4月24日,，國際學(xué)術(shù)期刊Cell Research于在線發(fā)表了上海生科院生化與細(xì)胞所劉默芳組關(guān)于Onconase抑制惡性間皮瘤細(xì)胞microRNA（miRNA）表達(dá)的最新研究成果。該工作與上海南方模式生物研究中心王慶誠教授合作完成。
Onconase是從北方豹蛙卵或胚胎中提取的一種核糖核酸酶,，是RNase A超家族中最小的成員，目前已被歐盟,、澳大利亞和美國FDA批準(zhǔn)作為罕見病藥物（Orphan drug）用于惡性間皮瘤臨床治療使用,。因接觸石棉是其主要誘因，惡性間皮瘤也俗稱為石棉癌,，該惡性腫瘤預(yù)后極差,，至今尚無有效的治療措施。Onconase特異性地誘導(dǎo)癌細(xì)胞凋亡,，而對正常細(xì)胞的毒性較低,，對非小細(xì)胞肺癌、乳腺癌等的臨床試驗(yàn)?zāi)壳耙舱谶M(jìn)行中,。然而,，作為一種很有前景的抗腫瘤藥物，Onconase的細(xì)胞毒性機(jī)理尚不完全清楚,。
劉默芳研究組研究生喬萌和祖立東等發(fā)現(xiàn),，Onconase對惡性間皮瘤細(xì)胞的miRNA表達(dá)具有普遍下調(diào)作用，而對細(xì)胞中一些oncomiR（如miR-155和miR-21）的下游靶基因如socs1,、pten,、pdcd4等腫瘤抑制基因有明顯上調(diào)作用。有趣的是,，該工作發(fā)現(xiàn)Onconase降解miRNA 前體,，而對miRNA成熟鏈無明顯作用,；與之一致的是，Onconase抑制Dicer對miRNA前體的加工,、降低Dicer生產(chǎn)成熟miRNA,。進(jìn)一步的研究發(fā)現(xiàn)，Onconase對miRNA前體的切割位點(diǎn)偏好于U-G和U-U,。鑒于miRNA在腫瘤發(fā)生發(fā)展中的重要作用,，該工作揭示了Onconase抗癌活性的一種新機(jī)制，完善了Onconase的抗癌作用機(jī)理,，為Onconase的更加合理,、有效、安全用藥提供了科學(xué)依據(jù),。
該項(xiàng)研究工作得到了國家科技部,、國家基金委、中國科學(xué)院及上海市科委的資助,。（生物谷Bioon.com）
doi:10.1038/cr.2012.67
PMC:
PMID:
Onconase downregulates microRNA expression through targeting microRNA precursors
Meng Qiao1,2,3,*, Li-Dong Zu1,2,3,*, Xiao-Hong He1,2,3, Ru-Ling Shen4, Qing-Cheng Wang4 and Mo-Fang Liu
Onconase, the smallest member of RNase A super family that was isolated from oocytes or early embryos of the Northern Leopard Frog (Rana pipiens), has been granted as an orphan drug for the treatment of malignant mesothelioma by US FDA1,2. It was also tested in clinical trials for patients with non-small-cell lung cancer, breast cancer, and renal cell cancer2. Onconase is extremely stable with a Tm of ~87 °C, resists degradation by various proteases, and evades ribonulease inhibitors (RI) present in mammalian cell cytosol3,4,5, which confers advantages to its application in cancer treatment. More importantly, onconase specifically induces apoptosis of cancer cells but has low cytotoxicity to their normal counterparts2. One rational hypothesis for this selectivity is that onconase, a highly cationic protein with calculated pI > 9.5, is selectively internalized by tumor cells given that tumor cells generally are more negatively charged than cognate normal cells2. Nevertheless, as an anti-cancer drug, the mechanisms of its antitumor activity are not well understood. The current model of onconase-mediated cytotoxicity favors that onconase degrades tRNAs in tumor cells after its cytosolic internalization, which leads to ubiquitous inhibition of protein synthesis and apoptosis2. However, increasing evidence indicates that degradation of tRNAs and inhibition of protein synthesis are not the sole cause of onconase-induced apoptosis6,7,8. Consistent with the well-documented causal roles of microRNAs (miRNAs) in cancers, a recent study indicates that onconase regulates the expression of miRNAs in malignant pleural mesothelioma cell lines (H2959, H2373, and H2591), and reveals that onconase controls cell proliferation, invasion, migration, and apoptosis through modulating miRNAs9. However, how onconase affects miRNA expression remains unclear. Here our biochemical studies showed that miRNAs are the direct downstream RNA species of onconase. Intriguingly, we found that onconase downregulates miRNAs by cleavage of miRNA precursors, thus reducing the amount of mature miRNAs produced from Dicer processing.
