胡玉霞，常福厚，白圖雅，呂曉麗，余婉佳

(內(nèi)蒙古醫(yī)科大學(xué) 藥學(xué)院 藥理教研室，內(nèi)蒙古自治區(qū) 呼和浩特 010110)

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多環(huán)芳烴類化合物及芳香烴受體在腫瘤發(fā)生發(fā)展中的作用

胡玉霞，常福厚Δ，白圖雅，呂曉麗，余婉佳

(內(nèi)蒙古醫(yī)科大學(xué) 藥學(xué)院 藥理教研室，內(nèi)蒙古自治區(qū) 呼和浩特 010110)

多環(huán)芳烴(polycyclic aromatic hydrocarbons, PAHs)是廣泛存在于環(huán)境中的污染物，其具有致癌作用已是不爭的事實。PAHs能與芳香烴受體(aryl hydrocarbon receptor, AhR)結(jié)合，產(chǎn)生某些毒性反應(yīng)而發(fā)揮致癌作用。AhR是一種配體依賴性激活轉(zhuǎn)錄因子，被PAHs等配體激活后，調(diào)控一系列與代謝有關(guān)的基因的表達，參與諸如信號轉(zhuǎn)導(dǎo)、細(xì)胞增殖與分化、細(xì)胞凋亡等重要的生物學(xué)過程，且與腫瘤的發(fā)生發(fā)展密切相關(guān)。因此探討PAHs與AhR在腫瘤發(fā)生發(fā)展中的作用，可能為腫瘤的預(yù)防和治療提供新途徑。

多環(huán)芳烴類；芳香烴受體；腫瘤

腫瘤的發(fā)生是多種因素共同作用的結(jié)果，其中環(huán)境因素占主導(dǎo)地位。在與腫瘤發(fā)生有關(guān)的諸多環(huán)境因素中，環(huán)境污染物—多環(huán)芳烴類化合物(polycyclic aromatic hydrocarbon, PAHs)起到至關(guān)重要的作用。其導(dǎo)致腫瘤發(fā)生的主要作用機制是與芳香烴受體(aryl hydrocarbon receptor, AhR)結(jié)合，誘導(dǎo)下游靶基因的表達，活化某些代謝酶，調(diào)控一些重要的生物學(xué)過程, 如信號轉(zhuǎn)導(dǎo)、細(xì)胞分化、細(xì)胞凋亡等。AhR是一種配體激活轉(zhuǎn)錄因子，它具有介導(dǎo)B[a]P及其他相關(guān)化合物的生理和毒理作用的功能。當(dāng)與配體結(jié)合后，AhR就會轉(zhuǎn)移到細(xì)胞核內(nèi)與AhR核易位體蛋白(aryl receptor nuclear translocator，ARNT)結(jié)合形成二聚體，隨后啟動外源性化學(xué)物質(zhì)反應(yīng)元件(xenobiotic-responsive element，XRE)的轉(zhuǎn)錄過程，誘導(dǎo)外源化學(xué)物代謝酶(CYP1A1，CYP1A2)的表達。AhR可與多種蛋白相互作用，亦是胞內(nèi)信號通路的調(diào)節(jié)因子。AhR的這些生物學(xué)功能與腫瘤的發(fā)生發(fā)展密切相關(guān)，因此探討PAHs與AhR在腫瘤形成中的作用可為腫瘤的預(yù)防和治療提供新思路及新途徑。

1 PAHs與腫瘤

1.1 PAHs 的概況 PAHs是指分子中含有2個或2個以上苯環(huán)的碳?xì)浠衔?。由于PAHs是不完全燃燒產(chǎn)生的污染物，在環(huán)境中難降解，包括香煙煙霧、汽車尾氣、化石燃料燃燒、垃圾焚燒和油炸食物等，廣泛存在于空氣、水、食物和土壤中[1-2]。PAHs能直接通過呼吸道、消化道、皮膚等被人體吸收，或通過食物鏈在動物和人的體內(nèi)蓄積。PAHs是公認(rèn)的致癌，致突變的毒性物質(zhì)，其中，苯并芘(Benzo[a]pyrene, B[a]P)及2,3,7,8‐四氯二苯并對二惡英(2,3,7,8-tetrachlorodibenzo-p-dioxin，TCDD)對人體的危害最大，主要表現(xiàn)在致癌性方面[3-4]。1933年英國學(xué)者J.Cook首次從煙焦油中分離出化學(xué)致癌物——B[a]P，并誘發(fā)出小鼠皮膚癌[5]。1983年，國際癌癥研究機構(gòu)(international agency for research on cancer，IARC)將B[a]P確認(rèn)為環(huán)境化學(xué)致癌物，并且B[a]P及TCDD被IARC列為I類人類致癌物[6-7]。

1.2 PAHs的致癌機制 Jerina[8]提出灣區(qū)理論，認(rèn)為PAHs最終致癌物是灣區(qū)環(huán)氧化物，灣區(qū)碳陽離子的穩(wěn)定性與致癌性呈正相關(guān)。Jerina在研究PAHs的代謝產(chǎn)物時發(fā)現(xiàn)，PAHs的最終致癌物為二氫二醇環(huán)氧化合物。B[a]P進入人體后，首先在CYP450 I相代謝酶的作用下，形成具有致癌作用的環(huán)氧化物和二醇環(huán)氧化物等。環(huán)氧化物又在II相代謝酶的催化作用下，形成7,8-二羥基-9,10-環(huán)氧苯并(a)芘(BPDE)[9]。BPDE是最終致癌物，具有親電性，易與DNA及蛋白質(zhì)等體內(nèi)大分子物質(zhì)結(jié)合，形成BPDE-DNA加合物，引起DNA損傷，導(dǎo)致遺傳學(xué)損傷效應(yīng)的出現(xiàn)，最終引起諸如癌癥等疾病的產(chǎn)生[10]。

2 AhR與腫瘤

2.1 AhR的簡介 AhR是一種配體激活轉(zhuǎn)錄因子，屬于堿性螺旋-環(huán)-螺旋(basic helix-loop-helix, bHLH)轉(zhuǎn)錄因子超家族中PAS (periodicity/aryl hydrocarbon receptor nuclear translocator /single-minded,PAS)的亞家族成員[11-12]。ARNT是AhR核轉(zhuǎn)位蛋白，存在于許多動物、植物以及原核生物中，定位于細(xì)胞核內(nèi)，并在體內(nèi)廣泛表達[13-14]。AhR的配體十分廣泛，包括花生四烯酸、血紅素、色氨酸等內(nèi)源性配體和PAHs、PCBs、鹵代芳烴等外源性配體[15]。AhR與配體結(jié)合并被其激活后，AhR與ARNT形成二聚體[16]，使之進入細(xì)胞核發(fā)揮作用，介導(dǎo)諸如上皮異型增生、致畸作用、低氧反應(yīng)、促進代謝酶基因的表達等一系列生物學(xué)效應(yīng)[17-19]，導(dǎo)致惡性腫瘤發(fā)生的危險性升高。AhR 還參與許多信號轉(zhuǎn)導(dǎo)途徑，在調(diào)控細(xì)胞增殖、分化、凋亡方面起著重要作用，而這些過程與腫瘤的發(fā)生、發(fā)展相關(guān)，并最終導(dǎo)致惡性腫瘤的形成[20]。

2.2 AhR介導(dǎo)的外源性代謝酶與腫瘤的關(guān)系 AhR與配體結(jié)合后，AhR 與ARNT形成二聚體，轉(zhuǎn)位至核內(nèi)，與外源性化學(xué)物質(zhì)調(diào)節(jié)元件(xenobiotic regulative element，XRE)結(jié)合，介導(dǎo)一系列外源性代謝酶的表達，包括I相代謝酶(主要是細(xì)胞色素P450超家族成員，如CYP1A1、CYP1A2、CYP1B1等)和II相代謝酶(谷胱甘肽轉(zhuǎn)移酶[GST]，葡萄糖醛酸轉(zhuǎn)移酶等)的表達，從而使機體對外源性化合物產(chǎn)生適應(yīng)性及毒性反應(yīng)[21-22]。

有研究報道，與正常細(xì)胞比較，多種癌細(xì)胞系的AhR mRNA的水平均表現(xiàn)為相對較高的表達，如軟骨肉瘤、食管癌、胰腺癌和肝癌細(xì)胞等[23]。π型GST與惡性腫瘤的關(guān)系最為密切，在胃癌、卵巢癌、尿道癌、結(jié)直腸癌、子宮內(nèi)膜癌、前列腺癌和膠質(zhì)細(xì)胞瘤等惡性腫瘤中GST-π水平顯著高于對照組[24]。在非小細(xì)胞肺癌中，AhR和其靶基因CYP1B1均表現(xiàn)為過表達，CYP1B1在晚期患者中表達更普遍[25]。機體的雙相解毒酶DT-硫辛酰胺脫氫酶(NQO1)具有化學(xué)保護和生物激活雙重作用，既可降解某些致癌物，亦可誘導(dǎo)某些致癌物的形成；NQO1在多種腫瘤細(xì)胞中的表達遠高于正常組織，特別是肺癌、結(jié)腸癌、乳腺癌[26]。

2.3 AhR對腫瘤細(xì)胞增殖作用的影響 AhR對細(xì)胞的增殖作用具有細(xì)胞特異性，當(dāng)被外源性配體激活后，用不同的細(xì)胞系進行實驗常常得到不同的、甚至相反的結(jié)果。AhR參與調(diào)控細(xì)胞的生長，并對其細(xì)胞生長具有促進作用，Abdelrahim[27]等利用siRNA干擾技術(shù)下調(diào)人乳腺癌細(xì)胞系MCF-7和肝癌細(xì)胞系HePG2中AhR基因的表達后，發(fā)現(xiàn)腫瘤細(xì)胞在體外的生長增殖受到顯著影響。某些情況下，AhR可以抑制腫瘤細(xì)胞的增殖和生長，TCDD或吲哚衍生物激活A(yù)hR信號通路，通過多種途徑引起細(xì)胞的生長抑制[28-29]。AhR被TCDD激活后可與視網(wǎng)膜母細(xì)胞瘤抑制蛋白結(jié)合，亦可通過影響TGF-p信號傳導(dǎo)，從而抑制細(xì)胞生長[30-31]。因此，AhR是促進或抑制細(xì)胞生長和增殖的重要因素是細(xì)胞類型。目前，需要更深入的研究AhR參與的信號通路及其與中間蛋白的相互作用。

2.4 AhR對腫瘤細(xì)胞周期及凋亡的調(diào)控 AhR對細(xì)胞周期的調(diào)控具有特異性，沒有配體存在，AhR促進細(xì)胞周期進展，而外源性配體激活A(yù)hR后與視網(wǎng)膜母細(xì)胞瘤蛋白(retinoblastoma protein，RB)相互作用擾亂細(xì)胞周期，使G0/G1期停滯，DNA復(fù)制能力減弱，細(xì)胞增殖受到抑制[32]。Ma等[33]研究顯示，AhR基因敲除的小鼠Hepa1c1c7細(xì)胞與野生型細(xì)胞相比，細(xì)胞分化緩慢，白蛋白表達水平降低；AhR的損失導(dǎo)致細(xì)胞增殖速率降低和停滯在G0/G1期的細(xì)胞數(shù)量增加。在MCF-7和BT474癌細(xì)胞中利用siRNA技術(shù)使AhR基因沉默，細(xì)胞增殖速率加快，G2/M期的細(xì)胞數(shù)增加，而G0/G1期的細(xì)胞數(shù)減少[34]。然而，有研究證明，不存在外源性配體時，乳腺癌細(xì)胞中AhR與細(xì)胞周期蛋白依賴激酶4(cyclin dependent kinase 4, CDK4)、周期素D1(cyclin D1) 相互作用，促進細(xì)胞周期的進程[35]。

AhR對細(xì)胞凋亡的影響取決于凋亡是由內(nèi)在還是外在途徑引起的。AhR通過內(nèi)在途徑誘導(dǎo)細(xì)胞凋亡，可能是肝內(nèi)視黃酸異常聚集，導(dǎo)致轉(zhuǎn)化生長因子β相關(guān)信號通路激活，加速了細(xì)胞凋亡。例如AhR基因敲除小鼠的肝細(xì)胞對FasL刺激的凋亡更加敏感，肝細(xì)胞凋亡速度明顯加快[36]。AhR通過外在途徑抑制細(xì)胞凋亡，AhR介導(dǎo)的細(xì)胞凋亡與環(huán)氧合酶-2(COX-2)的表達上調(diào)及Bcl-2家族基因的降解有關(guān)。研究顯示，暴露于TCDD的C57BL/10J小鼠，其淋巴瘤生長進度極其明顯，同時在受累淋巴結(jié)中COX-2的表達水平也明顯升高[37]。結(jié)果表明，活化的AhR 在淋巴瘤細(xì)胞抵抗凋亡的過程中發(fā)揮了重要作用。

2.5 AhR對腫瘤細(xì)胞遷移和侵襲的影響 研究顯示，被配體激活的AhR導(dǎo)致MCF-7和HepG2細(xì)胞遷移加快，這與Jun氨基末端激酶的活化和E-鈣粘附分子的表達下調(diào)有關(guān)[38]。Thiery等[39-40]的研究顯示，上皮細(xì)胞到間質(zhì)細(xì)胞的轉(zhuǎn)化(EMT)與腫瘤的遷移密切相關(guān)，尤其是上皮癌細(xì)胞，AhR作為細(xì)胞生長進程的調(diào)控因子，起調(diào)控EMT的作用，EMT又稱為細(xì)胞的可塑性。另外，有人發(fā)現(xiàn)了遷移標(biāo)志物：HEF1/NEDD9/CAS-L，是AhR的下游靶基因，也是AhR調(diào)節(jié)細(xì)胞可塑性的關(guān)鍵所在，它是一種影響細(xì)胞運動性和致癌性的多功能蛋白質(zhì)[41]。研究發(fā)現(xiàn)，在黑色素瘤、惡性膠質(zhì)瘤和肺腫瘤中，HEF1/NEDD9/CAS-L的表達增加，且腫瘤的轉(zhuǎn)移能力加強[42-44]。

腫瘤細(xì)胞的遷移和侵襲是一個非常復(fù)雜的過程，其中最關(guān)鍵的一步就是依賴基質(zhì)金屬蛋白酶(MMPs)的表達來降解細(xì)胞外基質(zhì)(ECM)和基底膜。腫瘤細(xì)胞的遷移和侵襲與AhR信號通路的激活存在相關(guān)性[45]。研究顯示，活化的AhR信號通路通過上調(diào)MMPs的表達增強了黑色素瘤和胃癌細(xì)胞的侵襲作用[46]。被TCDD激活的AhR通過AhR依賴途徑增強了T24膀胱癌細(xì)胞的侵襲作用，并伴隨MMP-1、MMP-9表達的增高[47]。TCDD作用于胃癌細(xì)胞AGS后，AGS的侵襲能力增強，MMP-9的表達增加；用siRNA技術(shù)沉默c-Jun基因后，這種效應(yīng)減弱，表明AhR通路激活后可能通過c-Jun依賴的途徑誘導(dǎo)MMP-9的表達，增強腫瘤細(xì)胞的侵襲能力[48]。

3 AhR與腫瘤靶向治療的關(guān)系

AhR作為與腫瘤發(fā)生發(fā)展相關(guān)的蛋白，有可能成為腫瘤治療的靶向分子。已有研究發(fā)現(xiàn)，在人乳腺癌細(xì)胞MCF7中，AhR的配體TCDD、MCDF(6-甲基-1,3,8-三氯二苯呋喃)、PAHs、PCBs(多氯聯(lián)苯)都具有抗雌激素活性的作用。AhR通過兩種途徑調(diào)控雌激素的作用：(1)通過誘導(dǎo)CYP1A1/CYP1B1的表達進而增加E2的氧化代謝；(2)通過配體激活蛋白酶體并且下調(diào)ERα的表達[49]。抑制AHR-ERα信號通路對于調(diào)節(jié)TCDD等AHR配體的抗雌激素活性起著關(guān)鍵作用；然而，配體激活的AHR通過調(diào)控多種基因和信號通路來抑制雌激素受體陽性乳腺癌的生長。研究表明，AhR的配體3,3′-吲哚甲烷(DIM)能通過AhR依賴的途徑強烈地抑制ER-α的表達及雌激素信號通路，防止嚙齒動物乳腺腫瘤，減少人類乳腺癌的發(fā)病風(fēng)險[50]。在大多數(shù)雌激素受體陰性乳腺癌細(xì)胞中AhR都有表達，而且在AhR受體激動劑6-甲基-1,3,8-三氯二苯呋喃(MCDF)存在的情況下，誘導(dǎo)CYP1A1的表達，抑制腫瘤細(xì)胞的增殖[51]。體內(nèi)實驗，以植入乳腺癌細(xì)胞的4T1.2小鼠為模型，發(fā)現(xiàn)MCDF有抑制腫瘤細(xì)胞轉(zhuǎn)移的作用[52]。

結(jié)構(gòu)不同的具有AhR激動劑活性的化學(xué)藥品包括幾個廣泛使用的藥物，如抗過敏的藥物曲尼司特(tranilast)。曲尼司特是AhR激動劑，抑制人乳腺癌MDA-MB-231細(xì)胞生長和遷移，抑制細(xì)胞集落和微球體的形成，抑制腫瘤細(xì)胞的轉(zhuǎn)移，可能成為治療乳腺癌的化療藥物[53]。近年來，實驗室研究已經(jīng)篩選出8種AHR活性藥物作為CYP1A1/CYP1B1的誘導(dǎo)劑和乳腺癌細(xì)胞BT474和MDA-MB-468的遷移抑制劑，包括氟他米特，來氟米特，尼莫地平，奧美拉唑，舒林酸，曲尼司特，4-羥基他莫昔酚，美西律，其中4-羥基他莫昔酚，美西律亦可用于雌激素受體陰性乳腺癌的治療[54]。顯而易見，從雌激素受體陽性及雌激素受體陰性這兩種乳腺癌細(xì)胞來研究AhR均是與治療腫瘤高度相關(guān)的藥物靶標(biāo)。

4 結(jié)語

綜上所述，AhR作為一種轉(zhuǎn)錄因子，直接或間接的與其他蛋白相互作用，調(diào)控一系列與代謝有關(guān)的基因的表達及胞內(nèi)信號通路。AhR在多數(shù)惡性腫瘤中的表達均高于正常組織，其不僅參與多種外源性物質(zhì)的代謝，還調(diào)控機體的多種生理過程(增殖，凋亡，遷移，侵襲等)。越來越多的研究證明AhR及其配體，如PAHs等在腫瘤的發(fā)生發(fā)展中起著至關(guān)重要的作用。與此同時，與AhR有關(guān)的治療腫瘤的藥物也受到了廣泛的關(guān)注。隨著對AhR在腫瘤形成的作用的進一步研究，有助于更深入的了解PAHs等環(huán)境污染物的致癌機制，更重要的是可從AhR信號通路入手，為腫瘤的防治提供新的途徑。

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(編校：譚玲)

Role of polycyclic aromatic hydrocarbons and aryl hydrocarbon receptor in the development of tumor

HU Yu-xia, CHANG Fu-houΔ, BAI Tu-ya, LV Xiao-li, YU Wan-jia

(Department of Pharmacology, School of Pharmacy of Inner Mongolia Medical University, Hohhot 010110, China)

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants, whose carcinogenicity is determinated.The mechanism of their carcinogenicity: PAHs are able to combine with aryl hydrocarbon hydrocarbon receptor(AhR), resulting in some toxicity and carcinogenicity.AhR is a ligand-dependent activation transcription factor, which is activated by a large variety of ligands, regulating the expression of a series of gene involved in metabolism, and participating in important biological processes, such as singal transduction, cell proliferation,differentiation and apoptosis,and so on. Besides, it’s closely related with the tumor development.Thus, it will provide a new approach for cancer prevention and treatment to study the role of PAHs and AhR in the development of tumor.

polycyclic aromatic hydrocarbons; aryl hydrocarbon receptor; tumor

國家自然科學(xué)基金(No.812604999，No.81160406)

胡玉霞，女，碩士在讀，研究方向：生化與分子藥理學(xué)，E-mail：15648116658@163.com；常福厚，通訊作者，男，博士，教授，研究方向：生化與分子藥理學(xué)，E-mail：Changfh@sina.com。

R966

A

1005-1678(2015)06-0185-04