In-depth characterization of microRNA transcriptome in melanoma.
In-depth characterization of microRNA transcriptome in melanoma.
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DOI：
10.1371/journal.pone.0072699
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dadras SS
中科院分区：
文献类型：
--
作者：
Kozubek J;Ma Z;Fleming E;Duggan T;Wu R;Shin DG;Dadras SS
人类microRNAs（miRNAs）的完整库，可以区分普通（良性）痣皮肤（恶性）黑色素瘤仍然有待建立。为了进一步深入了解miRNA在黑色素瘤中的作用，我们应用Illumina下一代测序（NGS）平台对痣、厚原发性（>4.0 mm）和转移性黑色素瘤的活检组织中的miRNA转录组进行深入分析，其中匹配的正常皮肤与黑色素细胞和黑色素瘤细胞系（原发性和转移性）平行（n = 28）。 从代表698种已知miRNA的数据中，我们定义了一组前40名列表，其正确地将正常与癌症分类;还确认了23种（58%）先前发现的miRNA，同时引入了另外17种（42%）已知的和前15种推定的在黑素瘤进展期间失调的新候选miRNA。令人惊讶的是，区分黑色素瘤和痣标本的miRNA特征与区分黑色素瘤细胞系和黑色素细胞的miRNA特征显著不同。在顶部列表中，miR-203、miR-204- 5 p、miR-205- 5 p、miR-211- 5 p、miR-23 b-3 p、miR-26 a-5 p和miR-26 b-5 p在黑素瘤中相对于痣减少。在验证队列（n = 101）中，我们通过qRT-PCR验证了NGS结果，并显示miR-211- 5 p表达的受试者操作特征曲线准确区分了侵袭性黑色素瘤（AUC = 0.933）、原位黑色素瘤（AUC = 0.933）和发育异常（非典型）痣（AUC = 0.951）与普通痣。 对共转录的miRNAs的靶点预测分析显示了MAPK信号通路中关键元件的协同调节。此外，我们发现了广泛的序列变异（isomiRs）和其他非编码小RNA，揭示了复杂的黑色素瘤转录组。直接从临床定义的标本中对小RNA进行深度测序提供了一种改进黑色素瘤诊断的稳健策略。
The full repertoire of human microRNAs (miRNAs) that could distinguish common (benign) nevi from cutaneous (malignant) melanomas remains to be established. In an effort to gain further insight into the role of miRNAs in melanoma, we applied Illumina next-generation sequencing (NGS) platform to carry out an in-depth analysis of miRNA transcriptome in biopsies of nevi, thick primary (>4.0 mm) and metastatic melanomas with matched normal skin in parallel to melanocytes and melanoma cell lines (both primary and metastatic) (n = 28). From this data representing 698 known miRNAs, we defined a set of top-40 list, which properly classified normal from cancer; also confirming 23 (58%) previously discovered miRNAs while introducing an additional 17 (42%) known and top-15 putative novel candidate miRNAs deregulated during melanoma progression. Surprisingly, the miRNA signature distinguishing specimens of melanoma from nevus was significantly different than that of melanoma cell lines from melanocytes. Among the top list, miR-203, miR-204-5p, miR-205-5p, miR-211-5p, miR-23b-3p, miR-26a-5p and miR-26b-5p were decreased in melanomas vs. nevi. In a validation cohort (n = 101), we verified the NGS results by qRT-PCR and showed that receiver-operating characteristic curves for miR-211-5p expression accurately discriminated invasive melanoma (AUC = 0.933), melanoma in situ (AUC = 0.933) and dysplastic (atypical) nevi (AUC = 0.951) from common nevi. Target prediction analysis of co-transcribed miRNAs showed a cooperative regulation of key elements in the MAPK signaling pathway. Furthermore, we found extensive sequence variations (isomiRs) and other non-coding small RNAs revealing a complex melanoma transcriptome. Deep-sequencing small RNAs directly from clinically defined specimens provides a robust strategy to improve melanoma diagnostics.
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