高 岑，盧朝輝，陳 杰

中國醫(yī)學科學院 北京協(xié)和醫(yī)學院 北京協(xié)和醫(yī)院病理科，北京 100730

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白細胞分化抗原147的生物學特性及其與腫瘤的關系

高 岑，盧朝輝，陳 杰

中國醫(yī)學科學院 北京協(xié)和醫(yī)學院 北京協(xié)和醫(yī)院病理科，北京 100730

白細胞分化抗原147(CD147)/細胞外基質金屬蛋白酶誘導因子(EMMPRIN)是一種跨膜糖蛋白，在腫瘤細胞表面廣泛高表達，其主要作用是誘導成纖維細胞和內皮細胞產(chǎn)生基質金屬蛋白酶，參與調控腫瘤細胞增殖、侵襲、轉移、凋亡、血管生成、化療耐藥及能量代謝等。本文總結了CD147的生物學特性及其在腫瘤中的多種生物學功能和可能的調控機制。

白細胞分化抗原147/細胞外基質金屬蛋白酶誘導因子；基質金屬蛋白酶；生物學特性

ActaAcadMedSin，2016,38(5)：589-593

白細胞分化抗原147(cluster of differentiation 147，CD147)或細胞外基質金屬蛋白酶誘導因子(extracellular matrix metalloproteinase inducer，EMMPRIN)是Ⅰ型跨膜糖蛋白，屬免疫球蛋白超家族成員，也被稱為basigin(BSG)，由basigin基因編碼[1]。CD147是一種多效性分子，在生理狀態(tài)和疾病尤其是腫瘤中發(fā)揮多種功能。

CD147的發(fā)現(xiàn)、命名及生物學特性

CD147的發(fā)現(xiàn)及命名 CD147最初是由Biswas[2]于1982年在肺癌細胞中發(fā)現(xiàn)，因其能誘導成纖維細胞表達膠原酶，被命名為腫瘤細胞膠原酶刺激因子(tumor cell-derived collagenase stimulatory factor，TCSF)。后來發(fā)現(xiàn)它能誘導多種基質金屬蛋白酶(matrix metalloproteinases，MMPs)的產(chǎn)生，被重命名為EMMPRIN[3]。CD147在不同種屬、不同組織中先后被賦予不同的名稱，如：EMMPRIN、TCSF、M6[4]、HAb18G[5](人類)，Neurothelin、5A11、HT7[6](雞)，OX47[7]、CE9[8](大鼠)，basigin、gp42[9](人類和小鼠)。

CD147的分子結構 CD147基因定位于染色體19p13.3，含有1797bp[10]，在基因的5’端-142～-112bp的30bp的元件含有特殊蛋白1(specificity protein 1，Sp1)、激活蛋白1(activator protein 1，AP1)、轉錄因子Ⅱ(transcription factor Ⅱ，TFⅡ)和早期生長反應因子- 2的結合位點，對CD147轉錄很重要[11]。在3’側翼序列有兩個低氧誘導因子(hypoxia-inducible factor，HIF)的結合位點[12]。

CD147編碼區(qū)編碼269個氨基酸殘基，其蛋白非糖基化形式的相對分子質量為 29 000，糖基化形式的相對分子質量介于 43 000～66 000之間，在不同器官或組織中其糖基化程度不同，可能是其發(fā)揮多種生理功能的原因[13]。CD147的蛋白結構包括N端的信號序列(21個氨基酸殘基)、細胞外免疫球蛋白樣結構域(185個氨基酸殘基)、單個跨膜結構域(24個氨基酸殘基)和C端的細胞內結構域(39個氨基酸殘基)[3，10]。晶體結構分析顯示，細胞外N端的ECⅠ結構域為IgC2結構域，C端的ECⅡ為IgI結構域[14]。

CD147的每一個結構域與不同的蛋白相互作用，發(fā)揮不同的功能。CD147的胞外區(qū)有3個天冬酰胺糖基化位點[13]。ECⅠ結構域的N糖基化對誘導MMPs產(chǎn)生[15]和CD147同型相互作用[16]非常重要。ECⅠ結構域與整合素α3β1和α6β1相互作用，影響細胞黏附遷移、骨架重排和細胞外基質(extracellular matrix，ECM)積聚[17]。ECⅡ結構域與微囊蛋白- 1相互作用，參與CD147在胞膜的聚集，調控其MMP- 1誘導活性[18]。親環(huán)素(cyclophilin，Cyp)A和B也與ECⅡ結構域結合，參與存活和趨化作用途徑[19]?？缒^(qū)含有保守的疏水氨基酸[3]，作為CD147的信號肽和細胞膜錨定位點[7]，可與Cyp60[20]、CD43[21]、syndecan[22]相互作用；218位的谷氨酸殘基可與單羧酸轉運蛋白(monocarboxylate transporter，MCT)- 1和MCT- 4的第八跨膜結構域的精氨酸殘基相互作用[23]。而且跨膜區(qū)含有典型的亮氨酸拉鏈結構域，參與膜-蛋白相互作用和多種細胞內信號途徑[7，24]。CD147的細胞內結構域高度保守，在與MCTs相互作用中發(fā)揮關鍵作用[25]。

CD147的亞型 選擇性剪接和選擇性啟動使CD147形成4種亞型(basigin- 1、2、3、4)。其中，basigin- 1是視網(wǎng)膜特異性亞型，含有3個胞外結構域[26]。Basigin- 2是最常見的經(jīng)典亞型，含有2個胞外結構域。basigin- 3和basigin- 4較少見，只含有1個胞外結構域(IgI)，basigin- 3可通過與basigin- 2形成異源二聚體對其發(fā)揮內源性抑制劑的作用[27]。

CD147在腫瘤中的表達及作用

CD147在腫瘤中的表達 CD147在許多常見腫瘤中通常過表達，包括肝細胞肝癌(hepatocellular carcinoma，HCC)[5]、肺癌[28]、乳腺癌[29]、胰腺癌[30]、結腸癌[31]、膠質瘤[32]、宮頸癌[33]、卵巢癌[12]、前列腺癌[34]、黑色素瘤[35]等。事實上，CD147的失調幾乎與所有腫瘤相關，是轉移的腫瘤細胞中表達最高的一種蛋白。CD147主要表達于細胞膜和/或細胞漿[36]，并常與其他參與病理過程的分子同時表達，如MCTs[37]。

CD147在腫瘤中的作用及其機制

CD147參與腫瘤的侵襲、生長和轉移：CD147的主要功能是誘導鄰近成纖維細胞和內皮細胞產(chǎn)生MMPs，大部分機制不明。腫瘤細胞釋放的富含CD147的膜囊泡能通過腫瘤-基質相互作用促進MMPs合成[38]。分泌的MMPs能降解ECM，促進腫瘤生長/進展、侵襲、轉移。同型相互作用在誘導MMPs的活性中發(fā)揮重要作用，MMPs經(jīng)CD147刺激而分泌，然后在細胞膜上將CD147切除，由此形成1個正反饋環(huán)[16]。

CD147與integrin相互作用能通過激活下游FAK信號通路影響細胞骨架重排，促進腫瘤生長、侵襲、轉移[17]。CD147與AnnexinⅡ相互作用能抑制HCC細胞的變形蟲樣運動，同時能通過STAT3/DOCK8促進Src依賴性的Rac1信號活化,從而調控HCC細胞的間葉細胞型運動[39]。最新研究發(fā)現(xiàn)，骨髓內皮細胞分泌的CypA可能通過與多發(fā)性骨髓瘤細胞CD147結合招募瘤細胞至骨髓，促進腫瘤歸巢[40]。

CD147介導MMP依賴性和非依賴性的血管生成：研究發(fā)現(xiàn)，在活化的人臍靜脈內皮細胞中CD147表達明顯上調，CD147能通過多種機制調控血管生成，包括增殖、存活、遷移和MMPs分泌[41]。CD147能通過活化PI3K/Akt和MAPK信號途徑誘導血管內皮生長因子(vascular endothelial growth factor，VEGF)的產(chǎn)生[42]。最新研究發(fā)現(xiàn)，CD147能與血管內皮生長因子受體(vascular endothelial growth factor receptor，VEGFR)- 2直接結合，調節(jié)VEGF介導的VEGFR- 2活化及其下游信號和功能作用[35]。CD147與胰島素樣生長因子(insulin-like growth factor，IGF)- 1之間形成正反饋誘導血管生成[43]。

CD147參與抗失巢凋亡：CD147表達上調促進腫瘤細胞抗失巢凋亡，部分通過抑制MAPK依賴性的Bim實現(xiàn)，促進腫瘤細胞與基質分離后的存活，并利于腫瘤細胞侵襲和轉移的其他分子事件[29]。CD147介導細胞-細胞接觸以E-cadherin依賴性方式促進抗失巢凋亡[44]，部分通過PI3K/Akt通路的活化[45]。

CD147參與調控化療耐藥：CD147在多藥耐藥的腫瘤中高表達[46]，敲除CD147能增加非小細胞肺癌對雙胍類藥物的敏感性[28]。CD147調節(jié)透明質酸(hyaluronan，HA)合成，與HA受體、CD44、淋巴管內皮透明質酸受體(lymphatic vessel endothelial hyaluronan receptor，LYVE)- 1相互作用。CD147表達上調，誘導多蛋白復合物的形成，包括CD44或LYVE- 1、膜型MMPs、受體酪氨酸激酶、ATP結合盒(ATP binding cassette，ABC)藥物轉運體或MCTs與CD147共同在特殊的脂筏結構域組裝。HA、HA受體和CD147可能是化療耐藥相關復雜通路中的主要驅動因素[47]。

抑制饑餓誘導的細胞自噬：在SMMC- 7721細胞中，CD147能通過下調Beclin1，抑制饑餓誘導的自噬細胞死亡,從而促進腫瘤進展[48]。在前列腺癌PC-3細胞的研究中發(fā)現(xiàn)，CD147能通過PI3K/Akt/mTOR通路抑制細胞自噬，使腫瘤細胞免于無限制自噬而存活[34]。

促進糖酵解能量代謝：腫瘤的能量代謝方式表現(xiàn)為較高水平的有氧糖酵解，即Warburg效應?？焖偕L的腫瘤需要維持能量和細胞內pH的平衡。過量的乳酸主要通過MCT1/MCT4運輸，需要輔助蛋白CD147的參與，因此CD147在調控腫瘤能量代謝中發(fā)揮決定性作用。CD147在上皮實性腫瘤組織的缺氧區(qū)域高表達，能促進缺氧微環(huán)境中腫瘤細胞糖酵解，促進腫瘤在低氧環(huán)境下的生長、侵襲，抑制凋亡[49- 50]。CD147敲除后，乳酸鹽轉運受阻，細胞內的乳酸鹽不能通過MCTs從細胞內輸出，顯著抑制腫瘤生長[32]。

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Biological Characteristics of Cluster of Differentiation 147 and Its Relationship with Tumour

GAO Cen，LU Zhao-hui，CHEN Jie

Department of Pathology，PUMC Hospital，CAMS and PUMC，Beijing 100730，China

CHEN Jie Tel： 010- 69155490，E-mail： xhblk@163.com

Cluster of differentiation 147(CD147)/extracellular matrix metalloproteinase inducer (EMMPRIN) is a widely distributed transmembrane glycoprotein that belongs to the immunoglobulin superfamily and is highly enriched on the surface of malignant tumour cells. A major function of CD147 is to stimulate matrix metalloproteinase production in stromal fibroblasts and endothelial cells. CD147 promotes growth，invasion，metastasis，and glycolysis of malignant cells，induces angiogenesis，multidrug resistance，and anoikis resistance，and inhibits starvation-induced autophagy et al. This review focuses on the structural and biological characteristics of CD147 as well as recent advances in its multiple functions in malignant tumours and underlining mechanisms.

cluster of differentiation 147/extracellular matrix metalloproteinase inducer； matrix metalloproteinases； biolog-ical characteristics

國家自然科學基金(81472326)Supported by the National Natural Sciences Foundation of China (81472326)

陳 杰 電話：010- 69155490，電子郵件：xhblk@163.com

R730.2

A

1000- 503X(2016)05- 0589- 05

10.3881/j.issn.1000- 503X.2016.05.018

2015- 09- 21)