2019, Vol. 40
宫颈癌是女性生殖系统第二常见的恶性肿瘤[1]。据美国癌症学会估计，到2019年将有13 170例新发侵袭性宫颈癌，且有4 250例女性患者因该病死亡[2]。宫颈癌的发生是一个循序渐进的过程，起病初表现为宫颈上皮内瘤变（cervical intraepithelial neoplasia，CIN），经CIN1、CIN2、CIN3、早期浸润癌多个阶段最终发展成浸润癌[3]。宫颈人乳头瘤病毒（human papilloma virus，HPV）的持续感染是宫颈癌癌前病变及宫颈癌发病的必要条件[4]。高危人乳头瘤病毒（high-risk human papilloma virus，hrHPV）感染已被证实为侵袭性宫颈癌的主要病因[5]。大量研究表明长链非编码RNA（long non-coding RNA，lncRNA）在宫颈癌的发生、发展过程中发挥着促癌或抑癌作用，其机制涉及E6和E7癌蛋白、微RNA（microRNA，miRNA）及多条信号通路[6-9]。本文就lncRNA在宫颈癌发生、发展中的机制进行综述。
1 LncRNA概述LncRNA是具有200多个核苷酸的异质性转录本，由于缺少所需长度的开放阅读框而不具备蛋白质编码能力，可以按照位置[如长基因间RNA（large intergenic noncoding RNA，lincRNA）]、结构[如环状RNA（circular RNA，circRNA）]、功能[如竞争性内源性RNA（competitive endogenous RNA，ceRNA）]和转录方向（如反义RNA）等进行分类[10]。
研究发现，lncRNA是一类新型的肿瘤主调控因子，在细胞增殖、细胞分化、染色质重构、基因组剪接、表观遗传调控、转录等重要生物学过程中发挥着关键作用[11]。如lncRNA肝细胞核因子1同源异型盒A（hepatocyte nuclear factor 1 homeobox A，HNF1A）反义RNA1在非小细胞肺癌组织和细胞系中表达上调，其高表达与晚期临床分期和转移相关[12]。LncRNA CCAAT/增强子结合蛋白α（CCAAT/enhancer binding protein α，CEBPA）反义RNA1是一种癌基因，其在口腔鳞状细胞癌中表达上调与临床晚期、分化不良、淋巴结转移相关[13]。
此外，lncRNA的细胞定位与其潜在功能信息有关。细胞核lncRNA可通过与关键表观遗传调控因子相互作用，增强染色质环化及与剪接因子相互作用调控剪接，从而实现转录调控[14]。目前发现的细胞核lncRNA有lncRNA-肺腺癌转移相关转录本1（metastasis-associated lung adenocarcinoma transcript 1，MALAT1）[15]和lncRNA-核富含丰富的转录本1（nuclear-enriched abundant transcript 1，NEAT1）[16]，细胞质lncRNA有lncRNA-分化拮抗非蛋白质编码RNA（differentiation antagonizing nonprotein coding RNA，DANCR）[17]和lncRNA-opa相互作用蛋白5-反义转录本1（opa-interacting protein 5 antisense transcript 1，OIP5-AS1）[18]，双定位lncRNA有lncRNA-牛磺酸上调基因1（taurine-upregulated gene 1，TUG1）[19]、lncRNA-癌症易感性候选基因7（cancer susceptibility candidate 7，CasC7）和lncRNA-HOX转录反义RNA（HOX transcript antisense RNA，HOTAIR）[20]。研究发现，细胞质lncRNA在转录后作为ceRNA发挥作用，通过充当miRNA海绵并与mRNA结合来招募RNA结合蛋白，从而促进降解、抑制翻译或启动翻译，例如lncRNA-FAM83H反义RNA1（FAM83H antisense RNA1，FAM83H-AS1）[14]。随着高通量测序等技术的应用，越来越多的研究表明lncRNA是多种生物学过程的重要调控因子，也是宫颈癌中新的生物学调控分子之一[6-8]。LncRNA通过调节HPV中E6、E7癌蛋白、作为诱捕lncRNA调控miRNA、调控Wnt等多条信号通路，从而参与宫颈癌的发生、发展。
2 E6、E7癌蛋白HPV是一种无包膜的双链DNA病毒，在鳞状上皮细胞中感染和复制[21-22]。HPV病毒基因组分为3个区域：（1）早期（E）区，包括E1~E7，与病毒复制相关；（2）晚期（L）区域，包括主要（L1）和次要（L2）衣壳蛋白；（3）非编码区（non-coding region，NCR），又称长控制区（long control region，LCR）。
病毒蛋白hrHPV E6参与了从HPV感染的早期阶段到癌变的整个进程。HPV E6癌蛋白与多种细胞蛋白相互作用而激活多种致癌途径，如导致细胞凋亡受阻、转录机制改变、细胞相互作用受到干扰和细胞永生。目前只有几个lncRNA被证明受到HPV-16 E6的特异性调控，包括lncRNA-MALAT1和宫颈癌增殖细胞核抗原表达调控lncRNA（cervical carcinoma expressed PCNA regulatory lncRNA，lncRNA-CCEPR）[14]。HPV E6可导致几种宿主lncRNA发生差异表达，包括lncRNA-生长停滞特异性转录本5（growth arrest-specific transcript 5，GAS5）、lncRNA-H19和lncRNA-FAM83H-AS1[14]。HPV E6蛋白的致癌活性之一是通过靶向p53（肿瘤抑制因子）降解使其失活，如lncRNA-WT1反义RNA（WT1 antisense RNA，WT1-AS）可通过miRNA-330-5p上调p53从而抑制宫颈癌细胞生长和侵袭[23]。
病毒蛋白hrHPV E6和E7在癌细胞中可组成性表达以维持致癌表型，也可相互拮抗抑制癌基因表达，如lncRNA-胸腺肽假基因2（thymopoietin pseudogene 2，TMPOP2）和HPV16/18 E6/E7在宫颈癌细胞中相互促进表达，增强致癌活性[24]。
3 诱捕lncRNA根据功能可将lncRNA分为4大类：信号lncRNA、诱捕lncRNA、向导lncRNA、支架lncRNA[25]。近年来，越来越多的研究报道lncRNA与miRNA结合并抑制其作用，从而发挥ceRNA或miRNA海绵的作用[26-27]。ceRNA理论认为，lncRNA在细胞质中高度表达，能够与miRNA竞争性结合调控其下游靶基因，从而抑制miRNA的生物学功能，参与肿瘤的发生、发展[28]。诱捕lncRNA可充当ceRNA[29]，犹如一种分子海绵，能结合和吸附其他调控蛋白质和miRNA等，从而抑制这些分子的功能间接调控基因的表达。详见表 1。诱捕lncRNA可能成为改善宫颈癌患者化学治疗反应和生存的一个新靶点。
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表 1 常见诱捕lncRNA及其在宫颈癌中的作用机制 Tab 1 Common decoy lncRNAs and its mechanisms in cervical cancer |
4 信号通路
目前关于宫颈癌相关lncRNA的研究多数仅局限于1个或2个孤立的lncRNA，涉及的细胞信号通路也不多。由于宫颈癌调控体系复杂，涉及的细胞通路多样，有必要对宫颈癌相关的lncRNA进行细胞信号通路层面的归纳和总结。
4.1 Wnt/β-连环蛋白（β-catenin）信号通路Wnt/β-Catenin信号通路在宫颈癌的发生和转移中扮演着关键角色。LncRNA-HOTAIR被定义为cMyc激活的恶性肿瘤驱动因子，在宫颈癌的进展中发挥重要作用。下调lncRNA-HOTAIR通过抑制Wnt信号通路抑制宫颈癌细胞自噬、增殖和上皮间质转化（epithelial-mesenchymal transition，EMT），从而增强宫颈癌细胞对放射治疗的敏感性[50]。LncRNA-DiGeorge综合征关键区域基因5（DiGeorge syndrome critical region gene 5，DGCR5）下调可激活Wnt信号，从而促进宫颈癌的进展[51]。过表达LINC00675增强了宫颈癌细胞中的Wnt/β-catenin信号[52]。
4.2 磷脂酰肌醇3激酶（phosphatidylinositol 3-kinase，PI3K）-蛋白激酶B（protein kinase B，Akt）-哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路激活PI3K/Akt/mTOR信号通路会促进肿瘤细胞的增殖。PI3K是一种异二聚体蛋白，由1个调控亚基（p85a/b）和1个催化亚基（p110a/b/g/d）组成。激活的PI3K通过调控其下游靶蛋白Akt进而调控细胞增殖、凋亡和肿瘤发生。下调lncRNA-LINC01305通过靶向TNXB抑制PI3K/Akt信号通路，最终抑制EMT、细胞侵袭和细胞迁移[53]。肿瘤抑制因子PTEN是PI3K/PTEN/Akt信号通路的负调控因子，它以Akt为靶点调控细胞生长、分化、增殖和迁移。
4.3 丝裂原激活蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路MAPK通路在细胞增殖、分化、血管生成和存活等关键过程中发挥重要作用。该通路的核心是一个三级级联的磷酸化-去磷酸化反应MAPK激酶激酶/MAPK激酶/MAPK，启动后导致基因转录。MAPK信号通路的下游是ERK通路，这是一个进化上保守的级联信号。ERK/MAPK通路是肿瘤治疗的重要靶点，例如在黑素瘤和肝细胞癌中，lncRNA-RMEL3[54]和lncRNA-URHC[55]下调可通过使ERK/MAPK通路失活调控肿瘤细胞增殖，诱导细胞凋亡；在子宫内膜癌中，lncRNA-BRAF激活的非编码RNA（BRAF-activated non-protein-coding RNA，BANCR）下调可通过降低基质金属蛋白酶（matrix metalloproteinase，MMP）-1和MMP-2抑制ERK/MAPK通路[56]；在胶质瘤中，lncRNA-MALAT1介导的肿瘤抑制可能通过下调MMP-2而降低ERK/MAPK信号通路活性[57]。关于宫颈癌中lncRNA对MAPK通路作用的报道较少，Liu等[58]发现lncRNA-MNX1 AS1可通过激活MAPK通路影响宫颈癌的进展。
5 小结与展望细胞信号通路等机制在宫颈癌的发生、发展、转归等过程中发挥着不可替代的作用，作为其中重要的组成部分，大量的lncRNA起着不可忽视的调控作用。LncRNA-HOTAIR已成为宫颈癌药物治疗的分子靶标。中药有效成分青蒿琥酯可通过抑制lncRNA-HOTAIR表达而下调环氧合酶2（cyclooxygenase 2，COX-2），继而抑制MMP和血小板源性生长因子（platelet-derived growth factor，PDGF）合成，发挥抑制宫颈癌细胞侵袭与转移的作用[59]。
由于宫颈癌调控体系的复杂性和涉及细胞通路的多样性，单一或少数的lncRNA并不足以产生决定性影响，应从整体层面把控lncRNA并进行总结归纳，分析lncRNA与miRNA、癌基因E6/E7、细胞信号通路之间的联系。基于细胞信号通路层面整体把控的宫颈癌lncRNA有望成为宫颈癌早期诊断和预后相关的生物标志物，从中筛选关键节点的lncRNA可能有助于开发新的治疗策略。
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