南大张辰宇教授1个月3篇miRNA论文,近期Nature综述TOP2、新进展TOP6
2016/06/19
据不完全统计,今年5月,南京大学张辰宇教授先后在Nature Communications 、Protein Cell、Scientific Reports上发表了3篇miRNA相关研究。本文汇总该领域近期部分综述和研究进展。


南京大学张辰宇教授

去年12月,笔者曾在《南大张辰宇半年8篇miRNA论文!2015年这12大miRNA突破成果你知道吗?》一文中介绍了多项miRNA领域的研究进展。据不完全统计,今年5月,南京大学张辰宇教授先后在Nature Communications 、Protein Cell、Scientific Reports上发表了3篇miRNA相关研究。

5月31日,发表在Nature Communications上的这一研究中,研究小组发现,在小鼠中通过抑制PRDM16,24小时禁食诱导了miRNA-149-3p介导的皮下向内脏脂肪转换。近期,皮下脂肪“褐变”能力引起了人们对于这一脂肪组织功能极大的兴趣。该研究证实在这一禁食诱导的“内在化”过程中,上调的miR-149-3p直接靶向了白色脂肪“褐变”必需的关键协调蛋白。更为重要地是,他们证实通过皮下抑制miR-149-3p激活了腹股沟脂肪中米色细胞形成,显著提高了全身能量消耗,且没有引起其它组织的功能障碍,这或许会成为对抗肥胖的一种潜在策略。

此外,5月26日发表在Protein Cell上的这一研究证实MiR-29b通过靶向CDK6抑制了骨肉瘤细胞的增殖与迁移。5月13日发表在Scientific Reports的研究证实Slug上调miR-221通过抑制E-cadherin表达促进了乳腺进展。

MicroRNAs (miRNA)是一类长度约为22个核苷酸的非编码RNAs,在调控基因表达、细胞周期、生物体发育等方面起重要作用。今年4月,Nature 旗下Reviews 系列相继发表了miRNA相关的综述。


The active transcriptome available for microRNA binding competition

4月4日,Nature Reviews Genetics上发表了一篇题为“Endogenous microRNA sponges: evidence and controversy”的综述,共介绍了六部分内容,包括人工miRNA抑制剂(miRNA海绵)、ceRNAs的实验证据、ceRNA网络、转录组广泛的RNA竞争、增强ceRNA活性的模型以及ceRNA验证的限制性。[详细]

4月28日,Nature Reviews Immunology上发表了一篇题为“MicroRNAs as regulatory elements in immune system logic”的综述。加州理工学院的David Baltimore教授是本文的两位作者之一,他曾获得1975年诺贝尔生理学或医学奖。

这一综述讨论了多种miRNAs影响免疫发展和造血输出的机制,介绍了miRNA对造血干细胞、先天免疫和适应性免疫细胞的影响,同时讨论了miRNA失调引发的病理后果。文章指出,miRNA是决定造血细胞命运的调控元件,此外,近年来越来越多的研究表明,在特定条件下(比如感染和衰老)miRNA对免疫细胞的发育非常重要。[文献]

以下汇总近期部分miRNA相关成果:

1)Nature Communications:miRNA阻断PD-L1激活免疫反应

miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint

5月5日,发表在Nature Communications上的一项研究中, 来自华中科技大学、同济大学医学院等机构的研究人员证实,miR-424(322)通过阻断PD-L1免疫检查点激活T细胞免疫反应逆转了化疗耐药。研究证实,在化疗耐药的卵巢癌中miR-424(322)调控了PD-L1/PD-1和CD80/CTLA-4信号通路。miR-424(322)与PD-L1、PD-1、CD80 和CTLA-4表达呈负相关。肿瘤中高水平的miR-424(322)与卵巢癌患者无进展生存率呈正相关。[文献]

2)Nature Communications:miRNA可能为AML带来新治疗靶标

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

4月26日,发表在Nature Communications上的一项研究中,辛辛那提大学的研究人员发现了microRNA (miR-22)中的一个特定信号通路,可能为AML带来新的治疗靶标。[文献]

3)Nature Communications:miRNA与鼻咽癌关系研究

miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR–p-PI3K/AKT-c-JUN

4月20日,发表在Nature Communications上的一项研究中,南方医科大学传统中西医医院方唯意研究组发现miRNA(miR-3188)可以调控鼻咽癌的增殖和化疗敏感性,揭示了miR-3188抑制肿瘤的分子机制。

研究显示,miR-3188可以抑制细胞周期过渡和细胞增殖,显著延长带瘤小鼠的生存时间,让癌细胞对化疗药物5-FU更加敏感。进一步研究表明,miR-3188作为肿瘤抑制子直接靶标mTOR来刺激自身表达,参与对细胞生长、肿瘤发生和NPC化疗抗性的抑制。[文献]


4)Cancer Research:华中科技大学揭示促癌miRNA

miR-146b-5p within BCR-ABL1-positive micro-vesicles promotes leukemic transformation of hematopoietic cells

3月24日,在线发表于Cancer Research上的一项研究中,华中科技大学生命科学与技术学院的郭安源教授带领的研究小组构建了K562细胞释放的微泡诱导正常造血干细胞癌变的模型,并对转化过程中不同阶段的样本进行RNA-seq和small RNA-seq测序。通过样本间的差异表达分析发现,在转化的初始阶段,抗癌miRNA以及抑制癌症发生的信号通路被激活;两周后,促癌miRNA上调,细胞周期、DNA损伤修复、能量代谢等信号通路被激活,诱导正常造血干细胞向白血病细胞转化。

基因调控网络分析发现,转录因子和miRNA的差异表达与多个癌症信号通路的失调有关。尤其是,微泡中高表达的miR-146b-5p,通过抑制抑癌因子NUMB的表达,加速了BCR-ABL1诱发的正常造血干细胞到癌细胞的转化。另外,miR-146b-5p的高表达也可提高受体细胞内的ROS水平和基因组不稳定性,导致癌症的发生。[文献]

5)Nature Communication:高通量miRNA药物精准筛选的新方法

高通量的药物筛选是具有挑战性的。信息化处理的基因网络能够对应这个挑战。它能将多个药物候选的潜在目标整合,处理成信息化的可读数据,同时报告特异性和非特异性的效果。2月16日发表在Nature Communication上的研究报告了基于细胞检验miRNA药物靶点的基因网络。[详细]

6)Nature Communications:定时定向递送miRNA的新载体治疗骨质疏松

1月14日,发表在Nature Communications上的一项研究中,科学家们报导了一个具有高亲和力和没有细胞毒性作用的miRNA的超支化聚合物,这个聚合物可以组装成双壳的纳米级复合物的高效率转染体系。该研究通过以GSK-3β为靶标,激活内源性干细胞的成骨活性,使骨质疏松小鼠骨再生,从而解决在实现基于不依赖于细胞的组织工程支架的miRNA治疗,即在再生医学上的一个重要的挑战。[详细]

特别备注:本文部分内容参考自生物通、生物帮、华中科技大学。

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  • Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16

    Visceral adiposity is strongly associated with metabolic disease risk, whereas subcutaneous adiposity is comparatively benign. However, their relative physiological importance in energy homeostasis remains unclear. Here, we show that after 24-h fasting, the subcutaneous adipose tissue of mice acquires key properties of visceral fat. During this fast-induced ‘visceralization’, upregulation of miR-149-3p directly targets PR domain containing 16 (PRDM16), a key coregulatory protein required for the ‘browning’ of white fat. In cultured inguinal preadipocytes, overexpression of miR-149-3p promotes a visceral-like switch during cell differentiation. Mice deficient in miR-149-3p display an increase in whole-body energy expenditure, with enhanced thermogenesis of inguinal fat. However, a visceral-like adipose phenotype is observed in inguinal depots overexpressing miR-149-3p. These results indicate that in addition to the capacity of ‘browning’ to defend against hypothermia during cold exposure, the subcutaneous adipose depot is also capable of ‘whitening’ to preserve energy during fasting, presumably to maintain energy balance, via miR-149-3p-mediated regulation of PRDM16.

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  • MiR-29b suppresses the proliferation and migration of osteosarcoma cells by targeting CDK6

    Osteosarcoma is the most common primary sarcoma of bone, and it is a leading cause of cancer death among adolescents and young adults. However, the molecular mechanism underlying osteosarcoma carcinogenesis remains poorly understood. Recently, cyclin-dependent kinase 6 (CDK6) was identified as an important oncogene. We found that CDK6 protein level, rather than CDK6 mRNA level, is much higher in osteosarcoma tissues than in normal adjacent tissues, which indicates a post-transcriptional mechanism involved in CDK6 regulation in osteosarcoma. MiRNAs are small non-coding RNAs that repress gene expression at the post-transcriptional level and have widely been shown to play important roles in many human cancers. In this study, we investigated the role of miR-29b as a novel regulator of CDK6 using bioinformatics methods. We demonstrated that CDK6 can be downregulated by miR-29b via binding to the 3′-UTR region in osteosarcoma cells. Furthermore, we identified an inverse correlation between miR-29b and CDK6 protein levels in osteosarcoma tissues. Finally, we examined the function of miR-29b-driven repression of CDK6 expression in osteosarcoma cells. The results revealed that miR-29b acts as a tumor suppressor of osteosarcoma by targeting CDK6 in the proliferation and migration processes. Taken together, our results highlight an important role for miR-29b in the regulation of CDK6 in osteosarcoma and may open new avenues for future osteosarcoma therapies.

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  • Slug-upregulated miR-221 promotes breast cancer progression through suppressing E-cadherin expression

    It is generally regarded that E-cadherin is downregulated during tumorigenesis via Snail/Slug-mediated E-cadherin transcriptional reduction. However, this transcriptional suppressive mechanism cannot explain the failure of producing E-cadherin protein in metastatic breast cancer cells after overexpressing E-cadherin mRNA. Here we reveal a novel mechanism that E-cadherin is post-transcriptionally regulated by Slug-promoted miR-221, which serves as an additional blocker for E-cadherin expression in metastatic tumor cells. Profiling the predicted E-cadherin-targeting miRNAs in breast cancer tissues and cells showed that miR-221 was abundantly expressed in breast tumor and metastatic MDA-MB-231 cells and its level was significantly higher in breast tumor or MDA-MB-231 cells than in distal non-tumor tissue and low-metastatic MCF-7 cells, respectively. MiR-221, which level inversely correlated with E-cadherin level in breast cancer cells, targeted E-cadherin mRNA open reading frame (ORF) and suppressed E-cadherin protein expression. Depleting or increasing miR-221 level in breast cancer cells induced or decreased E-cadherin protein level, leading to suppressing or promoting tumor cell progression, respectively. Moreover, miR-221 was specifically upregulated by Slug but not Snail. TGF-β treatment enhanced Slug activity and thus increased miR-221 level in MCF-7 cells. In summary, our results provide the first evidence that Slug-upregulated miR-221 promotes breast cancer progression via reducing E-cadherin expression.

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