徐國(guó)利(綜述),范躍祖(審校)

同濟(jì)大學(xué)附屬同濟(jì)醫(yī)院普外科,上海 200065

NADPH氧化酶-1(NADPH oxidase-1,NOX-1)是NADPH氧化酶(nicotinamide adenine dinucleo-tide phosphate oxidase,NADPH oxidase,NOX)家族成員之一。NOX是細(xì)胞內(nèi)一組具有氧化活性的蛋白[1],是由膜亞基gp91phox(即NOX-2)和跨膜亞基p22phox,胞漿亞基p47phox、p67phox、p40phox和小分子GTPase結(jié)合蛋白R(shí)ac 等組成的酶復(fù)合體[2-4]。還原型煙酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH)即還原型輔酶Ⅱ,在很多生物體化學(xué)反應(yīng)中起著遞氫體的作用,對(duì)機(jī)體具有重要意義。

1 NOX-1的結(jié)構(gòu)及基因定位

研究發(fā)現(xiàn),在不同種類的細(xì)胞中存在著一系列NADPH氧化酶催化亞基的同源氧化酶。NOX-1,亦即非吞噬細(xì)胞氧化酶1(Non-phagocytic cell oxidase 1),是哺乳動(dòng)物中第一個(gè)被確認(rèn)為NADPH氧化酶膜亞基gp91phox同源物的氧化酶[5];含有564 個(gè)氨基酸,與其同系物NOX-2(即膜亞基gp91phox)、NOX-3、NOX-4、NOX-5、DUOX-1和DUOX-2被稱為NOX家族。該家族蛋白分布于幾乎所有的器官、組織和細(xì)胞,其主要生物學(xué)功能是產(chǎn)生活性氧類(reactive oxygen species,ROS)。

人類NOX-1蛋白調(diào)控NOX-1基因,又名MOX-1(mitogenic oxidase-1,有絲分裂氧化酶-1)基因或NOH-1(NADPH oxidase homologue-1,NADPH 氧化酶同源物-1)基因[6-8];該基因位于X 染色體q22。NOX-1基因至少有3種剪切變構(gòu)體(splice variants),即NOX1α(外顯子1～13)、NOX1β(外顯子1～10,12,13)、NOX1γ(外顯子1～5,14);選擇性地剪接NOX-1外顯子11,不能編碼蛋白產(chǎn)生超氧化物[9]。

2 NOX-1的表達(dá)分布及生理學(xué)功能

2.1 NOX-1的表達(dá)分布

正常情況下,NOX-1在結(jié)腸上皮細(xì)胞內(nèi)有豐富表達(dá)[10],不僅調(diào)節(jié)組織增生和細(xì)胞分化相關(guān)的信號(hào)轉(zhuǎn)導(dǎo),還參與機(jī)體宿主防御[11]。NOX-1在血管平滑肌細(xì)胞、內(nèi)皮細(xì)胞、破骨細(xì)胞、周細(xì)胞、肺上皮細(xì)胞以及子宮、胎盤、前列腺等細(xì)胞和組織中低表達(dá),在前列腺癌、結(jié)直腸癌、胃腺癌等組織或細(xì)胞中高表達(dá)[12]。在前期試驗(yàn)中,我們還發(fā)現(xiàn)在膽囊癌相關(guān)成纖維細(xì)胞中NOX-1表達(dá)增高。

2.2 NOX-1的生理學(xué)功能

NOX-1等NOX家族蛋白的主要生物學(xué)功能是產(chǎn)生ROS[13]。ROS是一類在需氧代謝和有氧環(huán)境中形成、在分子組成上含氧,且比氧自身有更高化學(xué)活性的物質(zhì)的總稱[14]。ROS是氧衍生的小分子物質(zhì),包括超氧化物、羥自由基、過(guò)氧化氫和一些既是氧化因子又能被輕易轉(zhuǎn)換成自由基的物質(zhì)如次氯酸、臭氧及單態(tài)氧等[15]。機(jī)體內(nèi)ROS有許多來(lái)源,其主要生成途徑包括環(huán)氧化酶、細(xì)胞色素p450、內(nèi)皮一氧化氮合酶(nitric oxide synthase,NOS)、脂肪氧化酶、線粒體呼吸、NADPH 氧化酶NOX家族、黃嘌呤氧化酶(xanthine oxidase,XO) 和髓過(guò)氧化物酶(MPO)等[16]。其中,吞噬細(xì)胞NADPH氧化酶是最早被確認(rèn)的產(chǎn)生ROS的體系,它在正常情況下處于靜息狀態(tài),而在各種刺激因子作用下活化后參與了機(jī)體的宿主防御反應(yīng)[17]。

不同于吞噬細(xì)胞NADPH氧化酶,NOX家族在正常時(shí)保持一定活性,產(chǎn)生胞內(nèi)胞外ROS,通過(guò)此途徑產(chǎn)生的ROS并不主要起細(xì)胞防御功能,而是參與細(xì)胞分化、增殖、凋亡(細(xì)胞內(nèi)源性ROS)及細(xì)胞間信號(hào)通路的調(diào)控(細(xì)胞外源性ROS)等[18],起到信號(hào)分子和基因表達(dá)開(kāi)關(guān)的作用,從而參與了機(jī)體多數(shù)器官生理功能的調(diào)控。當(dāng)受到胞外刺激因子的刺激時(shí),NOX家族蛋白則過(guò)表達(dá),產(chǎn)生更高濃度的ROS,誘導(dǎo)人體疾病的發(fā)生、發(fā)展[19]。

可見(jiàn),適量的ROS可通過(guò)參與細(xì)胞生長(zhǎng)、分化、凋亡信號(hào)和酶活性的調(diào)控,通過(guò)刺激炎性因子產(chǎn)生參與炎癥反應(yīng),清除病原微生物和外源物質(zhì)從而保護(hù)機(jī)體;而過(guò)量的ROS則造成細(xì)胞發(fā)展異常,引起各種病理生理改變,甚至觸發(fā)細(xì)胞死亡從而對(duì)機(jī)體造成負(fù)面影響[20]。NOX源性ROS 牽涉到的疾病有慢性肉芽腫[21-22]、阿爾茨海默病[23]、胃腸道炎癥[24]、高血壓[25]、動(dòng)脈粥樣硬化[26]、腫瘤、甲狀腺功能減退[27]、囊腫性纖維化[28]、類風(fēng)濕性關(guān)節(jié)炎和糖尿病等[1,24,29-30]。

3 NOX-1與人類惡性腫瘤

腫瘤的發(fā)生常伴有多種基因的異常表達(dá)。NOX家族基因的過(guò)度表達(dá)是許多腫瘤細(xì)胞的特征之一。目前報(bào)道,與NOX-1相關(guān)的腫瘤包括結(jié)腸癌、胃癌、前列腺癌等。

研究報(bào)道,結(jié)腸癌NOX-1表達(dá)并不比正常結(jié)腸組織高[31],NOX-1表達(dá)水平與腫瘤惡性程度無(wú)明顯相關(guān)[32-33],說(shuō)明在結(jié)腸組織中NOX-1主要是調(diào)節(jié)細(xì)胞分化,而不是腫瘤生成;而另一項(xiàng)研究的結(jié)果則與此相反,NOX-1 mRNA在結(jié)腸癌中表達(dá)水平與原癌基因K-Ras激活變異及腫瘤表型相關(guān)[34]。從而推測(cè),在結(jié)腸癌的發(fā)生發(fā)展過(guò)程中,NOX-1可能主要在早期起促進(jìn)作用,而在腫瘤進(jìn)展階段表達(dá)反而降低[32]。

NOX-1同樣與胃癌相關(guān)。據(jù)報(bào)道,NOX-1在人胃正常上皮黏膜細(xì)胞、慢性萎縮性胃炎、胃腺瘤及胃癌周圍組織中表達(dá)水平較低,在胃的腸型及彌漫型腺癌包括印戒細(xì)胞癌中高表達(dá)[35]。研究表明,幽門螺桿菌脂多糖通過(guò)TLR4(Toll-like receptor 4)信號(hào)途徑激活NOX-1源性ROS[36],由于幽門螺桿菌感染與胃腺癌密切相關(guān)[37],故推測(cè)NOX-1可能通過(guò)上調(diào)炎癥反應(yīng)和氧自由基活性促進(jìn)胃癌發(fā)生;siRNA沉默NOX-1基因可抑制胃癌細(xì)胞生長(zhǎng)[9]。

在前列腺癌,NOX-1高表達(dá)且能介導(dǎo)產(chǎn)生血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor,VEGF),但具體機(jī)制尚不清楚[38]。腫瘤相關(guān)成纖維細(xì)胞(carcinoma-associated fibroblast,CAF)可通過(guò)促炎信號(hào)利用ROS介導(dǎo)前列腺癌上皮間質(zhì)轉(zhuǎn)化(epithelial mesenchymal transition,EMT)從而影響腫瘤生成[39]。

另有報(bào)道,NOX-1 可通過(guò)上調(diào)表皮生長(zhǎng)因子(epidermal growth factor,EGF)受體調(diào)控自分泌肝癌細(xì)胞體外生長(zhǎng)[40]。

4 NOX-1在腫瘤中的作用和分子機(jī)制

NOX-1在腫瘤中的作用與癌基因Ras激活變異相關(guān)。研究表明,正常情況下,生長(zhǎng)因子(growth factor,GF)激活受體酪氨酸激酶(receptor tyrosine kinase,TRK),通過(guò)Ras-Raf-有絲分裂原激活蛋白激酶(mitogen active kinase,MEK)-細(xì)胞外信號(hào)調(diào)節(jié)蛋白激酶(extracellar regulated kinase,ERK)-GATA結(jié)合蛋白(GATA binding protein,GATA-6)通路誘導(dǎo)NOX-1表達(dá)并產(chǎn)生H2O2;在病理?xiàng)l件下,癌基因Ras(Ras V12)持續(xù)刺激NOX-1過(guò)表達(dá)并產(chǎn)生大量ROS[41]。K-Ras轉(zhuǎn)化NRK細(xì)胞(K-Ras V12-transformed normal rat kidney cells)NOX-1 mRNA表達(dá)上調(diào),EGF刺激細(xì)胞也可達(dá)到相同的效果[42]。NOX-1 siRNA可阻斷K-Ras/NRK細(xì)胞錨定非依賴生長(zhǎng),逆轉(zhuǎn)形態(tài)學(xué)改變,抑制其裸鼠移植瘤生長(zhǎng)[42]。但NOX-1本身并不具備轉(zhuǎn)化能力[18]。在乳頭狀瘤病毒E6/E7轉(zhuǎn)化的人角質(zhì)細(xì)胞體外實(shí)驗(yàn)中可觀察到,ERK激活和NOX-1表達(dá)上調(diào)[43]。

NOX源性ROS在腫瘤形成的各個(gè)階段均發(fā)揮重要作用,ROS過(guò)表達(dá)長(zhǎng)期以來(lái)都被認(rèn)為是癌發(fā)生發(fā)展的高危因子。ROS能使細(xì)胞內(nèi)主要成分如DNA、蛋白質(zhì)和脂質(zhì)受到嚴(yán)重的氧化損傷;其中,DNA受損是最常見(jiàn)的一種類型,主要有嘌呤和嘧啶堿基、DNA-蛋白質(zhì)交聯(lián)的改變以及寡核苷酸鏈和堿基位點(diǎn)的斷裂等[44]。因此,參與腫瘤早期階段基因突變和DNA異常修飾而引起的DNA損傷,是NOX源性ROS的重要作用機(jī)制。

在腫瘤的發(fā)展階段,高表達(dá)NOX-1所產(chǎn)生的ROS不僅干擾細(xì)胞形態(tài),而且促進(jìn)腫瘤細(xì)胞的增殖、遷徙、轉(zhuǎn)移,抑制凋亡等[20]。ROS作為信號(hào)分子,通過(guò)調(diào)節(jié)ERK1/2通路及核轉(zhuǎn)錄因子(nuclear factor-κB,NF-κB)活化促進(jìn)細(xì)胞增殖和分化[45]。NOX-1源性ROS激活的NF-κB還能介導(dǎo)炎癥細(xì)胞因子及給腸道細(xì)胞提供強(qiáng)力的抗凋亡信號(hào)從而促進(jìn)結(jié)腸癌發(fā)展[46]。通過(guò)TLR4信號(hào)上調(diào)NF-κB介導(dǎo)的NOX-1轉(zhuǎn)錄,增加ROS,可加速結(jié)腸癌細(xì)胞粘附[47]。ROS還可通過(guò)增加細(xì)胞遷移速率而促進(jìn)腫瘤細(xì)胞侵襲、轉(zhuǎn)移[48]。另外,絲裂原活化蛋白激酶(mitogen-activated protein kinases,MAPKs)信號(hào)轉(zhuǎn)導(dǎo)通路在細(xì)胞增殖、分化、凋亡等生物學(xué)反應(yīng)中亦具有至關(guān)重要的作用,如NOX源性ROS可通過(guò)激活MAPKs通路促進(jìn)細(xì)胞進(jìn)展[49-50]。ROS通過(guò)累積缺氧誘導(dǎo)因子1α(hypoxia-inducible factor-1 alpha,HIF-1α)轉(zhuǎn)錄子(HIF-1α transcription factor)和CXCL12趨化因子促進(jìn)成纖維細(xì)胞轉(zhuǎn)化為具有高遷徙力的肌成纖維細(xì)胞(MF),進(jìn)而加速腫瘤播散[51]。NOX-1源性ROS還影響基質(zhì)金屬蛋白酶9(matrix metalloproteinase 9,MMP-9)和VEGF產(chǎn)生[41],而這兩者與多種腫瘤的增殖、侵襲、轉(zhuǎn)移尤其是血管/淋巴管生成密切相關(guān),從而促進(jìn)腫瘤細(xì)胞的增殖和腫瘤血管生成[6],最終促進(jìn)腫瘤發(fā)生。

5 結(jié)語(yǔ)

如上所述,NOX(包括NOX-1)源性ROS的作用主要依賴于其信號(hào)轉(zhuǎn)導(dǎo),但研究主要集中在體外細(xì)胞試驗(yàn)而體內(nèi)試驗(yàn)研究報(bào)道極少。在體內(nèi)環(huán)境中,與腫瘤進(jìn)展相關(guān)的不僅是癌細(xì)胞本身、癌基因和腫瘤抑制劑,還包含基質(zhì)細(xì)胞構(gòu)成的腫瘤微環(huán)境。目前,除了NOX-1生物學(xué)功能作用如NOX-1對(duì)腫瘤發(fā)生發(fā)展的作用、建立基因敲除/上調(diào)NOX-1表達(dá)和活性小鼠模型、NOX-1轉(zhuǎn)錄激活造成ROS過(guò)表達(dá)及其分子機(jī)制有待進(jìn)一步研究外,臨床驗(yàn)證NOX-1在膽囊癌細(xì)胞和間質(zhì)標(biāo)記陽(yáng)性的間質(zhì)細(xì)胞中的表達(dá),并探討與膽囊癌臨床病理參數(shù)與患者預(yù)后的相關(guān)性,顯得非常重要;但迄今未見(jiàn)相關(guān)報(bào)道?？梢约酵?通過(guò)探討NOX-1在膽囊癌等惡性腫瘤細(xì)胞和間質(zhì)標(biāo)記陽(yáng)性間質(zhì)細(xì)胞中表達(dá)及其臨床意義,有可能尋找到膽囊癌診斷、治療、預(yù)后判斷的新靶點(diǎn)。

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