中国医科大学学报  2023, Vol. 52 Issue (4): 366-370,378

文章信息

李海英, 吴涛, 乔宠
LI Haiying, WU Tao, QIAO Chong
长链非编码RNA NEAT1在妇产科疾病中的研究进展
Advances in long non-coding RNA NEAT1 in gynecology and obsterics diseases
中国医科大学学报, 2023, 52(4): 366-370,378
Journal of China Medical University, 2023, 52(4): 366-370,378

文章历史

收稿日期:2023-02-09
网络出版时间:2023-04-12 15:23:32
长链非编码RNA NEAT1在妇产科疾病中的研究进展
李海英1,2 , 吴涛3 , 乔宠1     
1. 中国医科大学附属盛京医院妇产科,沈阳 110004;
2. 大连市妇女儿童医疗中心(集团)妇产科,辽宁 大连 116000;
3. 大连医科大学附属第一医院麻醉科,辽宁 大连 116000
摘要:核斑点旁组装转录1(NEAT1)是近年来发现的一种新型长链非编码RNA(lncRNA),由多发性内分泌肿瘤Ⅰ型转录位点转录生成。NEAT1可通过参与调节肿瘤细胞生长、迁移、侵袭、转移等,驱动肿瘤的发生和发展,是新型的诊断生物标志物和治疗靶标。本文对NEAT1在妇产科疾病中的研究进展进行综述,系统分析NEAT1在妇产科疾病发生发展中的作用机制,以期为妇产科疾病的病因机制研究及靶向治疗提供新的思路。
Advances in long non-coding RNA NEAT1 in gynecology and obsterics diseases
LI Haiying1,2 , WU Tao3 , QIAO Chong1     
1. Department of Gynaecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang 110004, China;
2. Department of Obstetrics, Dalian Women's and Children's Medical Center (Group), Dalian 116000, China;
3. Department of Anesthesiology, The First Affliated Hospital of Dalian Medical University, Dalian 116000, China
Abstract: Nuclear paraspeckle assembly transcript 1 (NEAT1) is a recently discovered long non-coding RNA (lncRNA) that is transcribed from multiple endocrine tumor typeⅠtranscriptional sites. NEAT1 has been found to be involved in regulating the growth, migration, invasion, and metastasis of tumor cells to drive the occurrence and development of tumors. It plays an important role in the pathogenesis of many diseases, especially malignant tumors, and is a novel diagnostic biomarker and therapeutic target. This article reviews the progress of research into NEAT1 in gynecology and obstetrics diseases, systematically analyzing the role of NEAT1 in disease occurrence and development, in order to provide new directions for pathogenesis research and potential therapeutic targets for diseases in gynecology and obstetrics.

长链非编码RNA(long non-coding RNA,lncRNA)于20世纪90年代末在人类第22号染色体被偶然发现,可能参与多种生物学功能调控[1-4]。随着基因检测水平提高及高通量测序等方法的广泛应用,NONCODE生物数据库中收录的人lncRNA数量已达141 353个,鼠lncRNA数量达117 405个[5]。但在lncRNA数据库中人工注释过的人lncRNA和鼠lncRNA却分别只有166个和108个,lncRNA的结构、序列和功能等仍有待探索[5]。研究[6-7]发现,lncRNA在恶性肿瘤、循环系统疾病等多种疾病中发挥重要功能。最近在某些妇产科疾病中也发现了lncRNA功能的改变[8-10]

核斑点旁组装转录1(nuclear paraspeckle assembly transcript 1,NEAT1)是近年来发现的一种新型lncRNA,由多发性内分泌肿瘤Ⅰ型转录位点转录而来[11]。它含有NEAT1-1(3.7 kb)和NEAT1-2(23 kb)2种单体形式[12]。NEAT1是细胞核内“旁斑”的重要组成部分,是该结构的框架[13]。研究[14]发现,NEAT1主要通过稳定细胞核内的mRNA参与调节基因的表达过程。NEAT1通过参与调节肿瘤细胞生长、迁移、侵袭、转移、上皮-间充质转化(epithelial-mesenchymal transition,EMT)、干细胞样表型、化学药物耐药性的基因表达,驱动肿瘤的发生和发展,NEAT1在很多疾病尤其是恶性肿瘤的发病机制中扮演重要角色,是一种新型的诊断生物标志物和治疗靶标[15]。近年来,在多种妇产科疾病的研究中也发现了NEAT1的积极参与。

1 NEAT1在妇科疾病中的表达、作用及调控机制 1.1 NEAT1与卵巢癌(ovarian cancer,OC)

OC是女性常见的恶性肿瘤。研究发现,大多数作为竞争性内源性RNA(competing endogenous RNA,ceRNA)的lncRNA参与了OC的迁移、侵袭、EMT和转移。除了ceRNA机制之外,还包括直接与mRNA或蛋白质结合发挥作用。NEAT1是众多致癌物之一[16]。研究表明,OC中NEAT1竞争性结合let-7g并下调其表达,刺激了OC细胞的生长、迁移和侵袭。此外,沉默NEAT1可通过降低中胚层特异性转录物同时上调let-7g和脂肪甘油三酯脂肪酶,抑制异种移植肿瘤的生长[17]。YUAN等[18]研究发现,NEAT1通过海绵化miR-365上调FGF9,从而促进OC细胞增殖和血管内皮生长因子、血管生成素1和基质金属蛋白酶(matrix metallopeptidase,MMP)-2的表达,影响血管生成。LUO等[19]研究发现,在OC细胞系中,NEAT1通过海绵化miR-1321沉默其表达,调节紧密连接蛋白3表达,增强OC细胞的EMT、侵袭和迁移。XU等[20]研究发现,NEAT1通过OC中的miR-4500/含W2结构域的蛋白1轴调节细胞的增殖、集落形成、凋亡、迁移、侵袭和糖酵解。JIA等[21]的研究表明NEAT1和miR-491-5p直接相互作用,导致miR-491-5p靶向SOX3 mRNA的上调;且NEAT1在OC化疗耐药中通过调节miR-491-5p/SOX3通路发挥重要作用。提示NEAT1可能是OC的治疗靶点,且大多通过ceRNA机制参与OC发病。

1.2 NEAT1与宫颈癌(cervical cancer,CC)

CC在女性癌症死亡率中高居第二位,寻找用于检测和预测其预后、转移的标志物至关重要。研究[22]表明,NEAT1等多个lncRNA参与CC进展、侵袭和转移、细胞凋亡和预后等。GENG等[23]发现,在CC组织和细胞系中,抑制NEAT1可通过调节miR-377/成纤维细胞生长因子受体1轴,抑制细胞活力和迁移,促进CC细胞凋亡。EMT是导致CC转移的关键过程,miRNA可调节与EMT相关基因的表达。研究[24]表明,NEAT1作为致癌lncRNA发挥作用,抑制miR-361的表达并诱导CC细胞中EMT形成,在CC发病机制中起重要作用。SHEN等[25]研究发现,NEAT1在CC组织和细胞中表达上调,与TNM分期、淋巴结转移呈正相关。NEAT1通过调节通路miR-124/NF-κB促进CC细胞的迁移和侵袭。敲低NEAT1基因可通过抑制细胞增殖、集落形成、迁移和侵袭能力及诱导细胞凋亡,抑制CC的发展。NEAT1可海绵化miR-133a,从而发挥ceRNA的作用,并在CC的发病中调节SOX4表达[26]。研究[27]发现,NEAT1通过靶向miR-9-5p在调节CC细胞的生长中起着重要作用。转染NEAT1 siRNA可通过调节磷酸化蛋白激酶(phosphorylated protein kinase,p-AKT)/磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase,p-PI3K)信号通路抑制CC的增殖,促进细胞凋亡,抑制细胞侵袭。NEAT1可能通过调节AKT/PI3K信号通路参与CC细胞的生物学行为,可作为预测CC诊断和治疗的生物标志物[28]。具有较高NEAT1水平的CC患者临床特征较差,生存时间较短。NEAT1还可通过靶向miR-101促进CC的进展[29]。以上均表明NEAT1在CC中高表达,通过多种渠道参与CC的发病,ceRNA机制是重要的发病机制。

1.3 NEAT1与子宫内膜癌(endometrial cancer,EC)

EC是妇科常见的恶性肿瘤。EC组织和细胞系中NEAT1的表达水平升高,而NEAT1的表达水平与FIGO分期和淋巴结转移呈正相关。在HEC-59细胞中NEAT1过表达可促进细胞生长、集落形成能力及侵袭和迁移能力;转染siNEAT1效果则相反。流式细胞仪分析表明,NEAT1过表达导致S期细胞增加并减弱细胞凋亡,而敲除NEAT1则导致HEC-59细胞中G0/G1阻滞并诱导细胞凋亡。肿瘤转移实时PCR阵列显示,与转移相关的基因[c-myc、胰岛素样生长因子1(insulin like growth factor 1,IGF1)、MMP-2MMP-7]表达上调,HEC-59细胞中过表达NEAT1后钙黏蛋白1和MMP-2表达下调。进一步实验证实,c-myc、IGF1、MMP-2和MMP-7的表达受NEAT1调控[30]。孕酮处理的EC细胞中,NEAT1是最显著下调的lncRNA。孕酮通过调节lncRNA NEAT1/miR-146b-5p介导的Wnt/β-catenin信号通路,对EC的发展产生抑制作用[31]。NEAT1通过调节miR-144-3p/EZH2轴,促进EC细胞增殖和侵袭[32]。以上研究均提示了NEAT1在EC发生中的重要性,因此,NEAT1可能是EC的潜在治疗靶标。

1.4 NEAT1与外阴癌(vulvar cancer,VC)

VC是女性生殖器外表面的一种恶性肿瘤。VC易感风险包括人乳头瘤病毒感染和吸烟。据美国国家癌症研究所统计,2020年有6 120例VC新病例,因VC死亡1 350例。关于NEAT1在VC中作用的研究非常有限。研究[33]表明,75%的外阴鳞状细胞癌组织中NEAT1表达上调。此外,NEAT1高表达还与增加淋巴结转移有关。

1.5 NEAT1与子宫内膜异位症(endometriosis,EM)

EM是一种对女性健康构成严重威胁的妇科疾病,其发病机制尚未完全阐明。生物信息学分析研究[34]显示,NEAT1等lncRNA能与miR-200b-3p相互作用,并与转录因子FOXP3和YY1关联,参与EM发病。YUAN等[35]研究发现,lncRNA与EM的发生发展密切相关。NEAT1在EM中显著上调,通过靶向miR-124-3p表达促进EM的恶性行为。

1.6 NEAT1与多囊卵巢综合征(polycystic ovary syndrome,PCOS)

PCOS是妇科常见疾病,病因尚未完全清楚。研究[36]表明,NEAT1和含溴结构域3(bromodomain containing 3,BRD3)在患有PCOS的女性和PCOS小鼠中呈高表达,而miR-324-3p呈低表达。NEAT1通过下调miR-324-3p和上调BRD3加剧PCOS小鼠的代谢紊乱和卵巢病理变化。

2 lncRNA NEAT1在产科的研究进展 2.1 NEAT1与子宫内膜容受性(endometrial receptivity,ER)

体外受精和胚胎移植(in vitro fertilization and embryo transfer,IVF-ET)是治疗女性不孕症的有效方法之一。ER差是导致胚胎着床功能障碍的重要因素,可降低IVF-ET的妊娠率。不孕患者和胚胎植入功能障碍小鼠模型中,NEAT1和HOXA10水平升高。体外实验表明,NEAT1的下调改善了子宫内膜细胞(endometrial cell,EEC)的增殖和ER标志物的表达。NEAT1可通过与CCCTC结合因子结合上调HOXA10启动子的活性及其表达,从而促进EEC的增殖和ER的建立,最终促进胚胎着床[37]

2.2 NEAT1与黄体

黄体在妊娠维持中起着重要作用。研究发现,尽管排卵正常,但NEAT1基因敲除小鼠随机未能怀孕。野生型卵巢的单侧移植或孕激素的施用可部分挽救该表型,表明黄体功能障碍和伴随的低孕酮是生育力降低的主要原因。与大多数成年组织中观察到的微弱表达相反,NEAT1在黄体中高度表达,在近一半的NEAT1敲除小鼠中,黄体组织的形成受到严重损害。NEAT1对于黄体的形成以及随后尚未确定的次优条件下的妊娠的建立至关重要[38]

2.3 NEAT1与复发性流产(recurrent spontaneous abortion,RSA)

RSA影响约1%的夫妻,半数病例的病因仍然未知。NEAT1在绒毛组织中有表达,且在RSA中表达下调[37]。研究[39]发现,RSA患者NEAT1和MALAT1的水平显著降低,但只有MALAT1水平与p53蛋白水平呈负相关。RSA患者绒毛组织样本中,NEAT1和Bcl-2的表达降低,而miR-125b的表达增加。研究[40]证明,NEAT1/miR-125b/BCL-2轴在调节JEG-3细胞的活力和凋亡中起关键作用。上述研究结果为RSA的发病机制和治疗提供了新的见解。

2.4 NEAT1与胎儿宫内生长受限(intrauterine growth restriction,IUGR)

IUGR是一种多因素疾病,定义为胎儿无法达到其生长潜力。研究[41]发现,IUGR病例和对照组lnc-RNA表达水平间存在显著相关性,意味着这些转录物在胎盘中的表达可能存在共同的调控机制。某些胎盘蛋白已被证明与IUGR发育有关,如来自GH/IGF轴的蛋白和血管生成/细胞凋亡过程。与正常胎盘相比,IUGR的NEAT1 mRNA表达增加。NEAT1仅定位于绒毛滋养细胞的细胞核中,其在IUGR胎盘细胞核中的表达多于正常对照,且强度更高。IUGR胎盘中NEAT1-2 mRNA表达水平仅较对照胎盘中适度增加。这可能导致重要的mRNA在绒毛滋养层细胞核中的保留增加。绒毛滋养细胞对胎盘的屏障功能至关重要,因此可部分解释特发性IUGR胎儿的胎盘功能障碍[42]

2.5 NEAT1与子痫前期(preeclampsia,PE)

PE是妊娠特发疾病,以高血压为特征。PE病因不明确,滋养细胞浸润异常,胎盘浅着床是最为普遍接受的学说。研究[43]表明,NEAT1在PE中上调。滋养细胞中,沉默NEAT1可通过miR-485-5p/AIM2轴促进Treg/Th17平衡。ZHAO等[44]研究发现,NEAT1海绵化miR-205-5p并抑制miR-205-5p与MMP-9或VEGF的结合。FAN等[45]研究发现,在H2O2诱导的PE HTR8/SVneo细胞中,NEAT1表达增加,而miR-411-5p减少。干扰NEAT1可通过上调miR-411-5p和抑制PTEN表达介导促进细胞增殖,滋养细胞的迁移和侵袭。研究[46]表明,NEAT1可能通过调节滋养层细胞增殖和凋亡促进PE的发展。滋养细胞中,NEAT1在氧化应激条件下由p53诱导转录,NEAT1高表达随后通过海绵化miR-18a-5p增加ESRα的表达,从而诱导滋养层细胞凋亡[47]。NEAT1主要通过ceRNA机制影响滋养细胞生物学功能,参与PE发病。

2.6 NEAT1与分娩

分娩启动的原因至今没有定论,现认为是多因素综合作用的结果。炎症反应学说、内分泌控制理论、机械性刺激、子宫功能性改变均被认为与分娩启动有关。研究发现,NEAT1等15个新的lncRNA作为顶级基因中枢,3个组织因子(tissue factor,TF),即NFKB1、RELA和ESR1,作为主要调节因子,可能参与共同调控网络,驱动子宫肌层转化以产生雌激素敏感表型。靶向雌激素受体1和NF-κB途径的lncRNA和miRNA在人类分娩的启动中起关键作用。这些由mRNA、非编码RNA和TF组成的多层次基因组特征,可用于自发足月分娩研究[48]

3 展望

NEAT1作为近年新发现的lncRNA,积极参与影响肿瘤细胞生物学功能,在肿瘤细胞周期及凋亡中也有一定作用[11]。在某些实体肿瘤中,NEAT1发挥致癌基因的作用;在某些非实体肿瘤中,NEAT1则起抑癌基因的作用,这种表达失调提示其可能成为不同肿瘤诊断及预后的生物标志物[49-50]。NEAT1在妇科方面的研究相对较产科多,并被发现积极参与妇科肿瘤发生发展,ceRNA为其常见作用机制。基于肿瘤细胞和滋养细胞侵袭有一定程度的相似性,NEAT1在PE中的相关作用及机制也逐渐受到关注。

PE是妇产科常见并发症,目前对PE患者主要采用解痉、降压、镇静、利尿等保守治疗方法,虽能暂时缓解症状,但最有效的治疗方法仍是适时终止妊娠,产妇面对心脑肾等严重并发症的同时,也常因此导致早产及早产相关的围生儿患病率和病死率增加[51]。在PE的病因机制研究中,滋养细胞侵袭能力下降并因此而造成的受精卵着床过浅及后续异常的子宫螺旋小动脉重铸最为普遍认可并接受,因此,对PE患者改善妊娠早期“浅着床”,即改善子宫螺旋小动脉的重铸,从而终止其后的内皮细胞损伤等病理生理过程非常关键[52]

LIN28是1997年发现的一种RNA结合蛋白,伴随RNA的调控代谢过程,高度保守。近年来发现,在胚胎干细胞分化中可检测到LIN28B的表达和积极参与,在肿瘤细胞中也发现LIN28B参与细胞增殖及迁移等。本课题组前期研究结果提示LIN28B在人类胎盘组织中有表达,且PE中LIN28B的表达可能存在时序性差异,并与滋养细胞侵袭有关。进一步研究发现LIN28B与NEAT1可能存在一定的调控关系。未来将进一步探讨NEAT1在PE发生发展中的作用机制,寻找滋养细胞侵袭调控的关键途径和分子,或可为PE滋养细胞的异常侵袭机制提供新的思路。

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