白治苗，姚衛(wèi)衛(wèi)，李望舒，盧玉鳳，楊 眉，哈春芳

?

·論著·

·專題研究·

骨橋蛋白在子宮內(nèi)膜異位癥中介導(dǎo)細(xì)胞遷移與依賴核轉(zhuǎn)錄因子κB通路促進(jìn)基質(zhì)金屬蛋白酶及尿激酶型纖溶酶原激活物表達(dá)中的作用研究

白治苗，姚衛(wèi)衛(wèi)，李望舒，盧玉鳳，楊 眉，哈春芳

骨橋蛋白(OPN)是從骨細(xì)胞中提取出來的酸性糖蛋白，在細(xì)胞的黏附、侵襲、抗凋亡和促血管生成等方面具有重要作用，在胃癌、肝癌、卵巢癌及甲狀腺癌中均呈高表達(dá)，但在正常人體中一般呈弱表達(dá)或不表達(dá)。子宮內(nèi)膜異位癥(EMs)在病理上雖為良性疾病，卻有著類似于腫瘤的侵襲、種植及遠(yuǎn)處轉(zhuǎn)移等生物學(xué)行為，且其治療方案局限。因此，本文就OPN可能通過核轉(zhuǎn)錄因子κB(NF-κB)通路介導(dǎo)基質(zhì)金屬蛋白酶(MMPs)、尿激酶型纖溶酶原激活物(uPA)的表達(dá)來誘導(dǎo)EMs的發(fā)生和發(fā)展進(jìn)行綜述，并概述其生物學(xué)特點及各因子在EMs發(fā)病機制中的作用，旨在為EMs的靶向藥物治療提供一種新的思路。

子宮內(nèi)膜異位癥；骨橋蛋白質(zhì)；基質(zhì)金屬蛋白酶類；綜述文獻(xiàn)(主題)

白治苗，姚衛(wèi)衛(wèi)，李望舒，等.骨橋蛋白在子宮內(nèi)膜異位癥中介導(dǎo)細(xì)胞遷移與依賴核轉(zhuǎn)錄因子κB通路促進(jìn)基質(zhì)金屬蛋白酶及尿激酶型纖溶酶原激活物表達(dá)中的作用研究[J].中國全科醫(yī)學(xué)，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.

子宮內(nèi)膜異位癥(endometriosis，EMs)是指子宮內(nèi)膜異位至宮腔以外，引起女性慢性盆腔痛、性交痛、月經(jīng)失調(diào)及不孕等臨床癥狀，是婦女常見的疾病，尤其多發(fā)于育齡期婦女[1-2]。目前，EMs發(fā)病機制及病因尚不清楚，普遍被接受的是1921年SAMPSON提出的子宮內(nèi)膜種植學(xué)說，即子宮內(nèi)膜腺上皮細(xì)胞及間質(zhì)細(xì)胞在經(jīng)期隨經(jīng)血逆流并種植于宮腔以外的其他部位[3-4]。但異位內(nèi)膜如何黏附、種植并生長于宮腔以外部位的具體機制仍不清楚，且部分患者存在術(shù)后痛經(jīng)癥狀緩解不明顯等特點。本文就骨橋蛋白(osteopontin,OPN)是否通過核轉(zhuǎn)錄因子κB(NF-κB)通路及該通路是如何在EMs發(fā)揮作用綜述如下。

1　OPN的結(jié)構(gòu)與作用

OPN是一種富含精氨酸、甘氨酸及天冬氨酸的分子量為32 kD的酸性糖蛋白,主要由破骨細(xì)胞、巨噬細(xì)胞、T淋巴細(xì)胞、血管平滑肌細(xì)胞及乳腺腺泡上皮細(xì)胞等分泌，以碳水化合物的形式存在于1個N-糖基側(cè)或5、6個O型糖基側(cè)鏈，并發(fā)生不同程度的磷酸化，最多可達(dá)28個位點[5-7]。OPN的N-端序列是由9個連續(xù)酸性的天冬氨酸殘基和一個GRGDS細(xì)胞黏附序列組成[8]。OPN作為底物凝血酶和組織型谷氨酰胺轉(zhuǎn)氨酶，具有促進(jìn)細(xì)胞黏附和遷移的能力，尤其是當(dāng)其被凝血酶大幅度裂解時作用更為明顯。OPN通過RGD依賴或獨特的自身分子結(jié)構(gòu)特點，結(jié)合細(xì)胞表面受體avβ3和CD44，進(jìn)而介導(dǎo)其他細(xì)胞因子的趨化，發(fā)揮細(xì)胞黏附、遷移和細(xì)胞浸潤的作用[9-10]。在機體細(xì)胞免疫中，OPN與受體結(jié)合后通過與白介素12(IL-12)之間的相互作用而抑制巨噬細(xì)胞分泌白介素10(IL-10),也可以通過誘導(dǎo)免疫細(xì)胞遷移或侵入到炎癥部位，抵抗細(xì)菌和病毒的入侵，進(jìn)而增強宿主的抵抗力[11]。OPN也是血管形成過程中表達(dá)增強的一個重要基因，尤其是在與應(yīng)激相關(guān)的血管生成中，在ras和src活化的內(nèi)皮細(xì)胞中OPN與受體結(jié)合后激活NF-κB通路,促進(jìn)體內(nèi)異常細(xì)胞的增生，抑制其凋亡，誘導(dǎo)各種疾病的發(fā)生[12-13]。

2　OPN與EMs

研究顯示，OPN大量分泌會誘導(dǎo)細(xì)胞的黏附、侵襲、抗凋亡及促血管生成，是形成EMs的關(guān)鍵步驟，進(jìn)一步從蛋白和基因水平證實了EMs的發(fā)病機制[13-14]。通過免疫組化法、Western blotting法、反轉(zhuǎn)錄聚合酶鏈?zhǔn)椒磻?yīng)(RT-PCR)證明OPN及其mRNA在EMs大鼠模型及EMs患者的異位內(nèi)膜腺上皮細(xì)胞中的表達(dá)強于正常子宮內(nèi)膜，而OPN 及其受體αvβ3在子宮內(nèi)膜增殖期和分泌早期低表達(dá),在分泌中晚期高表達(dá)，提示OPN是與孕卵著床密切相關(guān)的一種窗口期黏附因子，受孕激素調(diào)控[15-16]。本課題組前期試驗已通過雌、孕激素干預(yù)EMs患者在位內(nèi)膜腺上皮細(xì)胞后發(fā)現(xiàn)OPN及其mRNA的表達(dá)明顯升高，干預(yù)后腺上皮細(xì)胞的侵襲性也明顯增加；而后進(jìn)一步采用OPN siRNA基因沉默后測定OPN及其mRNA的表達(dá)及細(xì)胞侵襲性變化發(fā)現(xiàn)，腺上皮細(xì)胞的侵襲性明顯降低[17]。由此得出，OPN與EMs

本文文獻(xiàn)檢索策略：

以“OPN、NF-κB通路、uPA、MMPs、子宮內(nèi)膜異位癥”為檢索，檢索中文數(shù)據(jù)庫：中國知網(wǎng)、萬方數(shù)據(jù)知識服務(wù)平臺、維普網(wǎng)；英文數(shù)據(jù)庫：PubMed、METSTR、Ovid、Foreign Medical Journal Service。檢索時間為建庫至2015年12月，對于檢索不到全文的文獻(xiàn)予以排除。

在位內(nèi)膜腺上皮細(xì)胞的侵襲性呈正相關(guān)。日本的ODAGIRI教授利用OPN基因剔除大鼠及OPN抗體抑制劑研究OPN在EMs中的作用，結(jié)果顯示OPN與EMs病灶的大小、體積及數(shù)目密切相關(guān)，本課題前期實驗結(jié)果與之基本一致[17]。

3　基質(zhì)金屬蛋白酶(MMPs)、尿激酶型纖溶酶原激活物(uPA)與EMs

蛋白水解酶在細(xì)胞表面和細(xì)胞外基質(zhì)中經(jīng)過磷酸化、甲基化等修飾后穿過細(xì)胞基質(zhì)屏障，是細(xì)胞發(fā)揮侵襲作用的前提條件，還可以誘導(dǎo)細(xì)胞遠(yuǎn)處遷移、黏附。與細(xì)胞基底膜及外基質(zhì)降解有關(guān)的酶主要有：MMPs和uPA兩大類?；|(zhì)金屬蛋白酶9(MMP-9)是MMPs家族中分子量最大的明膠酶,與基質(zhì)金屬蛋白酶2(MMP-2)一起能降解細(xì)胞外基質(zhì)中Ⅳ型、Ⅴ型膠原和明膠這3種主要成分，并能促進(jìn)血管內(nèi)皮細(xì)胞的出芽及新生血管的形成，進(jìn)而促使異位內(nèi)膜得以種植生長并不斷擴大，導(dǎo)致EMs的發(fā)生，在子宮內(nèi)膜細(xì)胞的異位黏附、種植和生長過程中發(fā)揮重要作用[18-20]。uPA是一種絲氨酸蛋白酶，可通過直接降解細(xì)胞基底膜及外基質(zhì)或?qū)⒗w維蛋白溶解酶原激活成纖維蛋白溶解酶或?qū)⑶盎|(zhì)蛋白轉(zhuǎn)化成基質(zhì)蛋白，介導(dǎo)細(xì)胞侵襲過程、細(xì)胞遷移、宿主免疫細(xì)胞的逃逸和新生血管形成等過程，進(jìn)一步加快EMs形成[21-22]。國外學(xué)者通過肝癌患者、小鼠黑色素瘤模型靜脈注射uPA抑制劑后發(fā)現(xiàn)，HEP-3細(xì)胞、小鼠黑色素瘤細(xì)胞的侵襲性、轉(zhuǎn)移性明顯降低[23-24]。此外，uPA的過度表達(dá)在ras基因轉(zhuǎn)化的細(xì)胞系中可以增強細(xì)胞的侵襲性及轉(zhuǎn)移性，再次證實了uPA與細(xì)胞的侵襲性密切相關(guān)，并促進(jìn)細(xì)胞的遠(yuǎn)處轉(zhuǎn)移?，F(xiàn)有研究表明，MMPs尤其是MMP-2/MMP-9與細(xì)胞的侵襲性有著密切的關(guān)系，通過在體內(nèi)試驗和體外實驗中給予MMP-2抑制劑(TIMP-1)可以減弱細(xì)胞侵襲性，誘導(dǎo)致瘤基因H-ras的表達(dá)，上調(diào)MMP-2/MMP-9的表達(dá)，進(jìn)而增強細(xì)胞的侵襲性[25-26]。本課題組前期實驗通過藥物上調(diào)EMs患者在位內(nèi)膜原代腺上皮細(xì)胞中MMP-9后測定細(xì)胞侵襲性的變化，發(fā)現(xiàn)其與細(xì)胞的侵襲性呈正相關(guān)[17]。通過免疫組化發(fā)現(xiàn)MMP-9、uPA在EMs患者異位、在位內(nèi)膜中高表達(dá)，在正常內(nèi)膜中弱表達(dá)或不表達(dá)[15]。因此，MMPs、uPA主要通過降解細(xì)胞基底膜及外基質(zhì)，為隨經(jīng)血逆流的腺上皮細(xì)胞、間質(zhì)細(xì)胞向?qū)m腔外移動、黏附、生長提供了有利的條件。

4　NF-κB通路調(diào)節(jié)OPN誘導(dǎo)uPA的表達(dá)及MMP-2的激活

OPN可通過許多信號轉(zhuǎn)錄通路來增強EMs患者在位內(nèi)膜腺上皮細(xì)胞的遷移和侵襲，但目前被普遍接受的是經(jīng)典的依賴 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) 亞基或p110g和具有調(diào)節(jié)作用的p85(a,b,p55g和p101)亞基組成，已證實其與細(xì)胞的遷移、侵襲相關(guān)[28]。在高度惡性的乳腺癌細(xì)胞中，其PI 3-K酶較低度惡性的乳腺癌細(xì)胞中活性更強。然而，PI 3-K酶抑制劑對白介素1(IL-1)、腫瘤壞死因子α(TNF-α)依賴的IkBa的降解、細(xì)胞核中NF-κB的集聚及NF-κB DNA的結(jié)合沒有任何影響。國外MAHABELESHWAR等[29]研究結(jié)果顯示：Syk是一個沒有受體的絡(luò)氨酸蛋白激酶，其通過抑制IkBa 與 PI 3-K酶的亞基p85 之間的相互作用而下調(diào)NF-κB的轉(zhuǎn)錄活性，可以揭示出OPN依賴于PI 3-K酶的調(diào)節(jié)亞基p85和催化亞基p110誘導(dǎo)AKt磷酸化以及磷酸化的AKt結(jié)合IKKa/b(磷酸化的IKB)，進(jìn)而激活I(lǐng)KK的活動，促使NF-κB從胞質(zhì)進(jìn)入胞核。OPN也可以通過PI 3-K 酶直接誘導(dǎo)IkBa磷酸化或促使其降解,進(jìn)而激活NF-κB通路。OPN也是一種轉(zhuǎn)移基因，通過與其受體整合素avβ3結(jié)合后，可誘導(dǎo)依賴于PI 3-K的NF-κB的激活。NF-κB家族是由同源性或異源性二聚體組成，包括:p65,p50,RelB及c-Rel等因子[30]。在靜息狀態(tài)下NF-κB存在于胞質(zhì)中，與其抑制劑IkB家族緊密地結(jié)合并受其控制，阻止NF-κB進(jìn)入胞核激活轉(zhuǎn)錄信號。當(dāng)機體內(nèi)外異常信號作用于細(xì)胞時，NF-κB與其抑制劑分離并快速進(jìn)入胞核，啟動信號轉(zhuǎn)錄通路并調(diào)節(jié)眾多基因表達(dá)，包括細(xì)胞因子、生長因子、急性期應(yīng)激蛋白、免疫受體及其他轉(zhuǎn)錄因子。已發(fā)現(xiàn)NF-κB在淋巴瘤、黑色素瘤、乳腺癌組織中呈高表達(dá)，也表明其與許多致瘤基因的激活密切相關(guān)[31-33]。OPN與其受體結(jié)合后，通過誘導(dǎo)NF-κB的活動增強依賴于NF-κB通路的uPA/MMPs表達(dá)(uPA/MMPs的催化區(qū)域中均有NF-κB的結(jié)合序列)，促進(jìn)細(xì)胞外基質(zhì)、基底膜的降解及細(xì)胞的增生，抑制細(xì)胞凋亡，進(jìn)而誘導(dǎo)眾多疾病的發(fā)生發(fā)展，如惡性腫瘤、EMs[34]。已經(jīng)證實在黑色素瘤細(xì)胞、乳腺癌細(xì)胞中，OPN通過促進(jìn)NF-κB p65從胞質(zhì)進(jìn)入胞核及與NF-κB DNA的結(jié)合及轉(zhuǎn)錄活性，促進(jìn)uPA/MMP-2的激活并增強了細(xì)胞的遷移、侵襲性[35-36]。OPN誘導(dǎo)NF-κB 的轉(zhuǎn)錄活性可以被ASOPN(整合素avβ3抗體，主要起作用的是p85亞基)阻止,以及依賴于NF-κB通路的uPA/MMPs分泌也可被ASOPN抑制,從而減弱細(xì)胞的遷移、侵襲能力[37]。以上研究結(jié)果均明確地揭示OPN通過與其受體avβ3結(jié)合后激活依賴于NF-κB的PI 3-K /AKt酶，進(jìn)而導(dǎo)致各種疾病的發(fā)生。

5　結(jié)語

EMs對女性健康的危害較大，且發(fā)病機制不明確,臨床治療主要以創(chuàng)傷性手術(shù)為主[38-40]。EMs手術(shù)尚無法清除患者體內(nèi)的所有病灶,術(shù)后復(fù)發(fā)不可避免，且術(shù)后腹痛癥狀改善不明顯，因此手術(shù)結(jié)合術(shù)后用藥抑制殘余病灶、推遲EMs復(fù)發(fā)一直是臨床治療的常用方法[41-42]。目前，以抗黏附、抗侵襲、抗血管生成作為EMs治療靶點或可成為臨床研究的新方向，本文從細(xì)胞信號通路的角度出發(fā)，闡明導(dǎo)致EMs的可能通路及誘導(dǎo)其發(fā)生的關(guān)鍵因子，為EMs的藥物治療提供一種新的想法及思路。但是本文對OPN如何通過NF-κB 通路而促進(jìn)MMPs及uPAs的分泌、加快細(xì)胞外基質(zhì)降解，誘導(dǎo)EMs發(fā)病的機制尚不清楚，有待本課題組接下來通過對EMs患者在位內(nèi)膜腺上皮的培養(yǎng)并進(jìn)行相應(yīng)地基因沉默及質(zhì)粒導(dǎo)入后，再次檢測OPN、NF-κB等因子表達(dá)的變化，進(jìn)一步分析其作用機制。

6　展望

EMs目前被臨床醫(yī)生稱為良性癌癥，即雖在病理上是良性的，但卻有著類似惡性腫瘤的眾多生物學(xué)行為，近幾年，該病的治療方案局限，患者癥狀緩解不明顯，嚴(yán)重危害育齡期女性的健康，是臨床婦科大夫亟待解決的難題之一，本文通過對OPN、NF-κB及uPA等因子及各因子之間的信號通路進(jìn)行闡述，結(jié)合后續(xù)的細(xì)胞水平的基因沉默及質(zhì)粒干預(yù)，揭示了這些因子是誘導(dǎo)EMs發(fā)生的關(guān)鍵因子，為EMs的靶向藥物治療提供一種新的思路。

作者貢獻(xiàn)：白治苗、李望舒進(jìn)行資料收集整理、撰寫論文、成文并對文章負(fù)責(zé)；姚衛(wèi)衛(wèi)、楊眉進(jìn)行相關(guān)的文獻(xiàn)查閱；盧玉鳳對查閱的文獻(xiàn)進(jìn)行翻譯、分析，并提供可靠的數(shù)據(jù)；哈春芳進(jìn)行質(zhì)量控制。

本文無利益沖突。

[1]WIMBERGER P,GRUBLING N,RIEHN A,et al.Endometriosis-a chameleon:patients′ perception of clinical symptoms,treatment strategies and their impact on symptoms[J].Geburtshilfe Frauenheilkd,2014，74(10):940-946.

[2]POP-TRAJKOVIC S,KOPITOVIC V,POPOVIC J,et al.In vitro fertilization outcome in women with endometriosis & previous ovarian surgery[J].Indian J Med Res,2014,140(3):387-391.

[3]BENAGIANO G,BROSENS I,LIPPI D.The history of endometriosis[J].Gynecol Obstet Invest,2014,78(1):1-9.

[4]LUE JR,PYRZAK A,ALLEN J.Improving accuracy of intraoperative diagnosis of endometriosis:role of firefly in minimal access robotic surgery[J].J Minim Access Surg,2016,12(2):186-189.

[5]SAFI S,CREFF G,JEANSON A,et al.Osteopontin:a uranium phosphorylated binding-site characterization[J].Chemistry,2013,19(34):11261-11269.

[6]KON S,NAKAYAMA Y,MATSUMOTO N,et al.A novel cryptic binding motif,LRSKSRSFQVSDEQY,in the C-terminal fragment of MMP-3/7-cleaved osteopontin as a novel ligand for α9β1 integrin is involved in the anti-type Ⅱ collagen antibody-induced arthritis[J].PLoS One,2014,9(12):1-15.

[7]PLATZER G,ZERKO S,SAXENA S,et al.(1)H,(15)N,(13)C resonance assignment of human osteopontin[J].Biomol NMR Assign,2015,9(2):289-292.

[8]YU W Q,XU L,ZHANG F Q.The effect of Ti anodized nano-foveolae structure on preosteoblast growth and osteogenic gene expression[J].J Nanosci Nanotechnol,2014,14(6):4387-4393.

[9]SODEK J,GANSS B,Mckee M D.Osteopontin [J].Crit Rev Oral Biol Med,2000,11(3):279-303.

[10]COLAIANNI G,CUSCITO C,MONGELLI T,et al.The myokine irisin increases cortical bone mass[J].Proc Natl Acad Sci U S A,2015,112(39):12157-12162.

[11]OH Y,MORIMOTO A,SHIODA Y,et al.High serum osteopontin levels in pediatric patients with high risk Langerhans cell histiocytosis[J].Cytokine,2014,70(2):194-197.

[12]TEUTSCHBEIN J,HAYDN J M,SAMANS B,et al.Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins[J].BMC Cancer,2010,21(10):386.

[13]XIAO Y,LI T,XIA E,et al.Expression of integrin β3 and osteopontin in the eutopic endometrium of adenomyosis during the implantation window[J].Eur J Obstet Gynecol Reprod Biol,2013,170(2):419-422.

[14]HE J,LIU M,LIU Z,et al.Recombinant osteopontin attenuates experimental cerebral vasospasm following subarachnoid hemorrhage in rats through an anti-apoptotic mechanism[J].Brain Res,2015,22:74-83.

[15]哈春芳，肖成明，劉培淑.OPN與MMP-9在大鼠子宮內(nèi)膜異位癥中的表達(dá)及意義[J].寧夏醫(yī)學(xué)雜志,2011，33(7)：585-587.

[16]YANG M,JIANG C,CHEN H,et al.The involvement of osteopontin and matrix metalloproteinase-9 in the migration of endometrial epithelial cells in patients with endometriosis[J].Reprod Biol Endocrinol,2015,20(13):95-102.

[17]楊眉，蔣春樊，哈春芳,等.雌激素對子宮內(nèi)膜異位癥內(nèi)膜OPN與MMP-9表達(dá)及腺上皮細(xì)胞侵襲性的影響[J].寧夏醫(yī)學(xué)雜志,2014,36(7):577-579.

YANG M,JIANG C F,HA C F,et al.OPN and MMP-9 production and cell invasion increasing induced by 17-βestradiol in endometriosis[J].Ningxia Medical Journal,2014,36(7):577-579.

[18]JIAO L,QI X,LU G,et al.Effect of traditional Chinese medicine (Xiaochaihu Tang) on the expression of MMP-2 and MMP-9 in rats with endometriosis[J].Exp Ther Med,2013,6(6):1385-1389.

[19]MA Y,SHEN A,LI C,et al.Targeted interruption of COX-2 gene by siRNA inhibits the expression of VEGF,MMP-9,the activity of COX-2 and stimulates the apoptosis in eutopic,ectopic endometrial stromal cells of women with endometriosis[J].Zhonghua Fu Chan Ke Za Zhi,2015,50(10):770-776.

[20]VAN TILBORG A A,SWEEP F C,GEURTS-MOESPOT A J,et al.Plasminogen activators are involved in angiostatin generation in vivo in benign and malignant ovarian tumor cyst fluids[J].Int J Oncol,2014,44(4):1394-1400.

[21]BRAZA-BOILS A,GILABERT-ESTELLES J,RAMON L A,et al.Peritoneal fluid reduces angiogenesis-related microRNA expression in cell cultures of endometrial and endometriotic tissues from women with endometriosis[J].PLoS One,2013,8(4):e62370.

[22]KO H S,KIM J S,CHO S M,et al.Urokinase-type plasminogen activator expression and Rac1/WAVE-2/Arp2/3 pathway are blocked by pterostilbene to suppress cell migration and invasion in MDA-MB-231 cells[J].Bioorg Med Chem Lett,2014,24(4):1176-1179.

[23]PHILIP S,BULBULE A,KUNDU G C.Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells[J].J Biol Chem,2001,27(6):44926-44935.

[24]TETI A,FARINA A R,VILLANOVA I,et al.Activation of MMP-2 by human GCT23 giant cell tumour cells induced by osteopontin,bone sialoprotein and GRGDSP peptides is RGD and cell shape change dependent[J].Int J Cancer,1998,77(2):82-93.

[25]HOJILLA C V,MOHAMMED F F,KHOKHA R.Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development[J].Br J Cancer,2003,89(13):1817-1821.

[26]SONG N R,HWANG M K,HEO Y S,et al.Piceatannol suppresses the metastatic potential of MCF10A human breast epithelial cells harboring mutated H-ras by inhibiting MMP-2 expression[J].Int J Mol Med， 2013,32(4):775-784.

[27]LIU J,LIU Q,WAN Y,et al.Osteopontin promotes the progression of gastric cancer through the NF-κB pathway regulated by the MAPK and PI3K[J].Int J Oncol， 2014， 45(1):282-290.

[28]GABELLI S B,ECHEVERRIA I,ALEXANDER M，et al.Activation of PI3Kα by physiological effectors and by oncogenic mutations:structural and dynamic effects[J].Biophys Rev， 2014， 6(1):89-95.

[29]MAHABELESHWAR G H,KUNDU G C.Syk,a proteintyrosine kinase,suppresses the cell motility and nuclear factor kappa B-mediated secretion of urokinase type plasminogen activator by inhibiting the phosphatidylinositol 3′-kinase activity in breast cancer cells[J].J Biol Chem,2003,2(78)：6209-6221.

[30]TIAN F,ZHOU P,KANG W,et al.The small-molecule inhibitor selectivity between IKKα and IKKβ kinases in NF-κB signaling pathway[J].J Recept Signal Transduct Res,2015,35(4)：307-318.

[31]CHICHE J,POMMIER S,BENETEAU M,et al.GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin′s B lymphomas via NF-κB-dependent induction of HIF-1alpha[J].Leukemia,2015,29(5):1163-1176.

[32]HUANG H,LANGENKAMP E,GEORGANAKI M,et al.VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation[J].FASEB J,2014,29(1)：227-238.

[33]ITO-KUREHA T,KOSHIKAWA N,YAMAMOTO M,et al.Tropomodulin 1 expression driven by NF-κB enhances breast cancer growth[J].Cancer Res,2015,75(1):62-72.

[34]Das R,PHILIP S,MAHABELESHWAR G H， et al.Osteopontin:it′s role in regulation of cell motility and nuclear factor kappa B-mediated urokinase type plasminogen activator expression[J].IUBMB Life,2005， 57(6):441-447.

[35]KISS T,ECSEDI S,VIZKELETI L,et al.The role of osteopontin expression in melanoma progression[J].Tumour Biol,2015,36(10):7841-7847.

[36]WEBER C E,KOTHARI A N,WAI P Y,et al.Osteopontin mediates an MZF1-TGF-β1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer[J].Oncogene,2015,34(37):4821-4833.

[37]LI Q,GAO Y,XU Z G,et al.Effect of antisense oligodeoxynucleotide targeted against NF-κB/P65 on cell proliferation and tumorigenesis of gastric cancer[J].Clin Exp Med,2013,13(1):11-19.

[38]孫彥,車艷辭.腹腔鏡手術(shù)聯(lián)合藥物治療子宮內(nèi)膜異位癥臨床效果的Meta分析[J].現(xiàn)代婦產(chǎn)科進(jìn)展,2015,29(1):1004-7379.

[39] MONCKEDIECK V,SANNECKE C,HUSEN B,et al.Progestins inhibit expression of MMPs and of angiogenic factors in human ectopic endometrial lesions in a mouse model[J].Mol Hum Reprod,2009,15(10):633-643.

[40]WITZ C A,THOMAS MR,MONTOYA-RODRIGUEZ I A,et al.Short-term culture of peritoneum explants confirms attachment of endometrium to intact peritoneal mesothelium[J].Fertil Steril,2001,75(2):385-390.

[41]STARZINSKI-POWITZ A,ZEITVOGEL A,SCHREINER A,et al.In search of pathogenic mechanisms in endometriosis:the challenge for molecular cell biology[J].Curr Mol Med,2001,1(6):655-664.

[42]UEDA M,YAMASHITA Y,TAKEHARA M,et al.Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis[J].Gynecol Endocrinol,2002,16(5):391-402.

(本文編輯：毛亞敏)

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)

國家自然科學(xué)基金資助項目(81160078)

719000，陜西省榆林市第二醫(yī)院婦產(chǎn)科(白治苗)；寧夏醫(yī)科大學(xué)(白治苗，姚衛(wèi)衛(wèi)，李望舒，盧玉鳳，楊眉)；湖北省襄陽市中心醫(yī)院 湖北文理學(xué)院附屬醫(yī)院婦產(chǎn)科(楊眉)；寧夏醫(yī)科大學(xué)總醫(yī)院婦科，生育力保持重點實驗室(哈春芳)

哈春芳，750004寧夏銀川市，寧夏醫(yī)科大學(xué)總醫(yī)院婦科，生育力保持重點實驗室；E-mail：hachunfang123@163.com

R 711.71

ADOI：10.3969/j.issn.1007-9572.2016.24.012

2016-03-15；

2016-07-09)