JAK2-STAT3信號(hào)通路在肝細(xì)胞癌中的研究進(jìn)展

廖明媚，王成志，楊滿意，潘一峰 綜述 趙勁風(fēng) 審校

（中南大學(xué)湘雅醫(yī)院 衛(wèi)生部納米生物技術(shù)重點(diǎn)實(shí)驗(yàn)室，湖南 長沙 410008）

肝癌是世界排名第五的惡性腫瘤，也是第三大致死率腫瘤，同時(shí)還是中國第二大導(dǎo)致死亡的癌癥。肝細(xì)胞癌（hepatocellular carcinoma，HCC）是最常見的一種肝癌，腫瘤的發(fā)生發(fā)展與原癌基因的過度表達(dá)和抑癌基因的沉默相關(guān)，在多種惡性腫瘤中，JAK2-STAT3持續(xù)性激活，使下游原癌基因過度表達(dá)。

Janus激酶（JAK）-信號(hào)轉(zhuǎn)導(dǎo)子與轉(zhuǎn)錄激活子（STAT）信號(hào)通路早在90年代就被發(fā)現(xiàn)了[1]，該通路能快速將膜外信號(hào)轉(zhuǎn)導(dǎo)進(jìn)入細(xì)胞核內(nèi)，調(diào)控下游相關(guān)基因survivin、c-Myc、JunB、clAP2、cyclin D1、MMP-2、ICAM-1、VEGF和Bcl-2基因家族的表達(dá)。隨著分子生物學(xué)的發(fā)展，JAK2-STAT3通路成為研究熱點(diǎn)，大量研究表明JAK2-STAT3通路的持續(xù)性激活與腫瘤的發(fā)生發(fā)展密切相關(guān)，JAK2-STAT3通路的持續(xù)性激活也與腫瘤的耐藥相關(guān)。索拉非尼作為分子靶向藥物現(xiàn)已經(jīng)用于晚期HCC的治療，可以改善晚期HCC患者的生存期，針對JAK2-STAT3和其下游基因設(shè)計(jì)小分子藥物，可以精確的靶向腫瘤細(xì)胞，減少對正常細(xì)胞的毒副作用。本文就JAK2-STAT3在HCC中的研究做一綜述，為HCC的靶向治療提供新思路。

1　JAK2-STAT3信號(hào)通路的組成與調(diào)控

1.1　JAK蛋白酪氨酸激酶

JAK家族現(xiàn)在已經(jīng)發(fā)現(xiàn)4個(gè)成員，包括JAK1、JAK2、JAK3、TYK2。它們的蛋白質(zhì)都超過1 000個(gè)氨基酸，分子量在120～140 kDa左右，都有著相似的同源結(jié)構(gòu)域，包括FERM結(jié)構(gòu)域、SH2結(jié)構(gòu)域、JAK假激酶區(qū)和蛋白質(zhì)酪氨酸激酶（PTK）結(jié)構(gòu)域[2]。JAK1、JAK2、TYK2幾乎在所有細(xì)胞中表達(dá)，而JAK3則主要在造血細(xì)胞中表達(dá)[3]。在急性骨髓性白血病中，p-JAK2過表達(dá)，與總體生存率相關(guān)，AZ960能抑制JAK2磷酸化，有一定療效[4]。在骨髓增生性疾病中，JAK2在V617F位點(diǎn)發(fā)生突變，G6[5-6]、AG490能選擇性抑制JAK2[7]，Ruxolitinib、Fedratinib[8]、BMS-911543[9]等能選擇性抑制JAK2，對骨髓瘤都有一定的療效。TG101348也能抑制JAK2，能克服非小細(xì)胞肺癌對埃羅替尼耐藥[10]。miR-135a抑制JAK2蛋白的表達(dá)[11]，阻止下游STAT3的磷酸化。

1.2　STATs家族

STAT信號(hào)轉(zhuǎn)導(dǎo)子和轉(zhuǎn)錄激活子是JAKs的下游底物，它能將信號(hào)帶到細(xì)胞核，調(diào)節(jié)基因的表達(dá)。STATs家族有7個(gè)成員STAT1、STAT2、STAT3、STAT4、STAT5a、STAT5b、STAT6。STAT蛋白質(zhì)約800個(gè)氨基酸，分子量在89～97 kDa左右。根據(jù)功能STATs蛋白家族可分為兩類[12]，STAT2，STAT4，STAT6這一類主要被一小部分細(xì)胞因子激活，在IFN信號(hào)和T細(xì)胞的發(fā)育中起作用。另一類由STAT1、STAT3、STAT5組成，它們由一系列配體激活，在不同的組織中均發(fā)揮作用，如乳腺的發(fā)育，生長激素的反應(yīng)，胚胎發(fā)育等等。STATs家族有著相似的6個(gè)同源結(jié)構(gòu)域，從氨基酸到羧基端依次為：氨基末端結(jié)構(gòu)域、coiled-coiled結(jié)構(gòu)域（CCD）、DNA結(jié)合結(jié)構(gòu)域（DBD）、linker結(jié)構(gòu)域、SH2結(jié)構(gòu)域、羧基末端轉(zhuǎn)錄活化結(jié)構(gòu)域（TAD）。STAT3可發(fā)生賴氨酸乙?；痆13]（Lys685），發(fā)生絲氨酸（Ser727）磷酸化[14]，還可以發(fā)生酪氨酸磷酸化（Tyr705），在Tyr705磷酸化促進(jìn)其核轉(zhuǎn)移，提高轉(zhuǎn)錄活性。SHP-1是SH2同源結(jié)構(gòu)域酪氨酸磷酸酶，可以抑制STAT3（T705）磷酸化，阻止STAT3的激活[15]。葫蘆素（JSI-124）[16]、LLL12[17]、SC-2001[18]、Niclosamide等能抑制STAT3，抑制下游基因的表達(dá) 。 MiR-125a[19]， MiR-143[20]靶 向 STAT3 mRNA的3'-UTR區(qū)抑制STAT3的蛋白表達(dá)水平，能抑制腫瘤細(xì)胞的增殖、侵襲與轉(zhuǎn)移。

1.3　JAK2-STAT3信號(hào)通路的過程及調(diào)控

細(xì)胞外信號(hào)或細(xì)胞因子通過特異性與細(xì)胞膜上受體結(jié)合使受體構(gòu)像變化，使JAK向膜受體移動(dòng)，JAK發(fā)生酪氨酸磷酸化而被激活，JAK招募STATs，使STATs磷酸化，形成同源或異源化磷酸二聚體，磷酸化的二聚體迅速進(jìn)入細(xì)胞核調(diào)控基因表達(dá)或與核內(nèi)的其他轉(zhuǎn)錄因子相互作用調(diào)控基因表達(dá)。

JAK2-STAT3信號(hào)通路的調(diào)節(jié)有多種機(jī)制共同參與，通常發(fā)生在JAK激活階段、STAT進(jìn)人細(xì)胞核過程以及負(fù)反饋途徑等多個(gè)環(huán)節(jié)進(jìn)行。STAT的翻譯后的修飾極大的影響了其轉(zhuǎn)錄活性，當(dāng)配體和受體相結(jié)合并使其活化后，其鄰近的受體可發(fā)生交互磷酸化或下調(diào)非特異抑制因子的作用，而使通路得以加強(qiáng)。JAK2-STAT3信號(hào)通路還被細(xì)胞因子信號(hào)抑制物（SOCSs）、含SH2的磷酸酶（SHPs）以及STATs蛋白抑制子（PIASs）3個(gè)蛋白家族迅速終止。SOCSs通過結(jié)合并抑制JAKs或與STAT競爭細(xì)胞因子受體的磷酸結(jié)合位點(diǎn)而終止JAK2-STAT3信號(hào)轉(zhuǎn)導(dǎo)，SHPs通過抑制STAT3的磷酸化而阻斷STAT3進(jìn)入細(xì)胞核。高水平的cAMP能抑制JAK1-STAT3信號(hào)通路[21]。多種抑制劑可以抑制JAK2-STAT3信號(hào)通路的進(jìn)程，調(diào)控基因的表達(dá)，調(diào)節(jié)細(xì)胞生長，增殖，分化等。

2　JAK2-STAT3信號(hào)通路與HCC

JAK2-STAT3信號(hào)通路是細(xì)胞內(nèi)的一條重要信號(hào)通路，與細(xì)胞的生長、分化、增殖、凋亡有密切關(guān)系，也與很多疾病的發(fā)生發(fā)展密切相關(guān)。有研究[22]表明JAK蛋白和STAT蛋白在HCC細(xì)胞中過表達(dá)，JAK1蛋白和STAT3蛋白與HCC患者的預(yù)后相關(guān)，預(yù)示著它可能與HCC的發(fā)生發(fā)展有關(guān)。LLL12能抑制STAT3的T705位點(diǎn)磷酸化，阻止其核轉(zhuǎn)移，抑制抗凋亡蛋白的表達(dá)，引起HCC細(xì)胞的凋亡[17]。B7-H3（免疫球蛋白）能促進(jìn)JAK2和STAT3的磷酸化，能促進(jìn)HCC細(xì)胞轉(zhuǎn)移的侵襲[23]，而對細(xì)胞的生長和增殖無影響。Ruxolitinib（INCB018424）是JAK2（V617F突變）抑制劑，初步臨床效果表明對骨髓瘤有較好的療效[24-25]，目前被FDA批準(zhǔn)用于治療該病的晚期治療。ruxolitinib對JAK有非常高的特異性，而對非JAK信號(hào)不敏感，在體外HCC實(shí)驗(yàn)[26]中，ruxolitinib有效抑制JAK，顯著減少其下游產(chǎn)物p-STAT1和p-STAT3，顯著減少HCC的增殖和克隆形成。ruxolitinib還能減輕CCL4引起的肝損傷和壞死性炎癥[27]。Ruxolitinib特異性的抑制JAK1、JAK2酪氨酸磷酸化，可能成為靶向治療HCC有較藥物。

在HCC中STAT3主要在SH2結(jié)構(gòu)域發(fā)生突變[28]，在T705位點(diǎn)磷酸化，影響著STAT3的二聚化作用和向核轉(zhuǎn)移運(yùn)動(dòng)。索拉非尼能抑制STAT3在T705位點(diǎn)和S727位點(diǎn)磷酸化而抑制STAT3的活性[29]，而在索拉非尼耐藥的HCC細(xì)胞中，p-STAT3和p-JAK1和p-JAK2顯著高表達(dá)，SC-2001能增強(qiáng)SHP-1的活性，抑制STAT3的磷酸化，SC-2001與索拉菲尼聯(lián)合治療能顯著抑制對索拉菲尼耐藥的HCC細(xì)胞的克隆形成，抑制腫瘤的生長[18]，索拉菲尼與mapatumumab，lexatumumab（TRAIL受體激動(dòng)劑）聯(lián)合治療抑制JAK2-STAT3通路，下調(diào)mcl-1表達(dá)，在體內(nèi)外均能引起HCC細(xì)胞其他實(shí)體瘤細(xì)胞凋亡[30]。NSC74859（S3I-201）能抑制p-STAT3，單獨(dú)作用對HCC細(xì)胞的活性影響不大，但它與cetuximab（表皮生長因子受體抑制劑）聯(lián)合治療對HCC細(xì)胞的治療效果比cetuximab單獨(dú)作用效果更顯著[31]。

乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）的感染是HCC發(fā)生發(fā)展的一個(gè)重要因素[32]。在HBV與HCV相關(guān)的HCC中，STAT3與己糖激酶II高表達(dá)，且STAT3與己糖激酶II的表達(dá)具有相關(guān)性[33]。HBV可以激活STAT3信號(hào)通路[34]，促進(jìn)HBV病毒的復(fù)制，阻斷STAT3信號(hào)可以抑制HBV陽性的HCC細(xì)胞的生長[35]，抑制STAT3可以減少HBV的表達(dá)[36]?；罨腟TAT3上調(diào)LncRNA（長鏈非編碼RNA Lethe、lncIGF2AS、lnc7SK）的表達(dá)[37-38]，促進(jìn)HCV的復(fù)制。Stat3調(diào)整微管動(dòng)力學(xué)影響HCV的復(fù)制，抑制STAT3可以抑制HCV的復(fù)制[39]。HCV核心蛋白通過STAT3通路調(diào)節(jié)NANOG的表達(dá)，促進(jìn)細(xì)胞生長和細(xì)胞周期進(jìn)程[40]。

瘦素（leptin）通過JAK2-STAT3信號(hào)通路引起ERK和AKT磷酸化，促進(jìn)HCC細(xì)胞遷移。通過JAK2-STAT3抑制劑或ERK和PI3K抑制劑能阻斷瘦素引起的HCC細(xì)胞侵襲[41]，對肥胖的HCC患者的治療具有潛在的臨床意義。有研究[42]表明CIMO能抑制JAK1、JAK2和STAT3 T705磷酸化，阻礙STAT3向核轉(zhuǎn)移，影響其與DNA結(jié)合，下調(diào)STAT3下游的靶基因（Bcl-2、Bxl-xL、cyclin D、survivin、ICAM-1、Bid）表達(dá)，使癌細(xì)胞停留在G1期，抑制HCC細(xì)胞的增殖、生存、侵襲與轉(zhuǎn)移，促進(jìn)細(xì)胞凋亡。

SOCS3是信號(hào)轉(zhuǎn)導(dǎo)器gp130生理上的抑制劑，能夠競爭性的抑制JAK2-STAT3信號(hào)通路，有研究[43]表明，相對臨近的非腫瘤組織，HCC組織中SOCS3表現(xiàn)出高甲基化，甲基化程度與SOCS3的表達(dá)呈負(fù)相關(guān)，而SOCS3的甲基化預(yù)示著JAK2-STAT3信號(hào)通路的過度活化。甲基化沉默SOCS3，增強(qiáng)JAK2-STAT3和FAK信號(hào)通路活性，因此促進(jìn)HCC細(xì)胞的生長和轉(zhuǎn)移[44]，在伊馬替尼耐藥的細(xì)胞中，SOCS3基因甲基化程度升高，SOCS3蛋白表達(dá)下調(diào)，STAT3過度活化，細(xì)胞過度增殖[45]。在HCC細(xì)胞中，信號(hào)轉(zhuǎn)導(dǎo)器gp130在SOCS3連接位點(diǎn)（Y186/Y759F）上發(fā)生雙突變[46]，通過特異性激活JAK1使STAT3過度活化。使用Ras和JAK2-STAT3抑制劑或SOCS3去甲基化藥物zebularine引起HCC細(xì)胞的強(qiáng)烈凋亡[47]。miRNA-155能下調(diào)SOCS1的表達(dá)[48]，使STAT3過度活化。

全基因組測序[49-50]顯示，在HCC中，Wnt/β-catenin和JAK2-STAT3信號(hào)通路是兩個(gè)主要的致癌通路。許多植物化學(xué)物質(zhì)[51]（白藜蘆醇、葫蘆素、姜黃色素等）對JAK2-STAT3信號(hào)通路表現(xiàn)出較好的抑制性，從而抑制腫瘤的發(fā)生和發(fā)展。

JAK2-STAT3信號(hào)通路在HCC的發(fā)生發(fā)展中起重要作用，明確JAK2-STAT3的上游物質(zhì)和下游底物，找到其激活劑或抑制劑，從而調(diào)節(jié)JAK2-STAT3信號(hào)通路和它的底物，從而調(diào)控基因表達(dá)，靶向治療HCC。

3　JAK2-STAT3信號(hào)通路和其他信號(hào)通路的聯(lián)系

細(xì)胞內(nèi)的信號(hào)通路是極其復(fù)雜的，縱橫交錯(cuò)（圖1）。細(xì)胞內(nèi)的信號(hào)通路不是單獨(dú)作用，而是與其他信號(hào)通路共同協(xié)調(diào)，調(diào)控細(xì)胞的各種生命活動(dòng)。細(xì)胞內(nèi)各信號(hào)通路協(xié)調(diào)作用與腫瘤的發(fā)生發(fā)展密切相關(guān)。Wnt/beta-catenin和JAK2-STAT3信號(hào)通路在HCC發(fā)生突變最高[49-50]，可能是主要的致癌通路?；罨腏AK1也可以激活PI3K信號(hào)通路，PI3K信號(hào)通路也可以作用于STAT3，調(diào)控基因表達(dá)。在許多疾病中PI3K信號(hào)通路和JAK2-STAT3信號(hào)通路都存在相互協(xié)調(diào)作用[52-54]。STATs還可以直接被受體酪氨酸激酶（RTK）激活，如表皮生長因子受體（EGFR）可以通過Src而使STAT3/5酪氨酸磷酸化[55]。環(huán)腺苷酸（cAMP）高水平表達(dá)能夠抑制JAK2-STAT3信號(hào)通路，從而在轉(zhuǎn)錄水平上下調(diào)MCL-1的表達(dá)[21]，可導(dǎo)致多發(fā)性骨髓瘤細(xì)胞凋亡。細(xì)胞內(nèi)的信號(hào)通路不是單獨(dú)作用，細(xì)胞內(nèi)的信號(hào)通路如一張縱橫交錯(cuò)的網(wǎng)，它們相互聯(lián)系，相互影響，形成復(fù)雜的網(wǎng)絡(luò)體系，控制著細(xì)胞的各種生命活動(dòng)。

圖1　JAK2-STAT3信號(hào)通路與調(diào)控Figure 1 JAK2-STAT3 signaling pathway and its regulation

4　展 望

晚期HCC的手術(shù)治療并無太大收益，分子靶向治療將是未來治療HCC的主要手段，而JAK2-STAT3信號(hào)通路在HCC的發(fā)生發(fā)展中扮演者重要角色，針對JAK2-STAT3信號(hào)通路的靶向治療將具有巨大的應(yīng)用潛力。明確JAK2-STAT3信號(hào)通路的組成及其調(diào)控機(jī)制，將更有利于理解HCC的發(fā)病的分子機(jī)理。找到JAK2-STAT3信號(hào)通路上游及其下游分子，可以找到更多的靶位點(diǎn)調(diào)節(jié)細(xì)胞的生命活動(dòng)。JAK2-STAT3信號(hào)通路持續(xù)性激活通過調(diào)節(jié)下游靶基因包括c-Myc、JunB、clAP2、Mcl-1、survivin、Bcl-2、Cyclin D1、MMP-2、Bcl-xl、ICAM-1、Bid和VEGF（血管內(nèi)皮生長因子）等的表達(dá)[17,42]，來促進(jìn)細(xì)胞增殖和生存，抑制凋亡，促進(jìn)腫瘤侵襲與轉(zhuǎn)移，促進(jìn)血管生成的。找到IL-6受體、信號(hào)轉(zhuǎn)導(dǎo)器gp130、JAK家族、STAT家族、SOCS3、PIAS、CIS及其它相關(guān)分子的激活劑或抑制劑，有效的調(diào)節(jié)JAK2-STAT3信號(hào)通路過程，JAK2-STAT3信號(hào)通路與Wnt/beta-catenin通路，Ras信號(hào)通路，PI3K信號(hào)通路，cAMP介導(dǎo)的第二信使通路等也存在著聯(lián)系。對JAK2-STAT3信號(hào)通路的調(diào)控可能成為調(diào)控細(xì)胞生命活動(dòng)的關(guān)鍵點(diǎn)，可能成為治療HCC的靶向位點(diǎn)。分子靶向藥物聯(lián)合起來抑制癌細(xì)胞的各種存活通路，抑制HCC細(xì)胞的增殖和侵襲，促進(jìn)HCC細(xì)胞凋亡，達(dá)到有效的靶向治療HCC。

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