文章信息
- 索金珊, 王欣玲
- SUO Jinshan, WANG Xinling
- microRNA在眼部的表达及研究进展
- The Expression and Research Progress of microRNAs in the Eye
- 中国医科大学学报, 2019, 48(6): 555-557, 573
- Journal of China Medical University, 2019, 48(6): 555-557, 573
-
文章历史
- 收稿日期:2018-11-02
- 网络出版时间:2019-05-27 16:42
人类基因组中大约50%的DNA可以转录为RNA,其中只有不到2%的RNA翻译成蛋白质(mRNA),其余的98%不能翻译成蛋白质,这些不能翻译成蛋白质的RNA称之为非编码RNA(non-coding RNA,ncRNA),微小RNA(microRNA,miRNA)是一类内源性非编码RNA,由20~22个核苷酸组成。miRNA通过完全或不完全互补配对,结合到靶mRNA的3’非翻译区(untranslated regions,UTR),引起靶mRNA的降解或翻译抑制,从而在转录后水平调控基因表达[1]。越来越多的研究者不断地研究和探索发现在眼部正常组织及眼部相关疾病中miRNA的差异性表达,为眼部组织生长发育及眼部组织疾病的研究提供了一个新的平台。
1 miRNA在眼表及相关疾病中的表达METLAPALLY等[2]首次测定了人类眼球不同发育阶段巩膜上miRNA的表达谱,发现胎儿巩膜上的miR-7b、miR-214、let-7c、let-7e、miR-103、miR-107和miR-98较成年人成倍增加,在不同发育阶段巩膜组织中miRNA表达差异有统计学意义。在形觉剥夺诱导的近视小鼠模型中发现,let-7a和miR-16呈倍数变化且有统计学意义[3],其中let-7a参与核因子Kappa B亚基(nuclear factor kappa B subunit,NF-κβ)信号通路,调控巩膜基质主要成分I型胶原蛋白的形成。
研究[4]发现,在角膜术后角膜上皮miR-151a-3p、miR-138-5p、miR-146b-5p、miR-194-5p、miR-28-5p和miR-181a-2-3p表达改变,在角膜鳞状上皮miR-151a-3p、miR-195-5p、miR-185-5p和miR-194-5p表达改变,同时发现圆锥角膜上皮基底细胞层S100钙结合蛋白A2(S100 calcium-binding protein A2,S100A2)高表达。miR-184(+8C > A)和miR-184(+3A > G)2个杂合子区突变后发现伴随圆锥角膜病变[5]。但是在780例圆锥角膜患者中仅发现2例miR-184突变者,只能说miR-184突变是圆锥角膜一个可能的原因。
在角膜炎中miR-183、miR-96和miR-182能够通过调节角膜内神经分布和内在免疫细胞功能在铜绿假单胞菌角膜炎中发挥作用,敲除后,角膜炎症反应减轻[6];miR-155 [7]的表达加重单纯疱疹性角膜炎的严重性;75个miRNA特异性表达于真菌感染的角膜上皮,miR-511-5p、miR-142-3p、miR-155-5p和miR-451a等表达可能在真菌感染的角膜上皮中参与调控损伤愈合过程,miR-451a表达增加与其靶基因、巨噬细胞迁移运动减少呈现一致性,可能具有很重要的调节功能[8]。
SEO等[9]发现在碱烧伤角膜损伤模型中,与血管内皮生长因子受体-3(vascular endothelial growth factor receptor-3,VEGFR-3)3’端非编码区连接的miR-466能够抑制血管和淋巴管的形成。CAKMAK等[10]局部应用贝伐单抗和舒尼替尼降低角膜新血管形成中VEGFR-2和VEGF-A的水平。miR-15b、miR-16和miR-126水平在舒尼替尼和贝伐单抗组中差异均有统计学意义。
MATTHAEI等[11]发现在迟发性Fuchs角膜营养不良(corneal endothelial dystrophy,FECD)角膜内皮中有78个miRNA表达下调,编码内切核糖核酸酶的DICER1呈现差异性低表达。
2 miRNA与晶状体及相关疾病研究[12]发现,在正常婴儿及先天性白内障患儿的中央区晶体上皮细胞中miR-182、miR-204和miR-124表达存在明显差异。WANG等[13]在H2O2诱导的人晶状体上皮细胞-B3(human lens epithelial cells-B3,HLE-B3)细胞氧化应激白内障模型中发现上调的miR-34a-5p和miR-630以及下调的miR-335-3p与年龄相关的核性白内障的进展有关。而在体外miR -181a的下调可能涉及抑制凋亡相关基因caspase-3(CASP-3),B细胞淋巴瘤相X蛋白(B-cell lymphoma associated protein X,Bax)和环氧化酶-2(cyclooxygenase-2,COX-2)的表达,以及抑制丙二醛(malondialdehyde,MDA)的产生减弱H2O2诱导的人晶状体上皮细胞凋亡[14]。miR-211通过上调肿瘤蛋白p53和Bax削弱了晶状体上皮抗氧化应激能力,促进晶状体上皮细胞的凋亡并抑制其分化[15]。这些miRNA在年龄相关性白内障形成中扮演重要角色。
HOFFMAN等[16]分析发现,在小鼠白内障手术后miR-184和miR-204在调控后发性白内障的形成过程中有重要作用。miR-204-5p的在混浊组织明显下调,而高水平miR-204-5P通过作用于下游的靶基因Smad4(small mother against decapentaplegic 4)而参与转化生长因子(transforming growth factor,TGF)TGF/Smad信号通路可促进人晶状体上皮细胞钙黏素E的表达,抑制波形蛋白、平滑肌肌动蛋白的表达[17]。在不同类型的白内障中miRNA可能扮演不同的角色,其结果影响了晶状体细胞的凋亡和代谢,进而影响晶状体的透明性。
3 miRNA与视网膜及相关疾病FENG等[18]发现,在激光诱导的大鼠脉络膜新生血管组织中miR-539-5p可通过直接抑制趋化因子受体7(chemokine receptor 7,CXCR7)抑制体外人类视网膜微血管内皮细胞(human retinal microvascular endothelial cells,HRMECs)存活和血管形成,并在体内抑制激光诱导的脉络膜新生血管。H2O2处理的视网膜色素上皮细胞中miR-125b诱导表达,在氧化应激过程中糖代谢受抑制,而miR-125b的过表达通过己糖激酶2途径导致细胞糖代谢紊乱[19]。
目前大量有关视网膜母细胞瘤(retinoblastoma,RB)的研究发现,miRNA能够靶向作用于相同或不同的信号通路直接或间接地影响RB的发展,如miR-29a能够抑制肿瘤的增殖、迁移和侵袭[20],而miR-498等能加速RB的进程[21]。
WANG等[22]发现基质金属蛋白酶(matrix metalloproteinase,MMP)-2和MMP-9同时靶向于miR-296-3p,miR-296-3p通过抑制细胞增殖、迁移、侵袭和诱导细胞凋亡,对脉络膜恶性黑素瘤细胞产生抑制肿瘤的作用。
在糖尿病性视网膜病变研究中,miR-21能下调过氧化物酶体增殖剂激活受体-α(peroxisome proliferator-activated receptor-α,PPAR-α)水平,促进炎症反应,导致血管损伤和细胞凋亡[23]。miR-200b/c通过抑制血管生成抑制蛋白2(vasohibin2,VASH2)对高葡萄糖诱导的HRMECs功能障碍具有保护作用[24]。这些miRNA可能为糖尿病性视网膜病变的患者提供更加精准的治疗方案,改善患者的生活质量。
ANASAGASTI等[25]通过对视网膜色素变性小鼠视网膜miRNA的研究发现,上调最显著的miRNA是miR-6240和miR-6970,显著下调的是miR-20b-5p和miR-19b-3p。
4 miRNA与青光眼在青光眼研究[26]中发现miR-450可以通过改变生肌决定因子(myoblast determination,MyoD)家族蛋白来调节小梁网的牵拉力。
WECKER等[27]发现房水中miR-451a、miR-21和miR -16的水平与血浆中的高度一致,而房水中表达丰度前20的miRNA(如miR-184、miR-4448、miR-30a、miR-29a、miR-29c、miR-19a、miR-30d、miR-205、miR-24、miR-22和miR-3074)水平与血浆中反向相关。研究[28]发现在原发性开角型青光眼(primary open-angle glaucoma,POAG)中,miR-125b-5p、miR-302d-3p和miR-451a在POAG表达差异有统计学意义,miR-122-5p可能靶向3种青光眼相关基因,参与黏着斑、紧密连接和TGF-β信号传导通路。
在青光眼视网膜中miR-181c、miR-497、miR-204、let-7a、miR-29b、miR-16、miR-106b和miR-25表达下调,与细胞外基质、免疫系统、细胞转导通路、蛋白酶级联通路有关[29]。上调的miR-93-5p能够通过蛋白激酶B/雷帕霉素靶蛋白(protein kinase B/mammalian target of rapamycin,PKB/Mtor)途径抑制N-甲基-D天冬氨酸(N-methyl-D-aspartic acid,NMDA)诱导的青光眼中视网膜神经节细胞自噬作用[30]。miRNA通过作用于与房水生成及房水排出相关的组织及通路来影响眼压的波动及视神经的状态,从而在青光眼的发生发展中发挥作用。
随着基因测序技术的不断发展,miRNA在眼部生物功能和致病机制的研究更加深入,这些miRNA在眼部组织及疾病中的角色仍然是研究者们探索的热点,需要研究者理性地对待基因测序,严谨认真地进行科学探索,为眼部疾病的诊断和治疗提供新的思路和方法。
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