenocarcinoma. Twenty microRNAs were intermittently altered (subtype IB), and six were transiently altered (subtype IC). In contrast, 33 microRNAs were altered late in high-grade dysplasia and adenocarcinoma (subtype IIA), and 63 in adenocarcinoma only (subtype IIB). Predicted targets in 12 molecular pathways were identified for highly altered microRNAs, including the Wnt signaling pathway leading to low-grade dysplasia. β-catenin expression correlated with downregulated microRNAs. Our findings suggest that numerous microRNAs play roles in the sequence of molecular events, especially early events, resulting in colorectal adenocarcinoma. The temporal patterns and complexity of microRNAome alterations during progression will influence the efficacy of microRNAs for clinical purposes.