Li Xiaoou, Liu Lian, Shen Yongchun, Wang Tao, Chen Lei, Xu Dan, Wen Fuqiang
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China; Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.
Biochem Biophys Res Commun. 2014 Nov 28;454(4):512-7. doi: 10.1016/j.bbrc.2014.10.106. Epub 2014 Oct 27.
MicroRNA-26a is a newly discovered microRNA that has a strong anti-tumorigenic capacity and is capable of suppressing cell proliferation and activating tumor-specific apoptosis. However, whether miR-26a can inhibit the over-growth of lung fibroblasts remains unclear. The relationship between miR-26a and lung fibrosis was explored in the current study. We first investigated the effect of miR-26a on the proliferative activity of human lung fibroblasts with or without TGF-beta1 treatment. We found that the inhibition of endogenous miR-26a promoted proliferation and restoration of mature miR-26a inhibited the proliferation of human lung fibroblasts. We also examined that miR-26a can block the G1/S phase transition via directly targeting 3'-UTR of CCND2, degrading mRNA and decreasing protein expression of Cyclin D2. Furthermore, we showed that miR-26a mediated a TGF-beta 2-TGF-beta 1 feedback loop and inhibited TGF-beta R I activation. In addition, the overexpression of miR-26a also significantly suppressed the TGF-beta 1-interacting-CTGF-collagen fibrotic pathway. In summary, our studies indicated an essential role of miR-26a in the anti-fibrotic mechanism in TGF-beta1-induced proliferation in human lung fibroblasts, by directly targeting Cyclin D2, regulating TGF-beta R I as well as TGF-beta 2, and suggested the therapeutic potential of miR-26a in ameliorating lung fibrosis.
微小RNA-26a是一种新发现的微小RNA，具有强大的抗肿瘤能力，能够抑制细胞增殖并激活肿瘤特异性凋亡。然而，miR-26a是否能抑制肺成纤维细胞的过度生长仍不清楚。本研究探讨了miR-26a与肺纤维化之间的关系。我们首先研究了miR-26a对经或未经转化生长因子-β1（TGF-β1）处理的人肺成纤维细胞增殖活性的影响。我们发现，抑制内源性miR-26a可促进增殖，而恢复成熟miR-26a则可抑制人肺成纤维细胞的增殖。我们还检测到miR-26a可通过直接靶向细胞周期蛋白D2（CCND2）的3'-非翻译区（3'-UTR）、降解mRNA并降低Cyclin D2的蛋白表达来阻断G1/S期转换。此外，我们表明miR-26a介导了一个TGF-β2-TGF-β1反馈环并抑制TGF-β受体I（TGF-βR I）的激活。另外，miR-26a的过表达也显著抑制了TGF-β1相互作用的结缔组织生长因子（CTGF）-胶原蛋白纤维化途径。总之，我们的研究表明miR-26a在TGF-β1诱导的人肺成纤维细胞增殖的抗纤维化机制中发挥重要作用，其通过直接靶向Cyclin D2、调节TGF-βR I以及TGF-β2来实现，并提示了miR-26a在改善肺纤维化方面的治疗潜力。
