PNAS：首次发现miRNA家族共同的功能

　　

生物通报道：德州大学西南医学中心的研究人员发现一组小RNA分子家族会影响进入胎盘的细胞发育，胎盘是氧气和营养物质给到胎儿的重要器官，研究人员指出 miRNA-515-5p 未来也许能作为血液检测，筛选先兆子痫患病风险。

这一研究成果公布在《美国国家科学院院刊》（PNAS）杂志上，文章通讯作者为西南医学中心生物化学教授Carole Mendelson博士。 Mendelson博士表示，这是首次发现大型多成员miRNA家族参与某种共同的功能。

miRNA-515-5p 定位在人类19号染色体上，研究发现这种小分子RNA只在灵长类动物中才有，主要在胎盘中表达。不过此前也有研究表明，miRNA-515-5p 可沉默MARK4基因，这个基因编码的蛋白在乳腺癌和肺癌中帮助细胞挣脱束缚，移动到身体的其他部位，如大脑和肝脏。一种miRNA可抑制癌症扩散

在怀孕的24周左右，一些孕妇在高血压，蛋白尿基础上，会出现头痛，眼花等症状，这就是先兆子痫（preeclampsia）。先兆子痫会引发早产，同时也是导致全球围产儿发病和死亡的主要因素。到目前为止，治疗的唯一方法是引产，造成了许多家庭的不幸。

在正常妊娠早期，胎盘滋养层细胞进入孕妇子宫壁，扩张血管，促进亲与胎儿之间氧和营养物质的交换。虽然胎盘发育出自己的血液系统，就能通过激素发出自己的化学信号，帮助维持妊娠，支持胎儿生长。

Mendelson博士等人采用了一种模拟滋养层细胞分化的人体胎盘细胞培养体系，在培养期间，细胞融合在一起，开始生成高水平的胎盘激素，比如雌激素和孕酮等。当细胞开始分化和融合时，研究人员发现miRNA-515-5p 的水平急剧下降，由此他们提出靶向miRNA-515-5p 的三种mRNAs和三种蛋白是胎盘发育的必要条件。

“这好像就是 miRNA-515-5p 踩着了分化的刹车，随着 miRNA-515-5p 水平降低，刹车就会松开，胎盘分化开始，”她说。

但是对于先兆子痫患者来说，miRNA-515-5 p 水平一直保持异常高，作为组织分化指标的mRNA水平和三种关键蛋白的表达水平均，相对于正常孕妇来说都明显下降。这一发现表明miRNA在正常胎盘发育和功能作用方法扮演了重要的角色。“我们认为 miRNA-515-5p 能令胎盘滋养层细胞保持未分化的干细胞样状态，直到怀孕的某个时刻松开刹车，开始分化。但是这项研究仍处于早期阶段，还有待更进一步的研究。”
（生物通：万纹）

原文摘要：
Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia

Dysregulation of human trophoblast invasion and differentiation can result in preeclampsia (PE), a hypertensive disorder of pregnancy with significant morbidity and mortality for mother and offspring. miRNA microarray analysis of RNA from human cytotrophoblasts (CytT), before and after differentiation to syncytiotrophoblast (SynT) in primary culture, revealed that members of miR-515 family—including miR-515-5p, miR-519e-5p, miR-519c-3p, and miR-518f, belonging to the primate- and placenta-specific chromosome 19 miRNA cluster (C19MC)—were significantly down-regulated upon human SynT differentiation. The proto-oncogene, c-MYC, which declines during SynT differentiation, interacted with E-boxes upstream of pri-miR-515-1 and pri-miR-515-2, encoding these mRNAs, to enhance their expression. Predicted targets of miR-515-5p, known to be critical for human SynT differentiation, including hCYP19A1/aromatase P450, glial cells missing 1 (GCM1), frizzled 5 (FZD5), WNT2, Sp1, and estrogen receptor-α (ERα) mRNA, were markedly up-regulated during SynT differentiation. Notably, overexpression of miR-515-5p in cultured primary human trophoblasts impaired SynT differentiation and specifically decreased expression of hCYP19A1, GCM1, and Fzd5, which were validated as its direct targets. Interestingly, miR-515-5p levels were significantly increased in PE placentas, whereas mRNA and protein levels of targets, hCYP19A1, GCM1, and FZD5, were significantly decreased, compared with placentas of normotensive women. Thus, miR-515-5p may serve a key role in human trophoblast differentiation; its aberrant up-regulation may contribute to the pathogenesis of PE.