Center for Human Genetics, University of Bremen, Bremen, Germany.
PLoS One. 2010 Mar 3;5(3):e9485. doi: 10.1371/journal.pone.0009485.
Thyroid adenomas are common benign human tumors with a high prevalence of about 5% of the adult population even in iodine sufficient areas. Rearrangements of chromosomal band 19q13.4 represent a frequent clonal cytogenetic deviation in these tumors making them the most frequent non-random chromosomal translocations in human epithelial tumors at all. Two microRNA (miRNA) gene clusters i.e. C19MC and miR-371-3 are located in close proximity to the breakpoint region of these chromosomal rearrangements and have been checked for a possible up-regulation due to the genomic alteration. In 4/5 cell lines established from thyroid adenomas with 19q13.4 rearrangements and 5/5 primary adenomas with that type of rearrangement both the C19MC and miR-371-3 cluster were found to be significantly overexpressed compared to controls lacking that particular chromosome abnormality. In the remaining cell line qRT-PCR revealed overexpression of members of the miR-371-3 cluster only which might be due to a deletion accompanying the chromosomal rearrangement in that case. In depth molecular characterization of the breakpoint in a cell line from one adenoma of this type reveals the existence of large Pol-II mRNA fragments as the most likely source of up-regulation of the C19MC cluster. The up-regulation of the clusters is likely to be causally associated with the pathogenesis of the corresponding tumors. Of note, the expression of miRNAs miR-520c and miR-373 is known to characterize stem cells and in terms of molecular oncology has been implicated in invasive growth of epithelial cells in vitro and in vivo thus allowing to delineate a distinct molecular subtype of thyroid adenomas. Besides thyroid adenomas rearrangements of 19q13.4 are frequently found in other human neoplasias as well, suggesting that activation of both clusters might be a more general phenomenon in human neoplasias.
甲状腺腺瘤是常见的良性人类肿瘤，即使在碘充足的地区，其发病率也高达成年人的 5%。19q13.4 染色体带的重排是这些肿瘤中常见的克隆细胞遗传学偏差，使其成为人类上皮肿瘤中最常见的非随机染色体易位。两个 microRNA（miRNA）基因簇，即 C19MC 和 miR-371-3，位于这些染色体重排的断裂点区域附近，并且已经检查了由于基因组改变而可能的上调。在 4/5 个从具有 19q13.4 重排的甲状腺腺瘤和 5/5 个具有该类型重排的原发性腺瘤建立的细胞系中，与缺乏该特定染色体异常的对照相比，C19MC 和 miR-371-3 簇均被发现显著过表达。在其余的细胞系中，qRT-PCR 显示 miR-371-3 簇的成员过表达，这可能是由于在这种情况下伴随染色体重排的缺失。对来自这种类型的一个腺瘤的细胞系中的断裂点进行深入的分子特征分析表明，存在大量的 Pol-II mRNA 片段，这是 C19MC 簇上调的最可能来源。簇的上调很可能与相应肿瘤的发病机制有关。值得注意的是，miRNAs miR-520c 和 miR-373 的表达被认为是干细胞的特征，并且在分子肿瘤学中已经涉及上皮细胞在体外和体内的侵袭性生长，从而允许描绘出甲状腺腺瘤的独特分子亚型。除了甲状腺腺瘤，19q13.4 的重排也经常在其他人类肿瘤中发现，这表明两个簇的激活可能是人类肿瘤中的一个更普遍的现象。
