In-Depth Characterization of the MicroRNA Transcriptome in Normal Thyroid and Papillary Thyroid Carcinoma
In-Depth Characterization of the MicroRNA Transcriptome in Normal Thyroid and Papillary Thyroid Carcinoma
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DOI：
10.1210/jc.2013-1214
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发表时间：
2013-08-01
影响因子：
5.8
通讯作者：
Jazdzewski, Krystian
中科院分区：
文献类型：
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作者：
Swierniak, Michal;Wojcicka, Anna;Jazdzewski, Krystian
背景：单个 microRNA 基因可能产生几种长度不同的成熟产物，称为 isomiR。已知 IsomiR 具有组织特异性和功能相关性。甲状腺的 microRNA 序列异质性尚未确定。 目的：本研究的目的是提供正常甲状腺和甲状腺乳头状癌 (PTC) 中 microRNA 转录组的全面视图。设计：我们使用下一代深度测序来分析 PTC 肿瘤 (n = 14)、未受影响的肿瘤邻近组织 (n = 14) 和对照非癌性甲状腺组织 (n = 14) 的 micro RNA 长度异质性和表达谱。结果通过另外一组 9 个 PTC 肿瘤/正常组织对的微阵列进行了验证。结果：与正常甲状腺组织相比，PTC 中的 89 个 microRNA 显着失调（错误发现率 < 0.05，倍数变化 0.13-20.7）。最失调的 miRNA 包括 miR-146b-5p、miR-221-3p、miR-7-3p、miR-551b-3p、miR-486-3p 和 miR-144-3p，证实了之前的微阵列分析。 miRNA 的表达不依赖于 BRAF 突变状态。有趣的是，85% 的最丰富的 microRNA 由与 miRBase 中存放的标准参考序列不同的亚型组成。此外，在正常甲状腺和PTC肿瘤中表达的microRNA中，分别有42.4%和35.9%完全不存在参考microRNA。许多 isomiR 改变了种子序列，从而产生了一组不同的靶基因。对于高度失调的 miR-146b-5p，我们检测到 6 个亚型（肿瘤/正常倍数变化 14.4-28.7，错误发现率 < 0.002），其 5' 末端有 1-nt 差异，从而产生了 2 个替代种子。这 2 个种子的靶基因仅在 13.1% 的基因中重叠。结论：几乎所有 microRNA 都表现出不同长度的亚型，并且在甲状腺肿瘤发生中具有潜在不同的功能。
Context: A single microRNA gene may give rise to several mature products that differ in length, called isomiRs. IsomiRs are known to be tissue specific and functionally relevant. The microRNA sequence heterogeneity of the thyroid gland has yet to be determined.Objective: The objective of the study was to provide a comprehensive view of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma (PTC).Design: We used next-generation deep sequencing to analyze micro RNA length heterogeneity and expression profiles of PTC tumors (n = 14), unaffected tissue adjacent to tumors (n = 14), and control, noncancerous thyroid tissue (n = 14). The results were validated with a microarray on an additional set of 9 PTC tumor/normal tissue pairs.Results: Eighty-nine microRNAs were significantly deregulated in PTC compared with normal thyroid tissue (false discovery rate < 0.05, fold change 0.13-20.7). Top deregulated miRNAs included miR-146b-5p, miR-221-3p, miR-7-3p, miR-551b-3p, miR-486-3p, and miR-144-3p, confirming previous microarray profiling. The expression of miRNAs did not depend on the BRAF mutation status. Interestingly, 85% of the most abundant microRNAs consisted of isoforms that differed from the standard reference sequence deposited in miRBase. Moreover, the reference microRNAs were completely absent in 42.4% and 35.9% of the microRNAs expressed in normal thyroid and PTC tumors, respectively. Numerous isomiRs had altered seed sequences, which led to a different set of target genes. For highly deregulated miR-146b-5p, we detected 6 isoforms (tumor/normal fold change 14.4-28.7, false discovery rate < 0.002) that varied at their 5' ends with a 1-nt difference that created 2 alternative seeds. The target genes for those 2 seeds overlapped in only 13.1% of genes.Conclusions: Almost all microRNAs exhibit isoforms of variable length and potentially distinct function in thyroid tumorigenesis.