王悅超， 亓文騫， 趙 平

(吉林大學(xué)中日聯(lián)誼醫(yī)院 消化內(nèi)科， 長春 130000)

胰島素樣生長因子1受體在胰腺癌治療中的機制及進展

王悅超， 亓文騫， 趙 平

(吉林大學(xué)中日聯(lián)誼醫(yī)院 消化內(nèi)科， 長春 130000)

胰島素樣生長因子(IGF)1受體(IGF-1R)廣泛存在于多種類型的細(xì)胞表面，與腫瘤細(xì)胞的形成、發(fā)展密切相關(guān)，也為腫瘤的靶向治療提供了新的方向。對IGF-1R在胰腺癌中的表達(dá)、發(fā)生、發(fā)展以及IGF-1R作為靶點治療腫瘤的進展作一綜述。

受體， IGF 1型； 胰腺腫瘤； 綜述

胰腺癌主要來源于胰腺導(dǎo)管上皮細(xì)胞，其起病隱匿，臨床癥狀出現(xiàn)晚，早期診斷困難，惡性度高，預(yù)后差。胰島素樣生長因子(insulin-like growth factors,IGF)家族是由具有2種同源氨基酸的低分子多肽(IGF-1、IGF-2)、2類特異性受體(IGF-1R、IGF-2R)以及6種結(jié)合蛋白組成[1]。有關(guān)研究[2]發(fā)現(xiàn)IGF-1R與胰腺癌及肝癌、乳腺癌、肺癌、婦科腫瘤等均具有一定相關(guān)性。IGFs在腫瘤細(xì)胞惡性表達(dá)中有明顯的增殖[3]。其中，IGF-1R相關(guān)的信號轉(zhuǎn)導(dǎo)通路在腫瘤的形成、發(fā)展中起著關(guān)鍵作用[4]。而以IGF-1R為靶標(biāo)的治療，可延緩惡性腫瘤細(xì)胞的生長轉(zhuǎn)移，增加惡性腫瘤對化療的敏感性，為潛在靶向治療腫瘤尋求明確方向。同時，也有研究[5]表明，IGF-1R對相關(guān)惡性腫瘤的早期診斷有一定幫助。

1 IGF-1R的結(jié)構(gòu)及信號傳導(dǎo)通路

1986年，IGF-1R基因序列首次通過克隆獲得。IGF-1R是一種跨膜四聚體，由2個位于細(xì)胞外的α亞基和2個位于細(xì)胞內(nèi)的β亞基通過二硫鍵連接而成。β亞基位具有酪氨酸激酶活性，通過催化其磷酸化位點磷酸化，可引起相應(yīng)的細(xì)胞內(nèi)信號轉(zhuǎn)導(dǎo)和轉(zhuǎn)化[6]。

能夠與IGF-1R結(jié)合的配體有IGF-1和IGF-2，通過與其配體結(jié)合，可啟動2條信號轉(zhuǎn)導(dǎo)途徑：有絲分裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路和磷脂酰肌醇-3-激酶(phosphatidylinositol-3 kinase,PI3K)/絲氨酸蘇氨酸蛋白激酶(Serine threonine protein kinase,AKT)通路(圖1)。MAPK通路在導(dǎo)致細(xì)胞增殖方面發(fā)揮重要作用，可被成倍增加的致癌性物質(zhì)(Ras、Raf等)激活，使參與細(xì)胞增殖的靶基因相繼啟動，發(fā)揮促進細(xì)胞增殖及浸潤的效應(yīng)。具體過程為：當(dāng)IGF-1R與其配體結(jié)合后，結(jié)構(gòu)被破壞，β亞基裸露，激活酪氨酸激酶，使配體本身磷酸化，形成由胰島素受體底物、鳥氨酸交換因子及生長因子結(jié)合蛋白-2等組成的復(fù)合物。該激活物能激活MAPK/細(xì)胞外調(diào)節(jié)蛋白激酶(extracellular regulated protein kinases,ERK)，ERK將信號傳遞到細(xì)胞核內(nèi)，從而啟動有絲分裂。同時，磷酸化的胰島素受體底物通過激活PIP3激酶啟動PI3K/AKT通路，傳遞細(xì)胞生長信號，發(fā)揮抑制腫瘤細(xì)胞凋亡的作用。此外，IGF-1R信號轉(zhuǎn)導(dǎo)通路還與表皮生長因子受體(epithelial growth factor receptor,EGF)1R、EGF-2R和血管生長因子等共享下游信號通路，相互影響[7-8]。因此，IGF-1R被認(rèn)為是治療腫瘤的有效靶點。

圖1 IGF-1R信號轉(zhuǎn)導(dǎo)通路 MEK，MAPK激酶；mTOR,哺乳動物雷帕霉素靶蛋白；→表示激活

2 IGF-1R與胰腺癌發(fā)生、發(fā)展的關(guān)系

IGF-1R存在于多種細(xì)胞表面，可以通過促進細(xì)胞有絲分裂，促進蛋白質(zhì)及核糖核酸的合成代謝，從而進一步參與細(xì)胞的轉(zhuǎn)化、增殖等過程。目前大量研究[9-13]表明，IGF-1R在胰腺癌、肝癌、胃腸道腫瘤、肺癌、前列腺癌及宮頸癌等中均呈高表達(dá)，且與腫瘤的發(fā)生、發(fā)展、浸潤、轉(zhuǎn)移及生存率均有一定關(guān)系。在胰腺癌組織，IGF-1R水平明顯高于正常組織，且與年齡、性別無關(guān)，與腫瘤的分化程度、淋巴結(jié)轉(zhuǎn)移、TNM分期預(yù)后有關(guān)，因此IGF-1R可作為胰腺癌預(yù)后的判斷指標(biāo)及藥物治療的靶點[14]。

2.1 IGF-1R與胰腺癌的發(fā)生 目前研究發(fā)現(xiàn)與胰腺癌發(fā)生發(fā)展相關(guān)的主要信號通路包括：MAPK、Wnt、Notch、Hedgehog以及PI3K/AKT信號通路。其中IGF-1R介導(dǎo)的2條信號通路(MAPK及PI3K/AKT通路)發(fā)揮重要作用。有研究[15]表明，在正常胰腺組織中PI3K/AKT信號通路處于活化狀態(tài)，一旦IGF-1R高表達(dá)，該通路被過度激活將可能導(dǎo)致胰腺癌的發(fā)生。在胰腺癌中，K-Ras的突變發(fā)生率較高，其促進胰腺癌形成的機制就是通過IGF-1R介導(dǎo)的MAPK信號轉(zhuǎn)導(dǎo)通路來實現(xiàn)的[16]。近年來關(guān)于胰腺癌的研究還發(fā)現(xiàn)熱休克蛋白(heat shock protein,HSP)、miRNA等均可通過IGF-1R的信號轉(zhuǎn)導(dǎo)通路參與腫瘤細(xì)胞的發(fā)生發(fā)展。HSP90在多種腫瘤中高表達(dá)[17]。研究[18]表明，當(dāng)HSP90被抑制時，依賴于HSP90的IGF-1R降解，PI3K/AKT和 Raf/ERK信號通路失活。因此，HSP90在胰腺癌中的作用機制之一就是保護IGF-1R的活性和穩(wěn)定性，借助IGF-1R下游的信號通路發(fā)揮促腫瘤生成及增殖的作用[19]。miRNA是一類長約22個核苷酸的非編碼單鏈小分子RNA，在腫瘤的發(fā)生、發(fā)展、增殖及轉(zhuǎn)移中發(fā)揮重要作用。目前研究[20]發(fā)現(xiàn)miR-497在胰腺組織中顯著下調(diào)，而IGF-1R被認(rèn)為是miR-497的靶標(biāo)，下調(diào)的miR-497通過上調(diào)IGF-1R激活A(yù)KT通路，進而參與胰腺癌的發(fā)生發(fā)展。

2.2 IGF-1R與胰腺癌的增殖及浸潤轉(zhuǎn)移 IGF-1R主要通過協(xié)同血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)發(fā)揮抗腫瘤細(xì)胞凋亡，促進腫瘤細(xì)胞增殖及浸潤的作用。VEGF在腫瘤細(xì)胞增殖、轉(zhuǎn)移過程中起重要作用。有研究[21]指出IGF-1R主要通過上調(diào)VEGF的表達(dá)來促進血管生成，加速胰腺癌細(xì)胞的轉(zhuǎn)移。VEGF-C是VEGF家族中首要的致淋巴管生長的因子，在子宮內(nèi)膜癌中發(fā)現(xiàn)IGF-1R的過表達(dá)與轉(zhuǎn)移發(fā)生密切相關(guān)，VEGF-C的表達(dá)與淋巴結(jié)轉(zhuǎn)移顯著相關(guān)，并提示其轉(zhuǎn)移可能與IGF-1R調(diào)節(jié)VEGF-C表達(dá)有關(guān)[22]。關(guān)于VEGF-C和IGF-1R在胰腺癌中表達(dá)的相關(guān)性，有研究[23]表明IGF-1R是VEGF-C的正調(diào)控因子，可誘導(dǎo)VEGF-C的合成，促進胰腺癌淋巴結(jié)轉(zhuǎn)移。另外，IGF-1R也可通過上調(diào)基質(zhì)金屬蛋白酶(matrixmetalloproteinases,MMP)2促進腫瘤浸潤轉(zhuǎn)移，后者被認(rèn)為是腫瘤浸潤和轉(zhuǎn)移過程中最主要的蛋白水解酶之一。Lee等[24]發(fā)現(xiàn)IGF-1與IGF-1R結(jié)合后，可激活PI3K/AKT信號通路，使MMP-2表達(dá)增加，從而促進腫瘤的侵襲、轉(zhuǎn)移。IGF-1R信號轉(zhuǎn)導(dǎo)還可以改變細(xì)胞黏附性使細(xì)胞惡性化生長[25]。

3 IGF-1R與胰腺癌治療的研究進展

由IGF-1R介導(dǎo)的信號轉(zhuǎn)導(dǎo)通路不僅與胰腺癌的發(fā)生發(fā)展有關(guān)，也在腫瘤的浸潤、轉(zhuǎn)移過程起作用。因此，以IGF-1R信號通路為靶點的研究，如小分子IGF-1R抑制劑、IGF-1R單克隆抗體及反義寡核苷酸等，可正確高效地治療腫瘤，明顯改善腫瘤患者的預(yù)后，為胰腺癌的靶向治療提供了新的思路。

3.1 小分子酪氨酸激酶抑制劑 近年來，對小分子酪氨酸激酶抑制劑的研究較多，其可通過阻止激酶或底物結(jié)合位點，抑制酪氨酸激酶激活。IGF-1R的自分泌活性可影響胰腺中VEGF的表達(dá)，因此小分子IGF-1R抑制劑可有效的減小胰腺腫瘤細(xì)胞的體積、質(zhì)量、腫瘤血管生成及轉(zhuǎn)移[26]。如OSI-906，是一種新型的小分子IGF-1R抑制劑，可阻斷IGF-1R的2條信號轉(zhuǎn)導(dǎo)通路，抑制IGF-1R的自身磷酸化及下游信號的轉(zhuǎn)導(dǎo)[27-28]；BMS-554417為苯并咪唑吡啶類化合物，可通過降低AKT的磷酸化活性，阻斷PI3K/AKT通路，抑制IGF-1R的活性，延緩腫瘤細(xì)胞的惡性增殖[29]；去甲二氫愈創(chuàng)木酚，是從植物中提取出來的一種多酚類物質(zhì)，對IGF-1R和HER2受體均有抑制作用，在胰腺癌、乳腺癌和肺癌中發(fā)揮抑制腫瘤細(xì)胞增殖的作用[30]；NVP-ADW742為吡咯并嘧啶類化合物，可增加腫瘤細(xì)胞對化療藥物的敏感性[31]。

3.2 IGF-1R單克隆抗體 IGF-1R單克隆抗體可競爭性的抑制IGF-1與IGF-1R結(jié)合，進而阻斷受體的信號轉(zhuǎn)導(dǎo)通路[32]。相關(guān)藥物均處于基礎(chǔ)或臨床試驗階段[33]。

3.2.1 Cixutumumab(IMC-A12) IMC-A12是抗IGF-1R的單克隆IgG1抗體，可誘導(dǎo)腫瘤細(xì)胞停滯在G0～G1期，使腫瘤細(xì)胞生長增殖受阻；IMC-A12還可作用于肌動蛋白纖維，抑制細(xì)胞運動，防止腫瘤轉(zhuǎn)移和擴散。但I(xiàn)MC-A12可引起高血糖癥，為IGF-1R單抗的常見副反應(yīng)[34-35]。

3.2.2 Ganitumab(AMG479) AMG479可特異性干擾IGF-1和IGF-2與配體結(jié)合，并且與胰島素受體不發(fā)生交叉反應(yīng)，現(xiàn)已進入臨床試驗階段[36]。

3.3 靶向IGF-1R的反義寡核苷酸(antisense oligocleoxyndeotides,ASODN) 1978年，Stephenson和Zamecnick首次提出了ASODN抑制基因表達(dá)的概念。ASODN可通過Watson-Crick堿基配對原理與mRNA的堿基對互補結(jié)合阻止其翻譯成蛋白質(zhì)[37]。ASODN可抑制人胰腺癌細(xì)胞系PC-3的生長，使腫瘤細(xì)胞更易凋亡[38]。王芝艷等[39]研究證實，ASODN通過抑制mRNA和蛋白質(zhì)的表達(dá)抑制腫瘤細(xì)胞增殖，該抑制作用呈劑量依賴關(guān)系。ASODN也可以增加腫瘤對化療藥物的敏感性。3.4 miRNA(microRNA) miRNA是指與被調(diào)控的RNA或DNA互補的小分子RNA，經(jīng)堿基互補配對與目標(biāo)mRNA或DNA形成雙鏈復(fù)合物，影響轉(zhuǎn)錄、翻譯等過程。特異性miR-122在肝細(xì)胞常過表達(dá)，其丟失能促進細(xì)胞惡性表型形成。外源性miR-122經(jīng)靶向編碼IGF-1R基因，可引起IGF-1R基因沉默，阻斷IGF-1R下游的PI3K、MAPK信號通路，是一種具有應(yīng)用前景的抗癌治療方案[40]。

4 結(jié)語

IGF-1R通過多個信號轉(zhuǎn)導(dǎo)通路參與胰腺癌、肝癌、肺癌等腫瘤細(xì)胞的生成和轉(zhuǎn)移，決定了其在腫瘤診斷及治療中的重要地位。通過小分子抑制劑、單克隆抗體、反義寡核苷酸及RNA干擾等藥物干預(yù)IGF-1R介導(dǎo)的信號通路及下游通路的傳導(dǎo)，抑制腫瘤細(xì)胞增殖和促進腫瘤細(xì)胞凋亡。目前，IGF-1R在各種分子干擾治療中的最關(guān)鍵靶標(biāo)尚有待明確，且關(guān)于探索與IGF-1R相關(guān)的靶向治療藥物、傳統(tǒng)化療藥物以及其他信號通路阻斷劑的聯(lián)合應(yīng)用，給藥順序，適用的治療人群以及臨床使用的安全性等問題均需要開展更多的臨床試驗。IGF-1R通路與腫瘤的關(guān)系日益成為基礎(chǔ)及臨床工作者研究的焦點，相信隨著研究的不斷深入，IGF-1R作為臨床靶向治療將有著更廣闊的前景。

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引證本文：WANG YC, QI WQ, ZHAO P. Research advances in insulin-like growth factor-1 receptor in pancreatic cancer[J]. J Clin Hepatol, 2017, 33(4): 790-794. (in Chinese) 王悅超, 亓文騫, 趙平. 胰島素樣生長因子1受體在胰腺癌治療中的機制及進展[J]. 臨床肝膽病雜志, 2017, 33(4): 790-794.

(本文編輯：邢翔宇)

Research advances in insulin-like growth factor-1 receptor in pancreatic cancer

WANGYuechao,QIWenqian,ZHAOPing.

(DepartmentofGastroenterology,China-JapanUnionHospitalofJilinUniversity,Changchun130000,China)

Insulin-like growth factor-1 receptor (IGF-1R) widely exists in the surface of various types of cells and is closely associated with the formation and development of tumor cells. It also provides a new direction for the targeted therapy for tumors. This article reviews the expression, development, and progression of IGF-1R in pancreatic cancer and research advances in IGF-1R as a target for tumor treatment.

receptor, IGF type 1； pancreatic neoplasms； review

10.3969/j.issn.1001-5256.2017.04.043

2017-01-13；

2017-02-07。

王悅超(1990-)，女，主要從事消化內(nèi)科腫瘤的研究;亓文騫(1985-)，女，主治醫(yī)師，博士，主要從事消化內(nèi)科方面的研究。二者對本文貢獻(xiàn)相同，同為第一作者。

趙平，電子信箱：drzhaoping@163.com。

R735.9

A

1001-5256(2017)04-0790-05