趙鳴綜述,李灼日,武金才審校
(1.南華大學(xué),湖南衡陽(yáng)421000;2.海南省人民醫(yī)院肝膽外科,海南???70311)
·綜述·
四跨膜蛋白CO-029在腫瘤的侵襲與轉(zhuǎn)移中的作用
趙鳴1,2綜述,李灼日2,武金才2審校
(1.南華大學(xué),湖南衡陽(yáng)421000;2.海南省人民醫(yī)院肝膽外科,海南海口570311)
CO-029作為四跨膜蛋白超家族的重要成員之一,已有研究顯示其在促進(jìn)腫瘤侵襲與轉(zhuǎn)移中的重要作用,但其具體機(jī)制仍知之甚少。研究明確其作用機(jī)制,有揭示腫瘤發(fā)生發(fā)展過(guò)程機(jī)制,作為預(yù)測(cè)腫瘤的進(jìn)展及預(yù)后,進(jìn)而開發(fā)新的腫瘤靶向治療藥物的潛在臨床價(jià)值。
CO-029;四跨膜蛋白;侵襲;轉(zhuǎn)移
癌癥被認(rèn)為是“永不愈合的傷口”(A wound that never heals)。與癌癥的長(zhǎng)期斗爭(zhēng)中,我們雖取得了不少成果,但對(duì)其發(fā)生發(fā)展的機(jī)制尚未完全明了,當(dāng)前的各種診斷、治療手段對(duì)腫瘤侵襲和轉(zhuǎn)移的防治并不樂(lè)觀,而腫瘤的廣泛侵襲和轉(zhuǎn)移是導(dǎo)致絕大多數(shù)患者無(wú)法手術(shù)治療,預(yù)后差,甚至死亡的主要原因之一。CO-029作為四跨膜蛋白超家族的重要成員之一,當(dāng)前研究已證實(shí)其在許多腫瘤的侵襲和轉(zhuǎn)移中的重要作用。本文就CO-029的蛋白結(jié)構(gòu),分子生物學(xué)效應(yīng)及在腫瘤發(fā)生、發(fā)展中的作用加以綜述。
CO-029是由237個(gè)氨基酸組成,其編碼分子量約32 kd的蛋白質(zhì),有4個(gè)高度疏水的跨膜結(jié)構(gòu)域,有錨定細(xì)胞膜和促進(jìn)其與其他蛋白結(jié)合的功能。胞漿區(qū)的N端及C端中C端可與胞內(nèi)的信號(hào)分子相連接,細(xì)胞外存在的2個(gè)EC環(huán)可結(jié)合胞外的蛋白及配體。SEC環(huán)是位于第一與第二跨膜結(jié)構(gòu)域之間較小的結(jié)構(gòu);LEC環(huán)位于第三與第四跨膜結(jié)構(gòu)域之間,通常由超過(guò)100個(gè)氨基酸殘基及一些特殊的結(jié)構(gòu)如CCG序列、高度保守的半胱氨酸序列組成[1]。
早在20世紀(jì)90年代初,Szala等[2]通過(guò)高效COS細(xì)胞表達(dá)系統(tǒng),成功分離得到了完整的CO-029cDNA片段,并闡明了CO-029是一種27~34 KDa的單克隆抗體細(xì)胞表面糖蛋白,是一種腫瘤相關(guān)性抗原,為其進(jìn)一步的分子生物學(xué)研究奠定了基礎(chǔ)。
2.1 CO-029與四跨膜蛋白Maecker等[3]最早提出四跨膜蛋白超家族(TM4SF)為一類特殊的四次跨膜蛋白,廣泛表達(dá)于大量不同物種,參與細(xì)胞生長(zhǎng)、粘附、遷移和信號(hào)轉(zhuǎn)導(dǎo)等多種生命活動(dòng),在許多疾病如艾滋病、丙肝等及腫瘤的發(fā)生發(fā)展過(guò)程中均起著重要作用[4]。CO-029(或TM4SF3,Tspan 8)是一種由TSPAN8基因編碼的進(jìn)化保守的細(xì)胞膜蛋白,屬于四跨膜蛋白超家族(TM4SF),是以4個(gè)高度保守的跨膜結(jié)構(gòu)為特征的蛋白,在基因水平與其他四跨膜蛋白超家族成員有一定的關(guān)聯(lián)性,其具有約1/4的同源氨基酸序列。CO-029作為四跨膜蛋白超家族中的重要一員,能結(jié)合膜內(nèi)、跨膜及膜外蛋白,起到連接膜內(nèi)外信號(hào)通道的作用,直接或間接作用于細(xì)胞的信號(hào)轉(zhuǎn)導(dǎo)通道從而影響細(xì)胞的各種生命活動(dòng)。
2.2 CO-029與四跨膜蛋白網(wǎng)絡(luò)四跨膜蛋白網(wǎng)絡(luò)(Tetraspanin Webs,TEM)是由各種四跨膜蛋白及細(xì)胞膜表面分子所構(gòu)成,其產(chǎn)生的生物學(xué)效應(yīng)遠(yuǎn)大于或不同于單個(gè)蛋白或分子的作用[5]。目前的研究結(jié)果表明四跨膜蛋白的功能主要是作為“分子促進(jìn)子”(Molecular facilitators),通過(guò)連接特異性的細(xì)胞表面蛋白增強(qiáng)功能性信號(hào)轉(zhuǎn)導(dǎo)復(fù)合物的形成和穩(wěn)定性,從而參與細(xì)胞的活化與增殖、粘附與遷移、分化與癌變等過(guò)程,發(fā)揮膜內(nèi)、跨膜和膜外蛋白募集或整合的作用,起到膜內(nèi)外信號(hào)通道橋梁的功能[6-7]。CO-029通過(guò)TEM這一重要信號(hào)平臺(tái),與許多不同類型的分子相互作用,從而產(chǎn)生各種分子生物學(xué)效應(yīng)。其能與整合素大量結(jié)合,通過(guò)整合素的α亞基與富含CCG及PxxCC序列的LEC鏈接產(chǎn)生相互作用。目前研究普遍認(rèn)為,整合素-四跨膜蛋白復(fù)合體依賴于鈣粘附蛋白的作用,改變細(xì)胞極性,影響細(xì)胞外基質(zhì)及血管的形成,促進(jìn)腫瘤細(xì)胞的侵襲轉(zhuǎn)移[8]。
基于對(duì)CO-029分子生物學(xué)效應(yīng)的初步探索,其在腫瘤發(fā)生發(fā)展中的重要作用,提示CO-029有揭示腫瘤侵襲轉(zhuǎn)移發(fā)生過(guò)程機(jī)制的潛在價(jià)值。當(dāng)前研究的取得的成果表明:CO-029可與整合素α4及血管細(xì)胞粘附因子-1(VCAM-1)等相結(jié)合,CO-029表達(dá)的腫瘤細(xì)胞可通過(guò)上調(diào)血管內(nèi)皮生長(zhǎng)因子(VEGF)及其受體的表達(dá),促進(jìn)相鄰的成纖維細(xì)胞分泌基質(zhì)金屬蛋白酶(MMPs)及尿激酶纖維蛋白溶酶原激活物(UPA),改變細(xì)胞基質(zhì)和細(xì)胞間粘附性,促進(jìn)血管的形成,推進(jìn)腫瘤細(xì)胞的侵襲轉(zhuǎn)移[9]。CO-029可能通過(guò)在不同腫瘤細(xì)胞中與特定整合素如α3β1,α6β1、α6β4、αvβ3、αvβ6等結(jié)合形成復(fù)合體[10-11],并通過(guò)TEM信號(hào)平臺(tái)(蛋白酶、細(xì)胞因子受體、生長(zhǎng)因子受體等),影響細(xì)胞基質(zhì)間或細(xì)胞間的粘附作用或骨架蛋白重建,改變細(xì)胞表型,從而使腫瘤細(xì)胞獲得移動(dòng)、遷徙和浸潤(rùn)能力。
3.1 CO-029與人黑色素瘤在人黑色素瘤細(xì)胞中檢測(cè)到CO-029是唯一過(guò)表達(dá)的侵襲相關(guān)性四跨膜蛋白[12]。TSPAN8基因的表達(dá)可能使黑色素瘤細(xì)胞能穿過(guò)皮膚基底膜,引起真皮侵襲和轉(zhuǎn)移,目前其細(xì)胞生物學(xué)機(jī)制雖尚不明確,但TSPAN8基因可能是一個(gè)黑色素瘤早期診斷和治療的新靶點(diǎn)。
3.2 CO-029與消化系統(tǒng)腫瘤有研究發(fā)現(xiàn)CO-029在食道癌、胃癌、胰腺癌及結(jié)直腸癌等消化系統(tǒng)腫瘤中CO-029與腫瘤的發(fā)生發(fā)展呈正相關(guān),可通過(guò)上調(diào)CO-029的表達(dá)促進(jìn)腫瘤的進(jìn)展[13-14]。相關(guān)報(bào)道有:①在胰腺癌細(xì)胞系中發(fā)現(xiàn)CO-029和α6β4組成復(fù)合體后可激活PKC,降低細(xì)胞對(duì)層粘連蛋白的粘附,使α6β4由粘附表型轉(zhuǎn)為遷移表型,促進(jìn)腫瘤細(xì)胞的轉(zhuǎn)移[11]。最近,德國(guó)的海德爾堡大學(xué)醫(yī)院腫瘤細(xì)胞生物學(xué)系研究人員首次報(bào)道了CO-029可作為免疫缺陷小鼠體內(nèi)胰腺癌啟動(dòng)細(xì)胞(PACIC)長(zhǎng)期生存、侵襲、遷移的生物標(biāo)記[15];②在人大腸癌細(xì)胞中下調(diào)CO-029表達(dá)能顯著抑制細(xì)胞運(yùn)動(dòng),提示CO-029表達(dá)與腫瘤細(xì)胞遷移密切相關(guān)[16]。有進(jìn)一步研究表明下調(diào)結(jié)直腸癌細(xì)胞CO-029表達(dá)可上調(diào)細(xì)胞基質(zhì)間層粘蛋白的整合素依賴粘附性和細(xì)胞間鈣依賴粘附性,其機(jī)制可能是下調(diào)CO-029表達(dá)的細(xì)胞CD44水平下降而細(xì)胞表面的層粘蛋白錨定整合素α3β1和纖連蛋白-整合素α5β1水平升高。由此得出結(jié)論:CO-029通過(guò)降低細(xì)胞粘附性,促進(jìn)結(jié)直腸癌細(xì)胞的轉(zhuǎn)移[17]。
3.3 CO-029與肝癌研究顯示在肝癌組織中CO-029的表達(dá)顯著增高,并且CO-029的表達(dá)越高則肝癌的進(jìn)展越快、預(yù)后越差。①早期研究表明CO-029mRNA水平在癌組織中的水平高出正常組織1.7倍(P=0.030),而CO-029的表達(dá)水平在發(fā)生肝內(nèi)轉(zhuǎn)移癌組織中與未發(fā)生轉(zhuǎn)移癌組織比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.019),表明CO-029可能促進(jìn)肝細(xì)胞肝癌(HCC)的血行性肝內(nèi)轉(zhuǎn)移,但其機(jī)制尚不明確[18-19]。隨后有研究顯示CO-029在肝癌組織中表達(dá)顯著高于及相應(yīng)癌旁組織,在高轉(zhuǎn)移潛能肝癌細(xì)胞系(MHCC97-H與MHCC97-L)的表達(dá)明顯高于低轉(zhuǎn)移潛能的肝癌細(xì)胞(PLC/PRF/5,SMMC7721與HepG2)。同時(shí)應(yīng)用慢病毒干擾發(fā)現(xiàn),在層粘蛋白-5(Laminin-5)刺激下,高轉(zhuǎn)移潛能細(xì)胞MHCC97-H發(fā)生上皮間質(zhì)轉(zhuǎn)變(EMT)過(guò)程(EMT在促腫瘤轉(zhuǎn)移、浸潤(rùn)中具有重要作用,是許多腫瘤侵襲和轉(zhuǎn)移早期的一個(gè)重要的過(guò)程[20]。EMT是指具有極性的上皮細(xì)胞轉(zhuǎn)換成為具有活動(dòng)能力的間質(zhì)細(xì)胞并獲得侵襲和遷移能力的過(guò)程,在哺乳動(dòng)物胚胎與器官發(fā)育、創(chuàng)傷愈合、組織纖維化、腫瘤形成與轉(zhuǎn)移等生理病理過(guò)程中均有表現(xiàn)。EMT以上皮細(xì)胞極性的喪失如E-cadherin、β-catenin等及間質(zhì)特性的獲得如Vimentin、N-cadherin等為重要特征,表現(xiàn)為上皮細(xì)胞獲得成纖維樣細(xì)胞的特征:細(xì)胞間粘附減弱、運(yùn)動(dòng)性增強(qiáng),且細(xì)胞間緊密連接及細(xì)胞極性均被破壞[20-21]),而慢病毒感染MHCC-97H-vshRNA-CO-029細(xì)胞則未見(jiàn)EMT過(guò)程,有進(jìn)一步研究表明其機(jī)制是CO-029能通過(guò)耦聯(lián)整合素α6介導(dǎo)EMT發(fā)生而促進(jìn)肝細(xì)胞癌的侵襲轉(zhuǎn)移[22-23];②最新研究發(fā)現(xiàn)CO-029在肝內(nèi)膽管細(xì)胞癌(ICC)組織中亦存在高表達(dá)現(xiàn)象,但相關(guān)報(bào)道很少。有研究檢測(cè)分析CO-029在肝內(nèi)膽管癌、癌旁組織及肝內(nèi)膽管癌細(xì)胞系HCCC-9810中的表達(dá)水平,結(jié)果顯示CO-029在膽管細(xì)胞癌組織高表達(dá),而在癌旁組織中則低表達(dá),提示CO-029在膽管細(xì)胞癌組織的高表達(dá)與腫瘤復(fù)發(fā)轉(zhuǎn)移密切相關(guān)[24]。然而,ICC起病隱匿,臨床表現(xiàn)缺乏特異性,早期確診困難,術(shù)后復(fù)發(fā)率高,預(yù)后極差,已成為肝內(nèi)原發(fā)腫瘤導(dǎo)致死亡的主要原因之一[25-27]。且絕大多數(shù)肝內(nèi)膽管癌患者死亡與肝內(nèi)外侵襲轉(zhuǎn)移、復(fù)發(fā)相關(guān)[27-28]。但目前相關(guān)報(bào)道甚少,所以,對(duì)CO-029在肝內(nèi)膽管癌侵襲轉(zhuǎn)移的分子機(jī)制的探索蘊(yùn)藏著巨大的臨床應(yīng)用價(jià)值,CO-029可能成為有效的肝內(nèi)膽管癌侵襲轉(zhuǎn)移、復(fù)發(fā)和預(yù)后判斷的指標(biāo)及防治手段和進(jìn)一步提高肝內(nèi)膽管癌治療效果的關(guān)鍵。
腫瘤侵襲轉(zhuǎn)移和復(fù)發(fā)是多因素參與的過(guò)程,包括腫瘤細(xì)胞粘附、遷移和對(duì)細(xì)胞外基質(zhì)的侵襲行為等[25,29-33],而慢性炎癥刺激和腫瘤炎癥微環(huán)境參與了上述各個(gè)環(huán)節(jié),在腫瘤的發(fā)生發(fā)展、侵襲轉(zhuǎn)移過(guò)程中扮演了非常重要的角色[26,31,34]。當(dāng)前,盡管慢性炎癥在癌癥中發(fā)揮作用的潛在機(jī)制仍未完全明了,但慢性炎癥與癌癥發(fā)生與發(fā)展的密切關(guān)系已被廣泛接受,且被稱為“癌癥的第七大特征”[34-37],是腫瘤發(fā)生、發(fā)展機(jī)制研究的熱點(diǎn)之一。越來(lái)越多的臨床和實(shí)驗(yàn)研究表明,炎性腫瘤微環(huán)境在腫瘤發(fā)生,生長(zhǎng)和侵襲轉(zhuǎn)移的各個(gè)環(huán)節(jié)均具有關(guān)鍵作用[34,36,38]。慢性炎性腫瘤微環(huán)境中,腫瘤-炎性微環(huán)境界面之間可以通過(guò)多種炎癥因子調(diào)節(jié)而互相作用,炎性腫瘤微環(huán)境不斷被重塑,以適應(yīng)腫瘤生長(zhǎng)和侵襲轉(zhuǎn)移[39-41]。臨床研究已經(jīng)表明,慢性炎癥刺激產(chǎn)生的炎性細(xì)胞因子TNFα在腫瘤微環(huán)境中的組成性表達(dá)是許多惡性腫瘤的共同特征,其存在通常與預(yù)后不良相關(guān)[41-43]。有研究指出TNFα可以作為連接炎癥和癌癥病理學(xué)的一個(gè)調(diào)控關(guān)聯(lián)子[20,44-48]。且已有研究證實(shí):四跨膜蛋白與整合素以及其下游的信號(hào)分子與TNFα/TNFαR1之間有交互作用[20,46,49-50]。鑒于慢性炎癥微環(huán)境與腫瘤關(guān)系密切、炎性因子TNFα在腫瘤的重要作用[49-50],及CO-029和TNFα均能誘發(fā)腫瘤細(xì)胞EMT過(guò)程[20,22-23],有進(jìn)一步探討CO-029和TNFα在腫瘤中可能存在互相作用關(guān)系的潛在價(jià)值。
CO-029作為四跨膜蛋白超家族中的重要一員,通過(guò)TEM這一重要信號(hào)平臺(tái)與許多不同類型的分子相互作用,從而產(chǎn)生各種分子生物學(xué)效應(yīng)。目前對(duì)其功能研究文獻(xiàn)報(bào)道很少,CO-029可能在腫瘤侵襲轉(zhuǎn)移、預(yù)后預(yù)測(cè)中具有重要的作用和潛在臨床價(jià)值,有待進(jìn)一步研究。今后或許可以通過(guò)CO-029解釋腫瘤侵襲轉(zhuǎn)移的發(fā)生機(jī)制,對(duì)其進(jìn)行檢測(cè),預(yù)測(cè)腫瘤的進(jìn)展及預(yù)后,進(jìn)而開發(fā)新的腫瘤靶向治療藥物,進(jìn)一步提高腫瘤的治療水平。
[1]Hemler ME.Tetraspanin functions and associated microdomains [J].Nat Rev Mol Cell Biol,2005,6(10):801-811.
[2]Szala S,Kasai Y,Steplewski Z,et al.Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens[J].Proc Natl Acad Sci USA, 1990,87(17):6833-6837.
[3]Maecker H,Todd SC,Levy S.The tetraspanins superfamily:molecular facilitates[J].FASEB,1997,11(6):428-442.
[4]Richardson MM,Jennings LK,Zhang XA,et al.Tetraspanins and tumor progression[J].Chin Exp Metastasis,2011,28(3):261-270.
[5]Anez-Mo M,Barreiro O,Gordon-Alonso M,et al.Tet?raspanin-enriched microdomains:a functional unit in cell plasmamembranes [J].Trends Cell Biol,2009,19(9):434-446.
[6]Zoller M.Tetraspanins:push and pull in suppressing and promoting metastasis[J].Nat Rev Cancer,2009,9(1):40-55.
[7]Hemler ME.Specific tetraspanin functions[J].J Cell Biol,2001, 155(7):1103-1107.
[8]Janes SM,Watt FM.New roles for integrins in squamous-cell carcinoma[J].Nat Rev Cancer,2006,6(3):175-183.
[9]Gesierich S,Berezovskiy I,Ryschich E,et al.Systemic induction of the angiogenesis switch by the tetraspanin D 6.1A/CO-029[J].Cancer Res,2006,66(14):7083-7094.
[10]Le Naour F,André M,Greco C,et al.Profiling of the tetraspanin web of human colon cancer cells[J].Molecular&Cellular Proteomics,2006,5(5):845-857.
[11]Herlevsen M,Schmidt DS,Miyazaki K,et al.The association of the tetraspanin D6.1A with the α6β4 integrin supports cell motility and liver metastasis formation[J].J Cell Sci,2006,116(Pt 21):4373-4390.
[12]Berthier-vergnes O,Kharbili ME,de la Fouchardière A,et al.Gene expression profiles of human melanoma cells with different invasive potential reveal TSPAN8 as a novel mediator of invasion[J]. Br J Cancer,2011,104(1):155-165.
[13]Le Naour F,Andre M,Greco C,et al.Profiling of the tetraspanin web of human colon cancer cells[J].Mol Cell Proteomics,2006,5 (5):845-857.
[14]Zhou Z,Ran YL,Hu H,et al.TM 4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression[J].Clin Exp Metastasis,2008,25(5):537-548.
[15]Wang H,Rana S,Giese N,et al.Tspan8,CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer-initiating cells[J].Int Cancer,2013,133(2):416-426.
[16]Greco C,Bralet MP,Ailane N,et al.E-cadherin/p120-catenin andtetraspanin CO-029 cooperate for cell motility control in human colon carcinoma[J].Cancer Res,2010,170(19):7674-7683.
[17]Wang H,Rana S,Giese N,et al.Tspan8,CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer-initiating cells[J].Int Cancer,2013,133(2):416-26.
[18]Kanetaka K,Sakamoto M,Yamamoto Y,et al.Overexpression of tetraspanin CO-029 in hepatocellular carcinoma[J].Hepatol,2002, 35(5):637-642.
[19]Kanetaka K,Sakamoto M,Yamamoto Y,et al.Possible involvement of tetraspanin CO-029 in hematogenous intrahepatic metastasis of liver cancer cells[J].J Gastroenterol Hepatol,2003 Nov,18(11): 1309-1314.
[20]Wu Y,Deng J,Rychahou PG,et al.Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion[J].Cancer Cell,2009,15(5):416-428.
[21]Zeisberg M,Neilson EG.Biomarkers for epithelial-mesenchymal transitions[J].J Clin Invest,2009,119(6):1429-1437.
[22]Jin-Cai Wu,Zhuo-Ri Li,Kai-Lun Zhou,et al.Overexpression of tetraspanin CO-029 induced epithelial-mesenchymal transition and its prognostic value in hepatocellular carcinoma[J].PLoS One,2014,9 (3):e90528.
[23]武金才,李灼日,周開倫,等.shRNA下調(diào)CO-029基因?qū)Ω伟┘?xì)胞侵襲與轉(zhuǎn)移的影響[J].中華肝膽外科雜志,2012,18(2): 126-129.
[24]Patsenker E,Wilkens L,Banz V,et al.The alphavbeta6 integrin is a highly specific immunohistochemical marker for cholangiocarcinoma[J].J Hepatol,2010,52(3):362-369.
[25]Blendis L,Halpern Z.An increasing incidence of cholangiocarcinoma:why?[J].Gastroenterology,2004,127(3):1008-1009.
[26]Patel T.Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States[J].Hepatology,2001,33 (6):1353-1357.
[27]Olnes MJ,Erlich R.A review and update on cholangiocarcinoma [J].Oncology,2004,66(3):167-179.
[28]Li SQ,Liang LJ,Hua YP,et al.Long-term outcome and prognostic factors of intrahepatic cholangiocarcinoma[J].Chin Med J(Engl), 2009,122(19):2286-2291.
[29]Gores GJ.Cholangiocarcinoma:current concepts and insights[J]. Hepatology,2003,37(5):961-969.
[30]Ustundag Y,Bayraktar Y.Cholangiocarcinoma:a compact review of the literature[J].World J Gastroenterol,2008,14(42):6458-6466.
[31]Meng F,Han Y,Staloch D,et al.The H4 histamine receptor agonist, clobenpropit,suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis [J].Hepatology,2011,54(5):1718-1728.
[32]Li ZR,Wu YF,Ma CY,et al.Down-regulation of c-Myc expression inhibits the invasion of bile duct carcinoma cells[J].Cell Biol Int, 2011,35(8):799-802.
[33]李振振,李灼日,廖春紅,等.黏蛋白1靶向小干擾RNA對(duì)膽管癌細(xì)胞侵襲力的影響[J].中華實(shí)驗(yàn)外科雜志,2010,27(11): 1654-1657。
[34]Mantovani A.Cancer:Inflaming metastasis[J].Nature,2009,457 (7225):36-37.
[35]Balkwill F,Mantovani A.Inflammation and cancer:back to Virchow?[J].Lancet,2001,357(9255):539-545.
[36]Hagemann T,Balkwill F,Lawrence T.Inflammation and cancer:a double-edged sword[J].Cancer Cell,2007,12(4):300-301.
[37]Hoffmann A,Xia Y,Verma IM.Inflammatory tales of liver cancer [J].Cancer Cell,2007,11(2):99-101.
[38]Balkwill FR,Mantovani A.Cancer-related inflammation:common themes and therapeutic opportunities[J].Semin Cancer Biol,2012, 22(1):33-40.
[39]Friedl P,Alexander S.Cancer invasion and the microenvironment: plasticity and reciprocity[J].Cell,2011,147(5):992-1009.
[40]Valastyan S,Weinberg RA.Tumor Metastasis:Molecular Insights and EvolvingParadigms[J].Cell,2011,147(2):275-292.
[41]Grivennikov SI,Greten FR,Karin M.Immunity,inflammation,and cancer[J].Cell,2010,140(6):883-899.
[42]Chechlinska M,Kowalewska M,Nowak R.Systemic inflammation as a confounding factor in cancer biomarker discovery and validation[J].Nat Rev Cancer,2010,10(1):2-3.
[43]Karin M,Lawrence T,Nizet V.Innate immunity gone awry:linking microbial infections to chronic inflammation and cancer[J].Cell, 2006,124(4):823-835.
[44]Pham CG,Bubici C,Zazzeroni F,et al.Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species[J].Cell,2004,119(4):529-542.
[45]Greten FR,Eckmann L,Greten TF,et al.IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer[J].Cell,2004,118(3):285-296.
[46]Charles KA,Kulbe H,Soper R,et al.The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans[J].J Clin Invest,2009,119(10):3011-3023.
[47]Hou CH,Yang RS,Hou SM,et al.TNF-α increases αvβ3 integrin expression and migration in human chondrosarcoma cells[J].J Cell Physiol,2011,226(3):792-799.
[48]Kurihara Y,Nakahara T,Furue M.αVβ3-integrin expression through ERK activation mediates cell attachment and is necessary for production of tumor necrosis factor alpha in monocytic THP-1 cells stimulated by phorbolmyristateacetate[J].CellImmunol,2011,270(1):25-31.
[49]Komori J,Marusawa H,Machimoto T,et al.Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma[J].Hepatology,2008,47(3):888-896.
[50]Jaiswal M,LaRusso NF,Burgart LJ,et al.Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism[J].Cancer Res,2000, 60(1):184-190.
Role of tetraspanin CO-029 in invasion and metastasis of carcinoma.
ZHAO Ming1,2,LI Zhuo-ri2,WU Jin-cai2.1. Nanhua University,Hengyang 421000,Hunan,CHINA;2.Department of Liver and Gallbladder Surgery,People's Hospital of Hainan Province,Haikou 570311,Hainan,CHINA
CO-029 belongs to the tetraspanins family,and has been revealed to play an important role in invasion and metastasis of carcinoma.However,how CO-029 promotes cancer invasion and metastasis is still poorly understood.Its explicit mechanisms in the development of tumor probably indicates that CO-029 has great potential clinical value in predicting the progression and the prognosis of cancer,and may be a potent molecular therapeutic target for cancer.
CO-029;Tetraspanin;Invasion;Metastasis
R73-37
A
1003—6350(2014)21—3191—04
10.3969/j.issn.1003-6350.2014.21.1251
2014-05-14)
李灼日。E-mail:LZR59@hotmail.com