Cross-kingdom inhibition of breast cancer growth by plant miR159
Cross-kingdom inhibition of breast cancer growth by plant miR159
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DOI：
10.1038/cr.2016.13
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发表时间：
2016-02-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Shizhen Emily
中科院分区：
文献类型：
--
作者：
Chin, Andrew R.;Fong, Miranda Y.;Wang, Shizhen Emily
MicroRNAs(MiRNAs)是基因表达的重要调控因子，对真核生物的发育、生理和疾病有着广泛的影响。在miRNA的生物发生和在动植物中的作用的分子基础上发现了高度的平行。最近的研究有趣地表明，植物来源的miRNAs通过饮食摄取，在调节哺乳动物基因表达方面可能有跨王国的作用。尽管在哺乳动物样本中检测到的植物miRNAs的来源和范围仍然存在争议，但这些初步研究启发我们确定是否可以在西方人类血清中检测到植物miRNAs，以及这些植物miRNAs是否能够影响与癌症等人类疾病相关的基因表达和细胞过程。在这里，我们发现西方捐赠者血清中含有miRNA miR159植物，其在血清中的丰度与患者乳腺癌的发生和进展呈负相关。在人血清中，miR159主要在胞外小泡中检测到，并且对高碘酸钠氧化具有抵抗力，提示植物起源的3‘末端核糖的2’-O-甲基化。在乳腺癌细胞中，而不是在非癌乳腺上皮细胞中，合成的miR159模拟物能够通过靶向Tcf7抑制增殖，Tcf7编码Wnt信号转录因子，导致MYC蛋白水平下降。口服miR159模拟物可显著抑制小鼠乳腺移植瘤的生长。这些结果首次证明了植物miRNA可以抑制哺乳动物的癌症生长。
MicroRNAs (miRNAs) are critical regulators of gene expression, and exert extensive impacts on development, physiology, and disease of eukaryotes. A high degree of parallelism is found in the molecular basis of miRNA biogenesis and action in plants and animals. Recent studies interestingly suggest a potential cross-kingdom action of plant-derived miRNAs, through dietary intake, in regulating mammalian gene expression. Although the source and scope of plant miRNAs detected in mammalian specimens remain controversial, these initial studies inspired us to determine whether plant miRNAs can be detected in Western human sera and whether these plant miRNAs are able to influence gene expression and cellular processes related to human diseases such as cancer. Here we found that Western donor sera contained the plant miRNA miR159, whose abundance in the serum was inversely correlated with breast cancer incidence and progression in patients. In human sera, miR159 was predominantly detected in the extracellular vesicles, and was resistant to sodium periodate oxidation suggesting the plant-originated 2'-O-methylation on the 3' terminal ribose. In breast cancer cells but not non-cancerous mammary epithelial cells, a synthetic mimic of miR159 was capable of inhibiting proliferation by targeting TCF7 that encodes a Wnt signaling transcription factor, leading to a decrease in MYC protein levels. Oral administration of miR159 mimic significantly suppressed the growth of xenograft breast tumors in mice. These results demonstrate for the first time that a plant miRNA can inhibit cancer growth in mammals.