干擾素調(diào)節(jié)因子在腫瘤發(fā)生中的研究進(jìn)展

陳妍潔， 吳 昊， 沈錫中

復(fù)旦大學(xué)附屬中山醫(yī)院消化科，上海 200032

·綜述·

干擾素調(diào)節(jié)因子在腫瘤發(fā)生中的研究進(jìn)展

陳妍潔， 吳 昊， 沈錫中*

復(fù)旦大學(xué)附屬中山醫(yī)院消化科，上海 200032

干擾素調(diào)節(jié)因子(interferon regulatory factors, IRFs)是一類(lèi)在干擾素表達(dá)調(diào)控中起重要作用的轉(zhuǎn)錄因子家族，目前共發(fā)現(xiàn)有10個(gè)成員，其在免疫調(diào)節(jié)、細(xì)胞分化、細(xì)胞凋亡和細(xì)胞周期調(diào)節(jié)中具有重要作用。本文就該家族成員的功能特點(diǎn)、免疫活性，特別是在細(xì)胞分化及腫瘤發(fā)生中的作用作一綜述。

干擾素調(diào)節(jié)因子；細(xì)胞免疫；免疫調(diào)節(jié)

20世紀(jì)中葉，干擾素作為抗病毒蛋白被發(fā)現(xiàn)，此后發(fā)現(xiàn)了干擾素調(diào)節(jié)因子家族(interferon regulatory factors,IRFs)。IRFs是一類(lèi)作用于干擾素(interferon,IFN)基因，調(diào)控其表達(dá)的轉(zhuǎn)錄因子[1]，由于在機(jī)體感染尤其是病毒感染時(shí)能夠結(jié)合到IFN啟動(dòng)子上誘導(dǎo)、調(diào)節(jié)IFN的表達(dá)而得名。所有IRF的氨基端都含有1個(gè)由115個(gè)氨基酸組成的結(jié)構(gòu)域(DNA binding domain,DBD)。該結(jié)構(gòu)域和Myb蛋白的DBD相似，可與DNA結(jié)合并含有5個(gè)色氨酸的重復(fù)序列；而IRF的羧基端則是1個(gè)可變區(qū)域，從而使得IRFs具備了多種生物功能[2]。目前，已發(fā)現(xiàn)的IRFs成員共有10個(gè)，IRF-1～I(xiàn)RF-9和病毒IRF(V-IRF)，起初這些成員被認(rèn)為是免疫細(xì)胞所特有的，然而近年來(lái)越來(lái)越多的該家族成員在其他組織細(xì)胞中被發(fā)現(xiàn)。迄今為止，多項(xiàng)研究表明，IRFs在細(xì)胞分化和凋亡、細(xì)胞周期調(diào)節(jié)、免疫調(diào)控中具有重要作用。近年來(lái)，人們開(kāi)始關(guān)注IRFs的抗腫瘤作用及其相關(guān)細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)通路，希望能找到治療腫瘤的新方法。

1 IRFs在固有免疫應(yīng)答中的作用

人類(lèi)的固有免疫應(yīng)答是機(jī)體抵御病原生物入侵的第一道防線，由模式識(shí)別受體(innate pattern recognition receptors,PRRs)介導(dǎo)，包括Toll樣受體(Toll-like receptor, TLR)、C型凝集素受體(C-type lectin receptor，CLRs)、RIG-Ⅰ樣受體(RLRs)和NOD樣受體(NLRs)[3]。當(dāng)這些模式識(shí)別受體識(shí)別不同病原相關(guān)分子模式(PAMPs)或損傷相關(guān)分子模式(DAMPs)后，通過(guò)胞內(nèi)分子級(jí)聯(lián)反應(yīng)誘導(dǎo)Ⅰ型IFN、促炎細(xì)胞因子和趨化因子的轉(zhuǎn)錄，從而殺滅病原微生物或感染的細(xì)胞。干擾素調(diào)節(jié)因子家族是傳遞模式識(shí)別受體信號(hào)，從而激活免疫細(xì)胞的重要分子[4]。例如，IRF3/7可誘導(dǎo)IFN的表達(dá)，從而激活I(lǐng)FN下游靶基因的表達(dá)，誘導(dǎo)T細(xì)胞分化，并可激活適應(yīng)性免疫途徑；PRRs激活后還可通過(guò)特定接頭蛋白和MyD88信號(hào)，引起IRF1/5/7和NF-κB的激活，從而誘導(dǎo)IFN、IL、TNF等的轉(zhuǎn)錄和表達(dá)，并激活非特異性免疫途徑和獲得性免疫。我們對(duì)IRF家族傳遞PRR信號(hào)的分子通路進(jìn)行了總結(jié)(表1)。

在固有免疫應(yīng)答的發(fā)生過(guò)程中，IRFs可由多種PRRs所激活，而單一的IRF分子又可參與不同PRR的下游信號(hào)通路。不同的IRF可被相同的分子所激活，如MyD88；而活化的IRF又可作用于相同的靶基因，如IFN相關(guān)靶基因，提示不同的應(yīng)答模式間具有相關(guān)性。由此可見(jiàn)，整個(gè)信號(hào)通路包括轉(zhuǎn)錄因子在免疫應(yīng)答中受到精確調(diào)節(jié)。闡明IRFs在信號(hào)網(wǎng)絡(luò)中所發(fā)揮的關(guān)鍵作用，有利于今后生物免疫治療、腫瘤免疫治療的研究。

表1 IRF家族傳遞PRR信號(hào)的分子通路

2 IRFs在免疫細(xì)胞發(fā)育中的作用

除了參與固有免疫應(yīng)答以外，IRF-1/2/4/6/8對(duì)免疫細(xì)胞(如樹(shù)突狀細(xì)胞、NK細(xì)胞、B細(xì)胞和T細(xì)胞等)的生長(zhǎng)也起到關(guān)鍵作用。通過(guò)基因敲除的小鼠實(shí)驗(yàn)[5]發(fā)現(xiàn)，CD4+DCs、CD8α+DCs和pDC的分化受到IRF-1/2/4/8的調(diào)控。IRF-1可誘導(dǎo)IL-15促進(jìn)NK細(xì)胞分化，而IRF-2則可通過(guò)細(xì)胞內(nèi)信號(hào)通路促進(jìn)NK細(xì)胞分化[5]。IRF-8可通過(guò)與EBF啟動(dòng)子結(jié)合激活EBF表達(dá)，從而激活B細(xì)胞分化的相關(guān)基因；而IRF-4通過(guò)調(diào)節(jié)Fas凋亡抑制分子，從而調(diào)節(jié)B細(xì)胞的凋亡[6]。IRF-1和IRF-2能強(qiáng)烈啟動(dòng)Th1應(yīng)答，而IRF-4則主要參與Th2的細(xì)胞分化過(guò)程[1]。IRF在免疫細(xì)胞發(fā)育中的作用如表2。

IRF可通過(guò)調(diào)節(jié)腫瘤免疫從而發(fā)揮抗癌效應(yīng)，如IRF-8可通過(guò)促進(jìn)APCs(如MФ、DCs和B細(xì)胞)的分化和成熟而起到抗癌作用[7]。因此，對(duì)于IRF的研究有利于深入闡明腫瘤免疫的特點(diǎn)，并為臨床抗腫瘤治療提供新思路。

表2 IRFs在免疫細(xì)胞發(fā)育中的作用

3 IRFs在促進(jìn)細(xì)胞周期、分化中的作用

目前發(fā)現(xiàn)，IRFs家族在細(xì)胞周期、細(xì)胞分化以及腫瘤形成中起到重要作用(表3)。早期認(rèn)為IRF-2與IRF-1競(jìng)爭(zhēng)識(shí)別位點(diǎn)[8]，從而發(fā)揮與IRF-1不同的作用，但近年來(lái)發(fā)現(xiàn)了IRF-2的其他作用。而IRF-4被認(rèn)為與血液系統(tǒng)惡性腫瘤密切相關(guān)。

3.1 IRF-2 IRF-2的基因位于染色體4q34.1-q35.1，目前尚無(wú)研究表明其表達(dá)有組織特異性。最初研究[8]認(rèn)為，IRF-2與抑癌基因IRF-1具有相似的識(shí)別位點(diǎn)。因此，推測(cè)IRF-2可能通過(guò)競(jìng)爭(zhēng)結(jié)合相同的識(shí)別位點(diǎn)從而抑制IRF-1的轉(zhuǎn)錄。另外，IRF-2能與Blimp-1共同結(jié)合于IFN-8基因的PRDI結(jié)構(gòu)域，故IRF-2能通過(guò)抑制Blimp-1而引起細(xì)胞癌變。乙?；蟮腎RF-2可結(jié)合到組蛋白H4的啟動(dòng)子上，從而引起細(xì)胞持續(xù)增殖[9]。一些研究[10-11]發(fā)現(xiàn)，IRF-2可在食管癌和胰腺癌組織中呈高表達(dá)。

3.2 IRF-4 IRF-4是一個(gè)與血液系統(tǒng)的惡性腫瘤密切相關(guān)的轉(zhuǎn)錄因子。當(dāng)感染了人類(lèi)T細(xì)胞白血病病毒1型(HTLV-1)后，IRF-4的表達(dá)明顯升高，從而降低了G2/M關(guān)卡基因Cyclin B1和多種DNA修復(fù)基因的正常表達(dá)[12]。部分多發(fā)性骨髓瘤(MM)患者可出現(xiàn)t(p25；q32)，從而導(dǎo)致IRF-4高表達(dá)；而IRF-4 mRNA表達(dá)水平的升高則提示MM患者預(yù)后不良[13]。在MM中，IRF-4可激活MYC基因的轉(zhuǎn)錄，而Myc蛋白的高表達(dá)則進(jìn)一步促進(jìn)IRF-4的表達(dá)，形成了正向調(diào)節(jié)環(huán)[14]。這個(gè)正向調(diào)節(jié)環(huán)促進(jìn)疾病的發(fā)生發(fā)展，打破該正向調(diào)節(jié)是否可以治療MM有待進(jìn)一步研究。

4 IRFs在抑制細(xì)胞周期、分化中的作用

目前，發(fā)現(xiàn)大部分的IRFs主要起到直接抑制細(xì)胞周期和分化，抑制腫瘤發(fā)生發(fā)展的作用，部分可通過(guò)腫瘤免疫抑制腫瘤的發(fā)生發(fā)展(表3)。

表3 IRF家族成員在調(diào)節(jié)細(xì)胞周期、分化中的作用

4.1 IRF-1 對(duì)于IRF家族在腫瘤中調(diào)節(jié)作用的研究最早集中于IRF-1。敲除了IRF-1的細(xì)胞喪失了DNA損傷引起的細(xì)胞周期停滯能力。另外，IRF-1可在轉(zhuǎn)錄水平激活CDK的抑制蛋白p21WAF1/CIP1的表達(dá)[15]。很多小分子(如IFN-γ)可促進(jìn)IRF-1的促凋亡作用[16]。

IRF-1基因位于染色體5q31.1，這是一個(gè)在白血病或骨髓異常增生綜合征中常出現(xiàn)突變的區(qū)域[17]。研究[18]發(fā)現(xiàn)，在血液系統(tǒng)相關(guān)疾病的患者中，IRF-1基因有單個(gè)或兩個(gè)等位基因發(fā)生突變或剪接突變。另外，食管癌和胃癌中也發(fā)現(xiàn)有IRF-1等位基因的缺失[19-20]。之后在慢性髓細(xì)胞白血病、乳腺癌、子宮內(nèi)膜癌和肝細(xì)胞肝癌患者中發(fā)現(xiàn)，IRF-1 mRNA表達(dá)降低[21]。

4.2 IRF-2 雖然早期研究[22]認(rèn)為，IRF-2對(duì)于腫瘤具有促進(jìn)作用，但近年來(lái)越來(lái)越多的研究表明，IRF-2對(duì)腫瘤的發(fā)生有抑制作用。研究[23]發(fā)現(xiàn)，IRF-2在乳腺癌組織中的表達(dá)與IRF-1正相關(guān)。而Sato等[24]發(fā)現(xiàn)，IRF-2可減弱Ⅰ型干擾素的應(yīng)答，從而促進(jìn)造血干細(xì)胞的分化并維持細(xì)胞的表型。研究等[25]則發(fā)現(xiàn)，肝細(xì)胞肝癌中的IRF-2發(fā)生基因突變。細(xì)胞功能學(xué)實(shí)驗(yàn)[25-26]提示，過(guò)表達(dá)IRF-2可抑制細(xì)胞增殖，并使細(xì)胞中p53含量明顯升高，而對(duì)IRF-2進(jìn)行沉默則得到相反的結(jié)果。進(jìn)一步研究[27-28]發(fā)現(xiàn)，IRF-2突變常與胚胎基因高表達(dá)或p53通路異常相關(guān)。這些研究均提示IRF-2更可能為抑癌基因。

4.3 IRF-3 由病毒引起的細(xì)胞凋亡主要是由IRF-3激活TRAIL所介導(dǎo)[29]。另外，由細(xì)菌感染通過(guò)TLR介導(dǎo)的凋亡途徑同樣需要IRF-3的參與。特定的細(xì)菌產(chǎn)生毒素因子，抑制p38或NF-κB通路，從而導(dǎo)致MФ的凋亡。而對(duì)p38和NF-κB通路的抑制主要由TLR4以及IRF-3等分子所介導(dǎo)[30]。

當(dāng)DNA受到損傷時(shí)，IRF-3會(huì)被DNA依賴(lài)的蛋白激酶(DNA-PK)磷酸化并從胞漿內(nèi)遷移至核內(nèi)，參與DNA損傷誘導(dǎo)的細(xì)胞凋亡[31]。因此，目前IRF-3也被認(rèn)為是一個(gè)腫瘤抑制因子。

4.4 IRF-5 高表達(dá)IRF-5可以抑制缺乏野生型p53的B細(xì)胞淋巴瘤的生長(zhǎng)[32]，并可促進(jìn)p53缺失的結(jié)腸癌細(xì)胞完成DNA損傷誘導(dǎo)的細(xì)胞凋亡[33]。也有研究[34]發(fā)現(xiàn)，IRF-5參與Fas/CD95誘導(dǎo)的凋亡。在白血病腫瘤細(xì)胞中，IRF-5的mRNA表達(dá)受到了明顯的抑制，這也意味著IRF-5可能在腫瘤的發(fā)生發(fā)展中起到抑癌作用[33]。

4.5 IRF-6 IRF-6可能通過(guò)與Maspin(抑癌基因)相互作用，從而發(fā)揮其抑癌的作用[35]。研究[36]發(fā)現(xiàn)，IRF-6的表達(dá)與乳腺癌的侵襲力呈負(fù)相關(guān)。在靜息期的乳腺上皮細(xì)胞中，IRF-6呈現(xiàn)未磷酸化的狀態(tài)，而在細(xì)胞分裂期時(shí)則被磷酸化并經(jīng)泛素蛋白酶體途徑被降解；而提高IRF-6的表達(dá)可導(dǎo)致細(xì)胞周期停滯。

4.6 IRF-7 當(dāng)機(jī)體受到病毒感染或特異性配體結(jié)合TLR而使TLR激活后，TBK1/IKK可誘發(fā)IRF-7磷酸化并使其轉(zhuǎn)移至細(xì)胞核內(nèi)，與IRF-3共同參與各種生物學(xué)功能。目前，IRF-7的具體抗腫瘤機(jī)制尚不明確，還有待進(jìn)一步研究。

4.7 IRF-8 IRF-8主要在造血細(xì)胞中表達(dá)。研究[37]表明，IRF-8的缺失會(huì)引起髓性白血病的發(fā)生，特別是慢性髓性白血病(CML)。在CML患者中發(fā)現(xiàn)，IRF-8功能缺失，IRF-8的靶基因(如Bcl2和Pml)的表達(dá)明顯降低。另外，IRF-8過(guò)表達(dá)可以通過(guò)間接抑制c-Myc通路而抑制細(xì)胞的有絲分裂[38-39]。體內(nèi)實(shí)驗(yàn)[40]表明，IFN-α治療CML可誘導(dǎo)IRF-8的表達(dá)，而IRF-8的表達(dá)水平也與IFN-α的治療效果密切相關(guān)。IRF-8在非造血腫瘤的發(fā)生發(fā)展中也起到重要作用。在鼻咽癌、食管癌、結(jié)腸癌等許多腫瘤中均發(fā)現(xiàn)IRF-8表達(dá)缺失[41-42]。

4.8 IRF-9 IRF-9是Ⅰ型干擾素和p53通路之間的重要聯(lián)系因子。Ⅰ型干擾素對(duì)p53通路的激活需通過(guò)ISGF3的復(fù)合物，而IRF-9為ISGF3復(fù)合物的一部分[42]。另外，還有文獻(xiàn)[43]報(bào)道，IRF-9基因可直接被c-Myc激活，因此IRF-9可能也參與細(xì)胞周期的調(diào)節(jié)。但I(xiàn)RF-9對(duì)于腫瘤發(fā)生發(fā)展的調(diào)節(jié)機(jī)制還有待進(jìn)一步的研究。

5 展 望

IRFs作為一類(lèi)轉(zhuǎn)錄因子在機(jī)體的固有免疫應(yīng)答、適應(yīng)性免疫應(yīng)答、細(xì)胞周期以及腫瘤發(fā)生中均發(fā)揮重要作用。對(duì)IRFs的研究有助于我們更深入了解腫瘤的發(fā)生發(fā)展，并為腫瘤的生物治療、靶向治療提供新思路。對(duì)于IRFs在腫瘤免疫中的具體作用，以及其是否可以作為腫瘤免疫治療的關(guān)鍵調(diào)控分子，都需要進(jìn)一步探究。

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[本文編輯] 葉 婷， 曉 路

Progress of the interferon regulatory factors in the development of tumor

CHEN Yan-jie, WU Hao, SHEN Xi-zhong*

Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China

Interferon regulatory factors (IRFs), which have 10 members, belong to the transcription factor family, and are named because of the regulation of interferon expression. They play important roles in the immune regulation, cell differentiation, cell apoptosis, and cell cycle regulation. This article will review the functional characteristics and immune activity of the family members, especially in the role of cell differentiation and tumor development.

interferon regulatory factors; cellular immunity; immune regulation

R 730.231

A

2016-09-11 [接受日期] 2017-02-06

上海市青年科技英才揚(yáng)帆計(jì)劃(16YF1401500)，復(fù)旦大學(xué)附屬中山醫(yī)院青年基金(2015ZSQN08). Supported by Project of Youth Science and Technology Excellence of Shanghai (16YF1401500) and Youth Found of Zhongshang Hospital, Fudan University (2015ZSQN08).

陳妍潔，博士，住院醫(yī)師. E-mail:chen.yanjie@zs-hospital.sh.cn

*通信作者(Corresponding author). Tel: 021-64041990, E-mail: shen.xizhong@zs-hospital.sh.cn

10.12025/j.issn.1008-6358.2017.20160800