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   大连医科大学学报  2022, Vol. 44 Issue (3): 249-254      DOI: 10.11724/jdmu.2022.03.12
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GPER在女性相关恶性肿瘤中作用的研究进展
刘欣悦1, 张裕民2, 张萍1    
1. 青岛市市立医院(集团) 妇科,山东 青岛 266011;
2. 菏泽市食品药品检验测研究院 生物所,山东 菏泽 274000
摘要:雌激素无论在女性生理还是病理改变中都发挥着重大的作用。传统理论认为,雌激素通过雌激素核受体ERα和ERβ发挥作用。作为一种新型的7次跨膜雌激素膜受体,G蛋白偶联雌激素受体(G protein-coupled estrogen receptor,GPER)区别于ERα、ERβ,可以与雌激素及其衍生物、激动剂和拮抗剂特异性结合从而发挥生物学效应。GPER广泛参与多种激素反应性肿瘤的发生发展,如乳腺癌、子宫内膜癌、前列腺癌和结直肠癌。然而,GPER在癌症中的作用仍存在争议。本文综述了GPER在女性相关恶性肿瘤,特别是乳腺癌、宫颈癌、子宫内膜癌和卵巢癌中的研究进展,以期为女性相关恶性肿瘤的诊疗提供参考。
关键词雌激素膜受体    G蛋白偶联雌激素受体    女性相关恶性肿瘤    
Research progress of GPER in female-related malignant tumors
LIU Xinyue1, ZHANG Yumin2, ZHANG Ping1    
1. Department of Gynecology, Qingdao Municipal Hospital (Group), Qingdao 266011, China;
2. Biological Institute, Heze Institute of Food and Drug Inspection, Heze 274000, China
Abstract: Estrogen plays an important role in the physiological and pathological changes of women. Traditional theory suggests that estrogen acts through nuclear estrogen receptor (ERα) and estrogen receptor (ERβ). G protein-coupled estrogen receptor (GPER), as a new type of seven-span transmembrane estrogen membrane receptor, is different from ERα and ERβ, and can specifically bind to estrogen or its derivatives and antagonists to exert its biological function. GPER is widely involved in the occurrence and development of hormone-responsive tumors, such as breast cancer, endometrial cancer, prostate cancer and colorectal cancer. However, the role of GPER in cancer is still controversial. This article reviews the research progress of GPER in female-related malignancies, especially breast, cervical, endometrial, and ovarian cancers, in order to provide reference for the diagnosis and treatment of female-related malignant tumors.
Keywords: estrogen membrane receptor    GPER    female-related malignancies    

雌激素是女性内分泌系统中一种重要的激素,不仅可以调节细胞的生长、分裂、分化等生理过程,还在稳定女性乳腺和生殖系统的功能、维持骨骼生长以及调节心血管、中枢神经系统功能和免疫反应等中发挥着重要作用。因此,雌激素的紊乱将会导致上述系统一系列病理状况,如子宫内膜、乳腺和骨骼疾病,甚至肿瘤[1]。经典理论认为,雌激素在人体内需要通过雌激素受体介导的基因组效应通路,即与雌激素受体(estrogen receptor, ER)α和ERβ结合发挥作用。但随着对雌激素效应的不断研究,发现了区别于经典效应通路且速度较基因组效应通路快的雌激素非基因组效应通路——G蛋白偶联雌激素受体(G protein-coupled estrogen receptor,GPER),过去称为G蛋白偶联受体30(G protein-coupled receptor 30, GPR30),且与ERα、ERβ没有同源性[2]。GPER几乎分布于全身各个组织器官,如乳腺、子宫、卵巢、心脑血管、肺脏及骨组织等雌激素敏感的部位,并参与恶性肿瘤、免疫反应、心脑血管疾病等雌激素相关疾病的发生发展[3]。雌激素相关恶性肿瘤已经成为威胁女性生存的重要病因,现就GPER在女性相关恶性肿瘤中的研究进展予以综述。

1 GPER的结构及信号通路

GPER基因位于染色体7p22区域,编码375个氨基酸共组成7个跨膜蛋白,理论分子质量41 kDa。GPER被描述为一种发挥快速信号作用的非基因组受体,属于GPCR家族,通常被归类为膜结合蛋白。然而,这种说法目前仍然存在争议,在某些情况下,它不仅在质膜上表达,也在内质网、细胞核和高尔基体上表达[4]。对GPER进行嗜水性分析表明,20~26个氨基酸的6个交互细胞内外袢在其7次跨膜疏水域上[5]。值得注意的是,GPER第三跨膜区后第二胞质内袢上的Asp-Arg-Tyr三联体(DRY)结构提示GPER在信号传导中可能起着关键的作用。雌激素可以三种生理形式(雌酮、雌二醇和雌三醇)与GPER结合。雌酮和雌二醇被认为是GPER的激动剂,而雌三醇则是拮抗剂。其他已发现的激动剂的分子包括己烯雌酚、他莫昔芬、双酚A等[6-7]。除此之外,其选择性激动剂G1和拮抗剂G15等已被广泛用于多种研究[8-9]。研究表明,GPER核心结构已用于生产具有活性的放射性标记物来靶向成像以及治疗体内高表达GPER的恶性肿瘤[10]

目前对GPER所介导的相关分子机制研究仍处于发展阶段,较为公认的理论有:(1)GPER刺激环腺苷酸(cyclic adenosine monophosphate, cAMP)的产生,进一步激活蛋白激酶A(protein kinase A, PKA)调节细胞的功能变化[11]。(2)促进Src蛋白表达从而激活基质金属蛋白酶2/9(matrix metalloproteinase, MMP-2/9),导致表皮生长因子受体(epidermal growth factor, EGFR)反激活继而活化促分裂原活化的蛋白激酶(mitogen activted protein kinase, MAPKs)、磷脂酰肌醇-3-激酶(phosphatidylinositol 3 kinase, PI3K)、蛋白激酶B(protein kinase B, PKB/Akt)和胞外信号调节激酶1/2(extracellular signal-regulated kinase, ERK1/2)等信号因子,促进与细胞存活、增殖、分化、迁移、侵袭相关的多个基因的表达[4, 12]

2 GPER在女性相关恶性肿瘤的表达及作用 2.1 GPER与乳腺癌

雌激素以及其类似物的长期刺激是乳腺癌发生发展的主要危险因素。使用雌激素拮抗剂他莫昔芬和芳香化酶抑制剂等阻断雌激素与其核受体(nuclear estrogen receptors, nERs)结合,对ER阳性的乳腺癌患者有良好的疗效,但对于ER阴性患者则收效极微[13]。然而,仍有ER阳性乳腺癌患者对内分泌治疗并不敏感,部分敏感患者最终也产生耐药反应。因此,找到nERs以外,能够改善疗效及耐药性的靶点成为当前研究的热点。研究表明,在ER阳性耐药乳腺癌细胞中,他莫昔芬、G1和ER拮抗剂ICI 182, 780均显著增强了耐药乳腺癌细胞中的三磷酸腺苷结合转运蛋白G超家族成员2(ABCG2)的表达,但在敏感性细胞中却未增强,且分别激活下游GPER/EGFR/ERK和GPER/EGFR/AKT信号通路来调节耐药细胞中ABCG2的表达和细胞膜定位[6]。在ER阴性的乳腺癌细胞中,也可通过GPER激活下游信号,诱导c-Fos等靶基因表达,参与乳腺癌的进展[14]。在三阴性乳腺癌(triple negative breast cancer, TNBC)细胞中GPER激活谷氨酸N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor, NMDAR)及其下游钙调蛋白依赖性激酶(calmodulin kinase, CaMK)和MAPK途径,从而增强体内外的细胞侵袭和转移[11]。黏着斑激酶(focal adhesion kinase, FAK)是与GPER相互作用的一种化合物,研究发现GPER导致TNBC细胞中FAK磷酸化,从而促进TNBC细胞的迁移[15]。在乳腺癌干细胞(breast cancer stem cells, BCSCs)中,GPER通过其配体的激活,诱导PKA和BAD-Ser118磷酸化以维持BCSC的生物学活性[16]。有研究显示,G15可以明显抑制乳腺癌细胞系SKBR3,MDA-MB-231和MDA-MB-468的增殖,27-羟基胆固醇(27-hydroxycholesterol, 27HC)是GPER新发现的配体,稳定沉默GPER可抑制核因子κB(nuclear factor kappa-B,NF-κB)的激活从而抑制27HC依赖性肿瘤生长[17]。然而也有研究者认为,E2或G1激活GPER可以通过CD151/miR-199a-3p生物轴抑制TNBC细胞恶性生物学行为[18]。还有研究证明,激活的GPER可以促进细胞中VEGF的表达和血管生成,在异种移植肿瘤体内也能抑制肿瘤的生长和血管生成,并降低了VEGF,NF-κB/p65,STAT3和内皮标记CD34的表达水平[19]。在体内研究中,GPER在癌组织中的表达对于乳腺癌患者的影响如今也各有分说,需要进一步在蛋白层面解释这些差异。

虽然GPER在乳腺癌中的研究目前仍无定论,但其广泛参与乳腺癌的发生、发展及耐药,为乳腺癌的早期诊断与靶向药物治疗的研究提供了新的思路。

2.2 GPER与宫颈癌

人乳头瘤病毒(human papilloma virus, HPV)已被证实是宫颈癌发生发展的必要条件。有研究者对156例宫颈癌组织进行免疫组化实验发现,大多数组织样本中(101/156,64.7%)细胞膜和细胞质同时出现表达GPER,且细胞质中GPER的表达与肿瘤抑制蛋白p16和p53呈正相关,其表达与疾病的良好预后有关[20]。应用特异性激动剂G1来刺激GPER的活性可使宫颈癌细胞系HeLa、SiHA和C-33A凋亡、周期阻滞以及坏死等来抑制癌细胞的恶性行为,说明GPER可作为预防宫颈癌发生发展的有效靶标[21]

然而也有学者发现,GPER在宫颈腺癌细胞系HeLa229、OMC4、HCA1、CAC-1和TMCC1以及宫颈腺癌组织中高表达。E2和G1刺激增加claudin-1的表达,通过MAPK/ERK和PI3K/Akt通路促进CAC-1和HCA1细胞的增殖,增加恶性潜能[22]。在小鼠异种移植模型中,GPER基因敲除组的肿瘤比对照组肿瘤更小,生长更慢。邻苯二甲酸单乙基己酯(phthalic acid mono-2-ethylhexyl ester, MEHP)是一种环境雌激素化学物质,有研究者将MEHP作用于宫颈癌细胞,发现其可通过GPER/PI3K/Akt途径促进宫颈癌细胞HeLa和SiHA的增殖[23]

综上所述,GPER为研究环境雌激素的致癌作用机制提供了新的思路,但是在不同病理类型的宫颈癌中的作用还有待进一步研究。

2.3 GPER与子宫内膜癌

子宫内膜癌根据临床特点可分两型:Ⅰ型为雌激素依赖为主的子宫内膜样腺癌,临床常见,预后较好;Ⅱ型为非雌激素依赖为主的浆液性乳头状癌、透明细胞癌等,预后较差[24]。研究发现,GPER在子宫内膜癌组织中过表达,并与疾病的终末期、病理分级高、组织学亚型多、肌层浸润范围深和较差的总生存率相关,它在Ⅰ型和Ⅱ型子宫内膜癌中表达基本无差异,这表明Ⅰ型和Ⅱ型子宫内膜癌可能有相似的发病机制[25-26]。已有多项研究报道,E2和G1的刺激可增加子宫内膜癌细胞系的增殖、迁移和侵袭等恶性生物学行为,涉及的机制包括激活MAPK/ERK和PI3K/AKT等信号通路,FAK的磷酸化,增加MMP-2/9、c-Fos等靶基因、细胞周期蛋白D1和CTGF的产生[27-31],上述过程均与GPER密切相关。研究人员通过体外构建miR-195过表达载体并转入AN3CA和Hec1A中,证明miR-195可以通过抑制GPER/GPR30的表达来抑制AN3CA和Hec1A的上皮间充质转化[30]。另有研究发现,自分泌运动因子(autocrine motility factor, AMF)能够与GPER相互作用,通过激活PI3K/AKT信号通路从而促进子宫内膜癌细胞SPEC-2的增殖,说明GPER和AMF的高表达与子宫内膜癌患者预后不良密切相关[32]。此外,有研究者利用G1来上调GPER发现其促进了GEC-1A和AN3CA细胞中苹果酸脱氢酶2(malate dehydrogenase 2, MDH2)的表达,下调肿瘤抑制因子人第10号染色体缺失的磷酸酶及张力蛋白同源基因(phosphatase and tensin homolog deleted on chromosome ten, PTEN)的表达,MDH2通过抑制PTEN的活性促进子宫内膜癌细胞株的增殖,迁移和侵袭[33]。在胰岛素抵抗条件下,上调的TET1蛋白(ten-eleven translocation 1)可以激活GPER表达并通过PI3K/AKT信号通路来促进子宫内膜癌细胞的增殖[34]。在体内研究中也有证据证明,GPER/GPR30激活可以促进RL95-2细胞系和HEC-1A细胞系在裸鼠异种移植模型中产生实体瘤的能力[31, 35]

现有研究显示,GPER高表达标志着子宫内膜癌的恶性行为及预后不良。随着研究的逐渐深入, GPER有望成为子宫内膜癌治疗的一个新的靶点,GPER靶向药物的临床运用或许能够为子宫内膜癌患者提供新的治疗方案。

2.4 GPER与卵巢癌

雌激素在卵巢癌的发生发展中起着至关重要的作用,GPER在卵巢癌组织及细胞学中的研究也仍存在争议。有实验发现,GPER无论在mRNA水平还是在蛋白表达水平均存在于卵巢肿瘤组织中,良性及恶性肿瘤表达无统计学意义,且GPER染色与临床分期,组织学分级和患者存活率之间没有相关性[36]。也有研究认为,GPER在卵巢癌组织中的表达明显高于癌旁组织,且与不良预后显著相关[37]。GPER在晚期和复发性浆液性和黏液性卵巢癌患者中的表达均较高,且其核表达预示着总体生存率和5年无进展生存率较差[38]。与之相反的是,一些研究发现GPER在卵巢癌组织中的表达显著低于良性和低恶性卵巢肿瘤,GPER表达与有利的临床结局相关[39]。另有研究者通过开放获取的mRNA和1 657例卵巢癌患者的临床数据进行生存分析发现,GPER高表达患者的总生存期及无进展生存期明显延长[40]

对GPER在卵巢癌细胞中发挥作用的机制研究中发现,在卵巢癌细胞系SKOV3(ER阳性,GPER阳性)、OVCAR5(ER阴性,GPER阳性)中,GPER通过非配体依赖的方式上调c-Fos、cyclin D1和MMP-9的表达,促进细胞的增殖、侵袭和迁移[41-42]。Atrazine是最常见的农药污染物之一,研究者发现它通过GPER/ERK途径促进卵巢癌细胞的增殖[43]。也有研究发现双酚A和四溴双酚A这两种外源性GPER配体可以刺激OVCAR-3和KGN细胞的增殖,GPER有望成为治疗卵巢癌发生发展的潜在靶点,且为植物雌激素致瘤作用提供思路[44]。然而,有学者在对Affymetrix基因芯片分析后发现,GPER和G1通过激活抗肿瘤转录组反应抑制卵巢癌细胞的生长[40]。G1通过将细胞周期阻滞在G2/M期以及刺激半胱天冬酶依赖性凋亡来抑制SKOV3和OVCAR3细胞的增殖[39]

GPER在卵巢癌中作用的研究中仍不明确,可能与卵巢癌病理类型丰富、恶性程度高有关。因此,探究不同病理组织类型中GPER的表达情况及与相关配体的机制研究可能成为今后研究的重点。

3 小结与展望

雌激素及其衍生物的长期刺激是女性相关恶性肿瘤产生的关键原因之一,GPER可诱导非基因组信号通路并调控某些基因转录,此过程主要受到雌激素相关信号的刺激。大部分研究结果表明,雌激素和G1对GPER的激活会导致下游信号和靶基因的激活,从而促进癌细胞的增殖、迁移和侵袭。然而,部分研究提出了相反的观点。不同的细胞类型、肿瘤微环境和激素水平可能影响GPER的功能。关于GPER的相关信号通路仍存在争议,阐明GPER在女性相关恶性肿瘤的功能及作用机制将会为更早发现及更好地治疗雌激素相关恶性肿瘤提供新思路。

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文章信息

刘欣悦, 张裕民, 张萍
LIU Xinyue, ZHANG Yumin, ZHANG Ping
GPER在女性相关恶性肿瘤中作用的研究进展
Research progress of GPER in female-related malignant tumors
大连医科大学学报, 2022, 44(3): 249-254.
Journal of Dalian Medical University, 2022, 44(3): 249-254.
通信作者
张萍,教授。E-mail: zpskx001@163.com.
基金项目
青岛市南区科技计划项目(2020-2-019-YY)

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