白治苗,姚卫卫,李望舒,卢玉凤,杨 眉,哈春芳
·论著·
·专题研究·
骨桥蛋白在子宫内膜异位症中介导细胞迁移与依赖核转录因子κB通路促进基质金属蛋白酶及尿激酶型纤溶酶原激活物表达中的作用研究
白治苗,姚卫卫,李望舒,卢玉凤,杨 眉,哈春芳
骨桥蛋白(OPN)是从骨细胞中提取出来的酸性糖蛋白,在细胞的黏附、侵袭、抗凋亡和促血管生成等方面具有重要作用,在胃癌、肝癌、卵巢癌及甲状腺癌中均呈高表达,但在正常人体中一般呈弱表达或不表达。子宫内膜异位症(EMs)在病理上虽为良性疾病,却有着类似于肿瘤的侵袭、种植及远处转移等生物学行为,且其治疗方案局限。因此,本文就OPN可能通过核转录因子κB(NF-κB)通路介导基质金属蛋白酶(MMPs)、尿激酶型纤溶酶原激活物(uPA)的表达来诱导EMs的发生和发展进行综述,并概述其生物学特点及各因子在EMs发病机制中的作用,旨在为EMs的靶向药物治疗提供一种新的思路。
子宫内膜异位症;骨桥蛋白质;基质金属蛋白酶类;综述文献(主题)
白治苗,姚卫卫,李望舒,等.骨桥蛋白在子宫内膜异位症中介导细胞迁移与依赖核转录因子κB通路促进基质金属蛋白酶及尿激酶型纤溶酶原激活物表达中的作用研究[J].中国全科医学,2016,19(24):2930-2934.[www.chinagp.net]
BAI Z M,YAO W W,LI W S,et al.Effects of osteopontin in mediating cell migration and promoting the expression of matrix metalloproteinases and urokinase-type plasmase activator through nuclear transcription factor κB pathway on endometriosis[J].Chinese General Practice,2016,19(24):2930-2934.
子宫内膜异位症(endometriosis,EMs)是指子宫内膜异位至宫腔以外,引起女性慢性盆腔痛、性交痛、月经失调及不孕等临床症状,是妇女常见的疾病,尤其多发于育龄期妇女[1-2]。目前,EMs发病机制及病因尚不清楚,普遍被接受的是1921年SAMPSON提出的子宫内膜种植学说,即子宫内膜腺上皮细胞及间质细胞在经期随经血逆流并种植于宫腔以外的其他部位[3-4]。但异位内膜如何黏附、种植并生长于宫腔以外部位的具体机制仍不清楚,且部分患者存在术后痛经症状缓解不明显等特点。本文就骨桥蛋白(osteopontin,OPN)是否通过核转录因子κB(NF-κB)通路及该通路是如何在EMs发挥作用综述如下。
OPN是一种富含精氨酸、甘氨酸及天冬氨酸的分子量为32 kD的酸性糖蛋白,主要由破骨细胞、巨噬细胞、T淋巴细胞、血管平滑肌细胞及乳腺腺泡上皮细胞等分泌,以碳水化合物的形式存在于1个N-糖基侧或5、6个O型糖基侧链,并发生不同程度的磷酸化,最多可达28个位点[5-7]。OPN的N-端序列是由9个连续酸性的天冬氨酸残基和一个GRGDS细胞黏附序列组成[8]。OPN作为底物凝血酶和组织型谷氨酰胺转氨酶,具有促进细胞黏附和迁移的能力,尤其是当其被凝血酶大幅度裂解时作用更为明显。OPN通过RGD依赖或独特的自身分子结构特点,结合细胞表面受体avβ3和CD44,进而介导其他细胞因子的趋化,发挥细胞黏附、迁移和细胞浸润的作用[9-10]。在机体细胞免疫中,OPN与受体结合后通过与白介素12(IL-12)之间的相互作用而抑制巨噬细胞分泌白介素10(IL-10),也可以通过诱导免疫细胞迁移或侵入到炎症部位,抵抗细菌和病毒的入侵,进而增强宿主的抵抗力[11]。OPN也是血管形成过程中表达增强的一个重要基因,尤其是在与应激相关的血管生成中,在ras和src活化的内皮细胞中OPN与受体结合后激活NF-κB通路,促进体内异常细胞的增生,抑制其凋亡,诱导各种疾病的发生[12-13]。
研究显示,OPN大量分泌会诱导细胞的黏附、侵袭、抗凋亡及促血管生成,是形成EMs的关键步骤,进一步从蛋白和基因水平证实了EMs的发病机制[13-14]。通过免疫组化法、Western blotting法、反转录聚合酶链式反应(RT-PCR)证明OPN及其mRNA在EMs大鼠模型及EMs患者的异位内膜腺上皮细胞中的表达强于正常子宫内膜,而OPN 及其受体αvβ3在子宫内膜增殖期和分泌早期低表达,在分泌中晚期高表达,提示OPN是与孕卵着床密切相关的一种窗口期黏附因子,受孕激素调控[15-16]。本课题组前期试验已通过雌、孕激素干预EMs患者在位内膜腺上皮细胞后发现OPN及其mRNA的表达明显升高,干预后腺上皮细胞的侵袭性也明显增加;而后进一步采用OPN siRNA基因沉默后测定OPN及其mRNA的表达及细胞侵袭性变化发现,腺上皮细胞的侵袭性明显降低[17]。由此得出,OPN与EMs
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在位内膜腺上皮细胞的侵袭性呈正相关。日本的ODAGIRI教授利用OPN基因剔除大鼠及OPN抗体抑制剂研究OPN在EMs中的作用,结果显示OPN与EMs病灶的大小、体积及数目密切相关,本课题前期实验结果与之基本一致[17]。
蛋白水解酶在细胞表面和细胞外基质中经过磷酸化、甲基化等修饰后穿过细胞基质屏障,是细胞发挥侵袭作用的前提条件,还可以诱导细胞远处迁移、黏附。与细胞基底膜及外基质降解有关的酶主要有:MMPs和uPA两大类。基质金属蛋白酶9(MMP-9)是MMPs家族中分子量最大的明胶酶,与基质金属蛋白酶2(MMP-2)一起能降解细胞外基质中Ⅳ型、Ⅴ型胶原和明胶这3种主要成分,并能促进血管内皮细胞的出芽及新生血管的形成,进而促使异位内膜得以种植生长并不断扩大,导致EMs的发生,在子宫内膜细胞的异位黏附、种植和生长过程中发挥重要作用[18-20]。uPA是一种丝氨酸蛋白酶,可通过直接降解细胞基底膜及外基质或将纤维蛋白溶解酶原激活成纤维蛋白溶解酶或将前基质蛋白转化成基质蛋白,介导细胞侵袭过程、细胞迁移、宿主免疫细胞的逃逸和新生血管形成等过程,进一步加快EMs形成[21-22]。国外学者通过肝癌患者、小鼠黑色素瘤模型静脉注射uPA抑制剂后发现,HEP-3细胞、小鼠黑色素瘤细胞的侵袭性、转移性明显降低[23-24]。此外,uPA的过度表达在ras基因转化的细胞系中可以增强细胞的侵袭性及转移性,再次证实了uPA与细胞的侵袭性密切相关,并促进细胞的远处转移。现有研究表明,MMPs尤其是MMP-2/MMP-9与细胞的侵袭性有着密切的关系,通过在体内试验和体外实验中给予MMP-2抑制剂(TIMP-1)可以减弱细胞侵袭性,诱导致瘤基因H-ras的表达,上调MMP-2/MMP-9的表达,进而增强细胞的侵袭性[25-26]。本课题组前期实验通过药物上调EMs患者在位内膜原代腺上皮细胞中MMP-9后测定细胞侵袭性的变化,发现其与细胞的侵袭性呈正相关[17]。通过免疫组化发现MMP-9、uPA在EMs患者异位、在位内膜中高表达,在正常内膜中弱表达或不表达[15]。因此,MMPs、uPA主要通过降解细胞基底膜及外基质,为随经血逆流的腺上皮细胞、间质细胞向宫腔外移动、黏附、生长提供了有利的条件。
OPN可通过许多信号转录通路来增强EMs患者在位内膜腺上皮细胞的迁移和侵袭,但目前被普遍接受的是经典的依赖 MAPK /PI 3-K酶的NF-κB通路[27]。PI 3-K是由具有催化作用的p110 (a,b,d) 亚基或p110g和具有调节作用的p85(a,b,p55g和p101)亚基组成,已证实其与细胞的迁移、侵袭相关[28]。在高度恶性的乳腺癌细胞中,其PI 3-K酶较低度恶性的乳腺癌细胞中活性更强。然而,PI 3-K酶抑制剂对白介素1(IL-1)、肿瘤坏死因子α(TNF-α)依赖的IkBa的降解、细胞核中NF-κB的集聚及NF-κB DNA的结合没有任何影响。国外MAHABELESHWAR等[29]研究结果显示:Syk是一个没有受体的络氨酸蛋白激酶,其通过抑制IkBa 与 PI 3-K酶的亚基p85 之间的相互作用而下调NF-κB的转录活性,可以揭示出OPN依赖于PI 3-K酶的调节亚基p85和催化亚基p110诱导AKt磷酸化以及磷酸化的AKt结合IKKa/b(磷酸化的IKB),进而激活IKK的活动,促使NF-κB从胞质进入胞核。OPN也可以通过PI 3-K 酶直接诱导IkBa磷酸化或促使其降解,进而激活NF-κB通路。OPN也是一种转移基因,通过与其受体整合素avβ3结合后,可诱导依赖于PI 3-K的NF-κB的激活。NF-κB家族是由同源性或异源性二聚体组成,包括:p65,p50,RelB及c-Rel等因子[30]。在静息状态下NF-κB存在于胞质中,与其抑制剂IkB家族紧密地结合并受其控制,阻止NF-κB进入胞核激活转录信号。当机体内外异常信号作用于细胞时,NF-κB与其抑制剂分离并快速进入胞核,启动信号转录通路并调节众多基因表达,包括细胞因子、生长因子、急性期应激蛋白、免疫受体及其他转录因子。已发现NF-κB在淋巴瘤、黑色素瘤、乳腺癌组织中呈高表达,也表明其与许多致瘤基因的激活密切相关[31-33]。OPN与其受体结合后,通过诱导NF-κB的活动增强依赖于NF-κB通路的uPA/MMPs表达(uPA/MMPs的催化区域中均有NF-κB的结合序列),促进细胞外基质、基底膜的降解及细胞的增生,抑制细胞凋亡,进而诱导众多疾病的发生发展,如恶性肿瘤、EMs[34]。已经证实在黑色素瘤细胞、乳腺癌细胞中,OPN通过促进NF-κB p65从胞质进入胞核及与NF-κB DNA的结合及转录活性,促进uPA/MMP-2的激活并增强了细胞的迁移、侵袭性[35-36]。OPN诱导NF-κB 的转录活性可以被ASOPN(整合素avβ3抗体,主要起作用的是p85亚基)阻止,以及依赖于NF-κB通路的uPA/MMPs分泌也可被ASOPN抑制,从而减弱细胞的迁移、侵袭能力[37]。以上研究结果均明确地揭示OPN通过与其受体avβ3结合后激活依赖于NF-κB的PI 3-K /AKt酶,进而导致各种疾病的发生。
EMs对女性健康的危害较大,且发病机制不明确,临床治疗主要以创伤性手术为主[38-40]。EMs手术尚无法清除患者体内的所有病灶,术后复发不可避免,且术后腹痛症状改善不明显,因此手术结合术后用药抑制残余病灶、推迟EMs复发一直是临床治疗的常用方法[41-42]。目前,以抗黏附、抗侵袭、抗血管生成作为EMs治疗靶点或可成为临床研究的新方向,本文从细胞信号通路的角度出发,阐明导致EMs的可能通路及诱导其发生的关键因子,为EMs的药物治疗提供一种新的想法及思路。但是本文对OPN如何通过NF-κB 通路而促进MMPs及uPAs的分泌、加快细胞外基质降解,诱导EMs发病的机制尚不清楚,有待本课题组接下来通过对EMs患者在位内膜腺上皮的培养并进行相应地基因沉默及质粒导入后,再次检测OPN、NF-κB等因子表达的变化,进一步分析其作用机制。
EMs目前被临床医生称为良性癌症,即虽在病理上是良性的,但却有着类似恶性肿瘤的众多生物学行为,近几年,该病的治疗方案局限,患者症状缓解不明显,严重危害育龄期女性的健康,是临床妇科大夫亟待解决的难题之一,本文通过对OPN、NF-κB及uPA等因子及各因子之间的信号通路进行阐述,结合后续的细胞水平的基因沉默及质粒干预,揭示了这些因子是诱导EMs发生的关键因子,为EMs的靶向药物治疗提供一种新的思路。
作者贡献:白治苗、李望舒进行资料收集整理、撰写论文、成文并对文章负责;姚卫卫、杨眉进行相关的文献查阅;卢玉凤对查阅的文献进行翻译、分析,并提供可靠的数据;哈春芳进行质量控制。
本文无利益冲突。
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(本文编辑:毛亚敏)
Effects of Osteopontin in Mediating Cell Migration and Promoting the Expression of Matrix Metalloproteinases and Urokinase-type Plasmase Activator Through Nuclear Transcription Factor κB Pathway on Endometriosis
BAIZhi-miao,YAOWei-wei,LIWang-shu,LUYu-feng,YANGMei,HAChun-fang.
DepartmentofObstetricsandGynecology,theSecondHospitalofYulin;NingxiaMedicalUniversity,Yinchuan750004,Yulin719000,China
HAChun-fang,DepartmentofGynecology,GeneralHospitalofNingxiaMedicalUniversity;KeyLaboratoryofFertilityPreservationandMaintenanceoftheMinistryofEducation,Yinchuan750004,China;E-mail:hachunfang@163.com
Osteopontin (OPN) is the acid glycoprotein that extracted from the bone cells,and it plays an important role in cell adhesion,invasion,anti-apoptosis and angiogenesis promotion.It presents high expression in gastric cancer,liver cancer,ovarian cancer and thyroid cancer,but weak or low expression in normal human bodies.Endometriosis (EMs) is pathologically a benign disease,but it has biological behaviors that similar to tumor,such as invasion,planting and distant metastasis,moreover it has limited treatment schedules.OPN may mediate the expression of matrix metalloproteinases (MMPs) and urokinase-type plasmase activator (uPA) through nuclear transcription factor κB (NF-κB) pathway,and then induce the occurrence and development of EMs.Therefore,the paper reviews the above process and summarizes its biological characteristics and the role of each factor in EMs pathogenesis,aiming to provide a new idea for targeted drug therapy of EMs.
Endometriosis;Osteopontin;Matrix metalloproteinases;Literature review (topic)
国家自然科学基金资助项目(81160078)
719000,陕西省榆林市第二医院妇产科(白治苗);宁夏医科大学(白治苗,姚卫卫,李望舒,卢玉凤,杨眉);湖北省襄阳市中心医院 湖北文理学院附属医院妇产科(杨眉);宁夏医科大学总医院妇科,生育力保持重点实验室(哈春芳)
哈春芳,750004宁夏银川市,宁夏医科大学总医院妇科,生育力保持重点实验室;E-mail:hachunfang123@163.com
R 711.71
ADOI:10.3969/j.issn.1007-9572.2016.24.012
2016-03-15;
2016-07-09)