余　平，　劉曉旺，　鐘麗菲，　丁維珂，陸凱強(qiáng)，　周志剛，　涂　劍*

(1a.南華大學(xué) 藥物藥理研究所,藥物蛋白質(zhì)組學(xué)湖南省高等學(xué)校重點(diǎn)實(shí)驗(yàn)室;1b.附屬第一醫(yī)院，湖南 衡陽(yáng) 421001;2.湖南環(huán)境生物職業(yè)技術(shù)學(xué)院 醫(yī)藥學(xué)院,湖南 衡陽(yáng) 421001)

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低氧微環(huán)境相關(guān)因子HIF-1α與癌癥的研究

余平1a,2，劉曉旺1a，鐘麗菲1a，丁維珂1a，陸凱強(qiáng)1a，周志剛1b，涂劍1a*

(1a.南華大學(xué) 藥物藥理研究所,藥物蛋白質(zhì)組學(xué)湖南省高等學(xué)校重點(diǎn)實(shí)驗(yàn)室;1b.附屬第一醫(yī)院，湖南 衡陽(yáng) 421001;2.湖南環(huán)境生物職業(yè)技術(shù)學(xué)院 醫(yī)藥學(xué)院,湖南 衡陽(yáng) 421001)

摘要：環(huán)境與癌癥的發(fā)生密切相關(guān).低氧微環(huán)境主要受缺氧誘導(dǎo)因子-1α(HIF-1α)調(diào)控.近年研究表明，低氧微環(huán)境HIF-1α可在癌癥中高表達(dá)，參與癌細(xì)胞的生長(zhǎng)繁殖、侵襲/遷移、新血管生成和細(xì)胞凋亡等過(guò)程.研究主要圍繞肝癌、乳腺癌和胃癌等與HIF-1α的關(guān)系進(jìn)行討論.參32.

關(guān)鍵詞：低氧微環(huán)境；缺氧誘導(dǎo)因子-1α；肝癌；乳腺癌；胃癌

正常機(jī)體是由不同組織器官構(gòu)成的一個(gè)不斷演進(jìn)的生態(tài)系統(tǒng).腫瘤細(xì)胞將正常生態(tài)位改造為適合其生存的低氧和酸性微環(huán)境.其中低氧微環(huán)境為腫瘤細(xì)胞提供了空間和營(yíng)養(yǎng)物質(zhì)，使其更適合生存；而腫瘤細(xì)胞自身，在性質(zhì)惡化后轉(zhuǎn)變成癌.缺氧誘導(dǎo)因子(Hypoxia-inducible factor-1,HIF-1)是一種DNA結(jié)合蛋白，被發(fā)現(xiàn)于低氧誘導(dǎo)Hep3B肝癌細(xì)胞株的細(xì)胞核提取物中[1].HIF-1是一種異二聚體蛋白結(jié)合物，包括HIF-1α和HIF-1β兩種亞基.其中，人的HIF-1α基因位于第14號(hào)染色體q21~24區(qū)，由826個(gè)氨基酸組成，主要存在于細(xì)胞核，少數(shù)位于細(xì)胞漿[2].作為一種氧分子感受器，常氧狀態(tài)下，HIF-1α受泛素-蛋白酶體系的降解而不穩(wěn)定；缺氧時(shí)，HIF-1α降解受抑制，導(dǎo)致其合成后不斷積累，使癌細(xì)胞不斷適應(yīng)低氧微環(huán)境，進(jìn)而為癌細(xì)胞的增殖和癌組織的侵襲/轉(zhuǎn)移等過(guò)程提供條件[3].因此，本文將主要圍繞幾種常見(jiàn)癌癥與低氧微環(huán)境關(guān)鍵調(diào)節(jié)因子HIF-1α的關(guān)系進(jìn)行討論.

1 HIF-1α與肝癌

肝癌是我國(guó)常見(jiàn)的惡性腫瘤之一，與肝炎病毒(HBV、HCV)的慢性感染或肝硬化的進(jìn)一步惡化密切關(guān)聯(lián)[4].肝癌細(xì)胞增殖周期的4個(gè)時(shí)期有多種生長(zhǎng)因子參與，如細(xì)胞周期素D1(cyclinD1)、轉(zhuǎn)化生長(zhǎng)因子α(transforming growth factor-α,TGF-α)、胰島素樣生長(zhǎng)因子-2(IGF-2)等.在低氧環(huán)境下，HIF-1α可以上調(diào)這些生長(zhǎng)因子，促進(jìn)肝癌細(xì)胞的增殖分化，從而完成細(xì)胞周期進(jìn)程[5].與此同時(shí)需要消耗大量的氧和能量，如其周邊的氧和能量不足以提供增殖的需求，將引發(fā)HIF-1α的大量表達(dá)與積聚.而積聚的HIF-1α則可以通過(guò)調(diào)節(jié)糖酵解活性、線粒體功能和自噬作用來(lái)為癌細(xì)胞提供能量，維持癌細(xì)胞的正常增殖和代謝平衡[6].如在肝細(xì)胞癌組織中檢測(cè)到HIF-1α與其下游靶基因葡萄糖轉(zhuǎn)運(yùn)蛋白Glut1 mRNA 和蛋白表達(dá)呈正相關(guān).兩者陽(yáng)性率均與腫瘤大小、臨床分期及淋巴結(jié)轉(zhuǎn)移情況相關(guān)，提示HIF-1α在肝癌的發(fā)生發(fā)展過(guò)程中起著關(guān)鍵作用[7].

肝癌細(xì)胞的增殖伴隨血管生成，此時(shí)主要的調(diào)節(jié)因子是血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor,VEGF).VEGF可有效的調(diào)節(jié)血管內(nèi)皮細(xì)胞的分裂、增殖和遷移過(guò)程.如遇低氧環(huán)境，積聚的HIF-1α將通過(guò)調(diào)控VEGF等因子的表達(dá)影響血管生成.如低氧環(huán)境中形成新的毛細(xì)血管網(wǎng)，可通過(guò)合成NO來(lái)上調(diào)VEGF及配體的表達(dá)參與血管生成啟動(dòng)階段；通過(guò)上調(diào)金屬蛋白水解酶配合VEGF和血管生成素-2(angiopoietin-2)參與進(jìn)展階段；通過(guò)上調(diào)血小板衍生生長(zhǎng)因子B(platelet derived growth factor B)和血管生成素-1來(lái)參與塑性改造階段等[8].在Liu等研究中[9]，利用一種多重激酶抑制劑索拉菲尼來(lái)抑制HIF-1α的表達(dá)，發(fā)現(xiàn)肝癌血管生成明顯減少了，此實(shí)驗(yàn)驗(yàn)證了HIF-1α與肝癌血管生成的相關(guān)性.

血管生成不僅與肝癌細(xì)胞增殖關(guān)聯(lián)，而且也是肝癌細(xì)胞侵襲/遷移等的必要條件之一.癌細(xì)胞侵襲/遷移過(guò)程需要滿足兩個(gè)必要條件：一個(gè)為新生血管生成，另一個(gè)是癌細(xì)胞破壞基底膜即細(xì)胞外基質(zhì)(extracellular matrix,ECM).新生血管生成在這一侵襲/遷移過(guò)程中，主要起橋梁和供能作用.基底膜的破壞將涉及到基質(zhì)金屬蛋白酶(matrix metallopreteinases,MMPs)的分泌，MMPs是腫瘤侵襲/遷移過(guò)程中降解ECM蛋白的重要酶類[10]，ECM由纖粘連蛋白、層粘連蛋白、膠原等多種物質(zhì)組成，控制著細(xì)胞形狀、分化和遷移等.低氧微環(huán)境中，HIF-1α?xí)T導(dǎo)一系列MMPs分泌，結(jié)果極易造成ECM的破壞.HIF-1α再通過(guò)調(diào)控ECM，使細(xì)胞間黏附性減弱，更有利于癌細(xì)胞的侵襲/遷移.此外，在張萬(wàn)秋等發(fā)現(xiàn)[11]，肝癌細(xì)胞的遷移還與Wnt5a蛋白介導(dǎo)的信號(hào)通路有關(guān).當(dāng)?shù)脱鮄IF-1α表達(dá)上調(diào)時(shí)，Wnt5a蛋白的表達(dá)也明顯上調(diào)，提示HIF-1α誘導(dǎo)Wnt5a 可促進(jìn)低氧條件下肝癌細(xì)胞的遷移.

2 HIF-1α與乳腺癌

乳腺癌的細(xì)胞增殖也受新生血管影響.低氧微環(huán)境下，HIF-1α表達(dá)增加，活性增強(qiáng)，上調(diào)VEGF及其受體表達(dá)，通過(guò)MAPK (Mitogen-activated protein kinase),PI3K/PKB (phosphatidylinositol 3 kinase/protein kinase B),PLC (Phospholipase C)等途徑促進(jìn)血管內(nèi)皮細(xì)胞生長(zhǎng)[12]，進(jìn)而加快新生血管生成，為腫瘤的生長(zhǎng)和轉(zhuǎn)移等創(chuàng)造條件.另外，王耕等的研究中還提到細(xì)胞增殖相關(guān)的另一因子——增殖細(xì)胞核抗原(proliferating cell nuclear antigen,PCNA，又稱Ki-67)[13-14]，是目前應(yīng)用最廣泛的增殖細(xì)胞評(píng)估指標(biāo)之一，能有效反應(yīng)腫瘤細(xì)胞增殖活性.而HIF-1α與PCNA呈正相關(guān)，在低氧環(huán)境中，HIF-1α能刺激細(xì)胞內(nèi)PCNA表達(dá)，進(jìn)而有效促進(jìn)癌細(xì)胞的增殖.

此外，PHD2也能影響乳腺癌細(xì)胞增殖.PHD2是降解HIF-1α的主要酶類，低氧時(shí)，PHD2活性降低，導(dǎo)致HIF-1α大量堆積；當(dāng)HIF-1α積聚到一定程度，又會(huì)負(fù)反饋地誘導(dǎo)PHD2的表達(dá).PHD2活性增強(qiáng)后可通過(guò)影響細(xì)胞轉(zhuǎn)化生長(zhǎng)因子-β1(transforming growth factor-β1,TGF-β1)途徑抑制癌細(xì)胞增殖[15].TGF-β1是一種細(xì)胞自分泌和旁分泌產(chǎn)生的多功能細(xì)胞因子，主要作用是刺激細(xì)胞增殖、分化和遷移[16].因此，HIF-1α還可通過(guò)調(diào)控PHD2靶基因間接影響乳腺癌細(xì)胞增殖[17].

HIF-1α也能通過(guò)調(diào)控多種因子如MMPs、LOX和COX-2等的表達(dá)來(lái)影響乳腺癌細(xì)胞的侵襲/遷移.如在乳腺癌MDA-MB-231細(xì)胞系中，HIF-1α可上調(diào) MMPs 的表達(dá)[18]，作用機(jī)制除與肝癌中提及一致之處外，MDA-MB-231乳腺癌細(xì)胞中還存在一種賴氨酰氧化酶(lysyl oxidase,LOX)的調(diào)節(jié).這是于ECM膠原與彈性蛋白聚合起始階段能穩(wěn)定ECM的一種關(guān)鍵酶，其表達(dá)異常與乳腺癌的侵襲/遷移密切相關(guān).在楊華偉等研究中發(fā)現(xiàn)[19]，LOX蛋白在高侵襲潛能的乳腺癌MDA-MB-231細(xì)胞中高表達(dá)，而在低侵襲性MCF-7細(xì)胞中低表達(dá)，且LOX的作用可受MMPs和HIF-1α異常表達(dá)的調(diào)控.

乳腺癌細(xì)胞的侵襲/遷移也少不了新生血管生成的影響.之前提及肝癌中已說(shuō)明，促血管新生的VEGF表達(dá)受HIF-1α的調(diào)控.其作用于癌細(xì)胞遷移的機(jī)制大致可概括為以下兩點(diǎn)：(1) HIF-1α高表達(dá)有助于VEGF的表達(dá)，促進(jìn)新生血管生成，新生血管為癌細(xì)胞供氧供能的同時(shí)也為其遷移提供通道；(2) HIF-1α表達(dá)增加，激活組織蛋白酶D，提高M(jìn)MPs、尿激酶型纖溶酶激活物受體、纖維連接素、TGF-α和自分泌移動(dòng)因子等侵襲相關(guān)基因的表達(dá)，增加對(duì)腫瘤細(xì)胞基底膜和細(xì)胞外基質(zhì)等的降解，使細(xì)胞-細(xì)胞、細(xì)胞-基質(zhì)間黏附力降低，侵襲性增加，最終導(dǎo)致細(xì)胞的分離和遷移[20].因此，HIF-1α對(duì)乳腺癌細(xì)胞的侵襲/遷移影響很大，發(fā)揮著重要的作用.

3HIF-1α與胃癌

胃癌是我國(guó)最常見(jiàn)的一種消化道惡性腫瘤，發(fā)病率約占40-50%[21].在胃癌細(xì)胞的失控增殖和侵襲/遷移導(dǎo)致的低氧微環(huán)境中，HIF-1α仍起主導(dǎo)的調(diào)節(jié)作用.在胃癌細(xì)胞增殖周期中，除激活cyclin 家族來(lái)參與調(diào)節(jié)細(xì)胞分裂外，還會(huì)刺激HIF-1α大量表達(dá)，促使其參與糖酵解途徑，為細(xì)胞增殖供氧供能.另外，在楊振等對(duì)胃癌的研究中[22]，發(fā)現(xiàn)HIF-1α在胃癌組織中高表達(dá)，會(huì)上調(diào)VEGF的表達(dá)，從而促進(jìn)癌細(xì)胞的增殖和遷移，其作用機(jī)制與之前提過(guò)的肝癌和乳腺癌相似.

在胃癌的發(fā)生發(fā)展過(guò)程中，還發(fā)現(xiàn)了一種調(diào)節(jié)細(xì)胞增殖分化的重要蛋白激酶——絲氨酸/蘇氨酸蛋白激酶(AKT).活化的AKT會(huì)促使HIF-1α活化及磷酸化,使HIF-1α的穩(wěn)定性增加,并激活其下游的靶分子,從而導(dǎo)致腫瘤發(fā)生.AKT 參與PI3K- AKT/PKB信號(hào)通路，協(xié)同HIF-1α調(diào)節(jié)癌細(xì)胞的增殖和活性，導(dǎo)致正常細(xì)胞惡性轉(zhuǎn)化[23].因此，在胃癌中，HIF-1α可與多種因子共同參與癌細(xì)胞的增殖，為癌細(xì)胞的侵襲/遷移奠定基礎(chǔ).

近年研究已證實(shí)，免疫組化檢測(cè)的胃癌標(biāo)本中，HIF-1α在胃癌細(xì)胞轉(zhuǎn)移組的表達(dá)明顯高于未轉(zhuǎn)移組[24-26].高表達(dá)的HIF-1α可通過(guò)調(diào)節(jié)MMPs家族，破壞ECM的基底膜，打破阻止癌細(xì)胞侵襲/遷移的屏障，促進(jìn)胃癌細(xì)胞遷移.HIF-1α受如半胱氨酸61(cysteinerich61,Cyr61)等蛋白的調(diào)控也可影響胃癌細(xì)胞的侵襲/遷移.Cyr61可通過(guò)核因子κB(nuclear factor of κB,NF-κB)與PI3K/mTOR和MAPK依賴的信號(hào)通路增加HIF-1α的合成，進(jìn)一步可促進(jìn)胃癌細(xì)胞的侵襲/遷移[27].

4HIF-1α與其他癌癥

宮頸癌中，低氧能誘導(dǎo)HIF-1α的表達(dá)[28]；PI-3K/AKT通路可抑制HIF-1α降解[29].低氧微環(huán)境中，HIF-1α還參與了卵巢癌、肺癌和腎透明細(xì)胞癌等多種惡性腫瘤的發(fā)生發(fā)展[30-32].

5展望

隨著中國(guó)經(jīng)濟(jì)的飛速發(fā)展，環(huán)境與癌癥的發(fā)生密切相關(guān)，影響著肝癌、乳腺癌和胃癌等多種癌癥，發(fā)病率逐年升高.因此，我們對(duì)癌癥的防治任重而道遠(yuǎn).盡管許多研究已了解到低氧微環(huán)境關(guān)鍵調(diào)控因子HIF-1α與癌癥關(guān)系密切，并且知道HIF-1α可能成為癌癥診斷和治療的一個(gè)重要的預(yù)測(cè)指標(biāo)，但仍需進(jìn)一步的臨床實(shí)驗(yàn)予以證實(shí).綜上所述，以HIF-1α因子為主的信號(hào)通路和以HIF-1α為靶點(diǎn)的癌癥預(yù)防和治療的新思路有待進(jìn)一步發(fā)展成熟，真正發(fā)揮HIF-1α在癌癥中的重大作用，造福人類.

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Biography：YU Ping, Male,born in 1978,Intermediate Technician,research diection for molecular pharmacology.

Study on Related Factor HIF-1α in Hypoxic Microenvironment and Cancer

YU Ping1a,2,LIU Xiao-wang1a,ZHONG Li-fei1a,DING Wei-ke1a,

LU Kai-qiang1a,ZHOU Zhi-gang1b,TU Jian1a*

(1a.Institute of Pharmacy and Pharmacology,Learning Key Laboratory for Pharmacoproteomics;1b.The First Affiliated Hospital,University

of South China,Hengyang 421001,China;2.Medical College,Hunan Polytechnic of Environment and Biology,Hengyang 421001,China)

Abstract：The environment is closely related with the occurrence of cancer.Hypoxic microenvironment is mainly regulated by Hypoxia-inducible factor-1α (HIF-1α).In recent years,studies have shown that in hypoxia environment,HIF-1α could be abundantly expressed in many kinds of cancer,involved with the growth,invasion/migration,angiogenesis and apoptosis process of cancer cells.This article is mainly discussed around the relationship between HIF - 1α and cancer such as liver cancer,breast cancer and gastric cancer.32refs.

Keywords：Hypoxic microenvironment,Hypoxia-inducible factor-1α(HIF-1α),liver cancer,breast cancer,gastric cancer.

中圖分類號(hào)：R73-3

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：2095-7300(2015)02-052-05

通訊作者*,E-mail:tujian0734@aliyun.com.

作者簡(jiǎn)介：余平(1978-)，男，湖南衡陽(yáng)人，碩士研究生，實(shí)驗(yàn)師，研究方向：分子藥理.

基金項(xiàng)目：湖南省自然科學(xué)基金青年項(xiàng)目(編號(hào)：2015JJ3101)；衡陽(yáng)市科技局課題(編號(hào)：2013KJ22)

收稿日期：2015-05-13