L1細(xì)胞黏附分子在胰腺癌侵襲轉(zhuǎn)移作用機(jī)制的研究進(jìn)展*

王奕智 綜述 葛春林 審校

·綜 述·

L1細(xì)胞黏附分子在胰腺癌侵襲轉(zhuǎn)移作用機(jī)制的研究進(jìn)展*

王奕智 綜述 葛春林 審校

胰腺癌是當(dāng)今世界上死亡率最高的腫瘤之一。以其早期癥狀不明顯、診斷手段缺乏、腫瘤標(biāo)志物不特異、容易發(fā)生早期淋巴結(jié)轉(zhuǎn)移以及晚期難以手術(shù)治愈而被稱為“癌中之王”。由于胰腺癌手術(shù)治療晚期癌癥療效不佳及對放化療方案的耐藥性，目前對于胰腺癌靶向治療的研究越來越多。L1細(xì)胞黏附分子（L1CAM）是細(xì)胞黏附分子免疫球蛋白超家族中的一員，通常表達(dá)于正常的神經(jīng)組織中。近年來的研究表明，L1CAM在胰腺癌細(xì)胞中表達(dá)異常增多，并且可以與α5-integrin結(jié)合，作用于下游TGF-β1/ JUK/slug通路，激活下游腫瘤侵襲轉(zhuǎn)移相關(guān)因子，介導(dǎo)腫瘤細(xì)胞的上皮間質(zhì)轉(zhuǎn)化（epithelial-mesenchymal tromsition，EMT）、耐藥性以及異常血管生成等方面的效應(yīng)，從而促進(jìn)胰腺癌細(xì)胞的侵襲轉(zhuǎn)移。因此，深入的研究和實驗或許可以促進(jìn)胰腺癌未來的治療發(fā)展，為胰腺癌提供一個新的治療手段。

胰腺癌 L1細(xì)胞黏附分子 侵襲 轉(zhuǎn)移

胰腺癌是世界上十大最常見的惡性腫瘤之一，患者平均生存率不足6個月，確診后的5年生存率＜5%［1］。在我國，胰腺癌業(yè)已成為第六大致死性腫瘤。由于胰腺癌早期癥狀缺乏，易發(fā)生侵襲轉(zhuǎn)移，晚期能夠產(chǎn)生耐藥性，故總體治愈率不高［1-2］。L1細(xì)胞黏附分子（L1CAM或CD171）是細(xì)胞黏附分子免疫球蛋白超家族中的一員，通常表達(dá)于正常的神經(jīng)組織中，并在神經(jīng)系統(tǒng)的發(fā)育中起重要作用。最近有研究發(fā)現(xiàn)，L1CAM具有多種生物活性，并且在已知的多種病變組織中也有一定的表達(dá)。例如在多種腫瘤細(xì)胞中［3-6］，L1CAM呈現(xiàn)不同程度的異常表達(dá)，其中包括人類腦膠質(zhì)瘤、非小細(xì)胞肺癌、卵巢癌及結(jié)直腸癌。L1CAM在腫瘤組織與胰腺癌細(xì)胞系中的表達(dá)與腫瘤預(yù)后不良密切相關(guān)［7-8］。聯(lián)合應(yīng)用L1CAM抗體和吉西他濱或紫杉醇相較單獨應(yīng)用細(xì)胞毒性化療藥物，能更加有效地延緩嚴(yán)重聯(lián)合免疫缺陷小鼠模型皮下Colo357胰腺癌細(xì)胞系的生長速度［9］，由此證明L1CAM在胰腺癌發(fā)生中的重要作用。本文就近年來關(guān)于L1CAM在胰腺癌侵襲轉(zhuǎn)移中作用機(jī)制的研究做一綜述，希望能夠闡明L1CAM在胰腺癌治療中的重要作用，為胰腺癌的治療增加一個新的靶點。

1 L1CAM的結(jié)構(gòu)和生物學(xué)功能

L1CAM屬于免疫球蛋白超家族中的一員，是長度為200～220 kDa的跨膜糖蛋白。其中包含6個球蛋白樣區(qū)域和5個Ⅲ型纖連蛋白重復(fù)區(qū)，之后連接一個跨膜區(qū)和一個高度保守的胞質(zhì)尾區(qū)［10］。除了上述的這種全長型L1CAM，另外一種剪接變異型L1CAM則缺乏2號外顯子，存在27號外顯子。雖然在非神經(jīng)組織中，后一種類型表達(dá)居多，但在腫瘤的發(fā)生發(fā)展中，全長型L1CAM的表達(dá)才真正起到關(guān)鍵作用［11］。全長型L1CAM的Ig6區(qū)上，存在Arg-Gly-Asp（RGD）蛋白序列區(qū)支持L1CAM與整合素相互結(jié)合發(fā)揮生物學(xué)作用［12］。同時有報道稱，在L1胞外區(qū)上存在構(gòu)象變化區(qū)域能夠直接與Ⅲ型纖連蛋白的第三區(qū)相互作用調(diào)節(jié)受體多聚化和整合素募集。胞外區(qū)另外一個特點是同質(zhì)性結(jié)合位點以及成纖維細(xì)胞生長因子受體（FGFR）同源區(qū)［13］。L1CAM的跨膜編碼區(qū)位于25號外顯子上，羰基端胞內(nèi)區(qū)由26、27、28號外顯子編碼［14］。除同質(zhì)性結(jié)合之外，L1CAM還可以異質(zhì)性結(jié)合許多其他類型的蛋白分子，包括L1CAM家族的其他成員、背中線球蛋白相關(guān)軸突表面蛋白、神經(jīng)蛋白聚糖、層纖連蛋白以及多種整合素［15］，這些異質(zhì)性結(jié)合可以促進(jìn)神經(jīng)外生。

L1CAM最初被認(rèn)為在神經(jīng)組織的發(fā)育和再生中起作用［16］，而且能夠促進(jìn)神經(jīng)的外生、集束、突觸形成以及神經(jīng)細(xì)胞在發(fā)育神經(jīng)及成人大腦中的存活［17］，因此編碼L1CAM的基因變異往往會導(dǎo)致許多疾病的發(fā)生，如胼胝體發(fā)育不全、神經(jīng)發(fā)育遲緩、痙攣性截癱、拇指內(nèi)收、強(qiáng)直狀態(tài)以及腦積水（CRASH綜合征）［18］。除了表達(dá)在正常與異常的神經(jīng)組織當(dāng)中，L1CAM近來也越來越多地被發(fā)現(xiàn)表達(dá)于諸多癌細(xì)胞系與腫瘤組織當(dāng)中［19］，而高水平L1CAM的表達(dá)往往意味著患者預(yù)后不良，生存時間較短。

近年來大量研究發(fā)現(xiàn)，L1CAM不僅在正常神經(jīng)系統(tǒng)中起作用，同時也能夠促進(jìn)腫瘤的發(fā)生發(fā)展。過表達(dá)的L1CAM已經(jīng)被證明可以促進(jìn)腫瘤的增殖［20］。另外，有研究還表明抑制L1CAM的表達(dá)可以減緩膽管癌［21］及卵巢癌［22］的增殖。有研究利用延時及流式細(xì)胞周期分析法，證明L1CAM能夠通過纖維母細(xì)胞生長因子受體（FGFR），增加膠質(zhì)瘤細(xì)胞的移動及增殖能力。L1CAM同時在腫瘤的侵襲與轉(zhuǎn)移中發(fā)揮作用。在腫瘤的轉(zhuǎn)移灶以及原發(fā)腫瘤的侵襲部位，都發(fā)現(xiàn)了高表達(dá)水平的L1CAM［23-24］。而在腫瘤的上皮間質(zhì)轉(zhuǎn)化（EMT）中，L1CAM也起到重要的作用。在對子宮內(nèi)膜癌的研究中發(fā)現(xiàn)，L1CAM表達(dá)于腫瘤的侵襲部位，而E-鈣黏蛋白表達(dá)缺失，這成為L1CAM可以促進(jìn)腫瘤EMT發(fā)生的一個重要證據(jù)［25-26］。

2 L1CAM在胰腺癌侵襲轉(zhuǎn)移中的作用

隨著L1CAM在腫瘤細(xì)胞中的異常表達(dá)被逐漸證實，L1CAM在胰腺癌中的作用也越發(fā)重要。在一項針對107例手術(shù)切除的PDAC組織進(jìn)行免疫組織化學(xué)的實驗中發(fā)現(xiàn)，107例PDAC組織標(biāo)本中，23例組織L1CAM免疫組織化學(xué)陽性，而其中大多數(shù)（21例）顯示L1CAM主要表達(dá)在胰腺癌組織向外侵襲的部分。并且證明L1CAM的陽性率與胰腺癌的組織分期，淋巴結(jié)轉(zhuǎn)移及遠(yuǎn)處轉(zhuǎn)移關(guān)系密切。在一項多變量分析中，L1CAM的陽性表達(dá)與患者生存率縮短相一致（P=0.000 2），并在多變量分析中意義顯著（P= 0.009）［27］。在一項囊括123例胰腺癌前病變、原發(fā)胰腺導(dǎo)管腺癌（PDAC）以及胰腺癌肝轉(zhuǎn)移組織的大樣本隊列試驗中，原發(fā)PDAC中L1CAM免疫組織化學(xué)陽性率達(dá)92.7%，淋巴結(jié)轉(zhuǎn)移達(dá)80.0%，肝轉(zhuǎn)移率100%［28］。另外，Ben等［29］研究發(fā)現(xiàn)，L1CAM陽性表達(dá)與胰腺癌淋巴結(jié)轉(zhuǎn)移（P=0.007）、血行播散（P=0.012）以及周圍神經(jīng)轉(zhuǎn)移（P=0.001）有關(guān)。研究表明，L1CAM在胰腺癌中主要通過以下幾種途徑促進(jìn)癌細(xì)胞的侵襲轉(zhuǎn)移。

2.1 1L1CAM與EMT

腫瘤的發(fā)生發(fā)展與EMT密不可分。EMT分為3種類型，其中Ⅲ型EMT與腫瘤的轉(zhuǎn)移擴(kuò)散存在密切關(guān)系，而轉(zhuǎn)化生長因子-β（TGF-β）信號通路被認(rèn)為在EMT中扮演重要角色［30］。Geismann等［31］研究表明，正常胰腺導(dǎo)管細(xì)胞系H6c7與間質(zhì)胰腺成肌纖維細(xì)胞（PMF）共培養(yǎng)時發(fā)現(xiàn)，PMF分泌的TGF-β1可刺激L1CAM的表達(dá)，從而使正常的H6c7細(xì)胞系獲得轉(zhuǎn)移增強(qiáng)的表現(xiàn)型，另外在自分泌TGF-β1的胰腺癌細(xì)胞系Colo357和Panc-1的實驗中同樣證明了這一點。但TGF-β1下游通路卻并不通過經(jīng)典的smad 2/ 3，而是通過JUK/slug通路介導(dǎo)L1CAM的產(chǎn)生。Western blot檢測表明，共培養(yǎng)細(xì)胞H6c7co失去了E-鈣黏蛋白而表達(dá)大量波形蛋白，這正是細(xì)胞EMT增強(qiáng)的表現(xiàn)。在動物實驗中，種植正常H6c7細(xì)胞系后，6只小鼠僅有2只表現(xiàn)微小病變；種植H6c7co的8只小鼠中7只出現(xiàn)胰腺腫瘤的生長，且通過抗體抑制L1CAM表達(dá)能夠顯著減少細(xì)胞生長和轉(zhuǎn)移［32］。為了證明slug是與L1CAM基因直接相互作用來激活L1CAM的表達(dá)，利用生物工程學(xué)預(yù)測出slug與L1CAM啟動子上可能的結(jié)合位點，之后利用siRNA干擾上述預(yù)測位點1241和433確實可使L1CAM的表達(dá)減少，由此說明slug可通過結(jié)合L1CAM啟動子直接誘導(dǎo)L1CAM的生成［33］。后續(xù)的研究表明，TGF-β1不僅可以通過JUK/slug通路介導(dǎo)EMT，同時還可以通過促進(jìn)胰腺癌細(xì)胞IL-1β和NF-kB的激活起到同樣效果。在實驗中，阻斷L1CAM表達(dá)能夠減少TGF-β1介導(dǎo)的IL-1β分泌以及NF-kB的激活，而通過小白菊內(nèi)酯抑制NF-kB的活性同樣可以抑制癌細(xì)胞的侵襲和轉(zhuǎn)移，說明NF-kB在腫瘤轉(zhuǎn)移侵襲中也扮演著重要角色［34］。另有國內(nèi)的研究表明，運用構(gòu)建質(zhì)粒轉(zhuǎn)導(dǎo)痘病毒技術(shù)及Western blot、PCR等技術(shù)證明L1CAM不通過TGF-β1途徑，而是p38/ERK1/2信號通路調(diào)節(jié)癌細(xì)胞侵襲轉(zhuǎn)移［35］。

2.2 L1CAM與血管異常生成

胰腺癌的侵襲轉(zhuǎn)移離不開腫瘤內(nèi)新生血管的生成，而血管生成主要由眾多生長因子及相關(guān)受體酪氨酸激酶所調(diào)控［36］，其中最重要的調(diào)控成血管細(xì)胞分化和血管生成的因子當(dāng)屬VEGF蛋白家族以及其受體。在VEGF亞型中，VEGF-A明顯增加胰腺癌細(xì)胞的運動性，在誘導(dǎo)胰腺癌細(xì)胞的遷徙和轉(zhuǎn)移方面起重要作用，VEGF-A陽性的患者預(yù)后比較差［37］。另外，許多蛋白分子可作用于PI3K/AKT、Notch3、MET/ VEGF-B、IL-6/STAT3以及Src/STAT3信號通路，對VEGF產(chǎn)生作用，從而影響胰腺癌中的血管生成［38-42］。Magrini等［43］在小鼠實驗中證明，L1CAM在小鼠胰腺癌異常血管生成中發(fā)揮作用，使用L1CAM抗體能夠減少血管生成，減緩腫瘤的生長和轉(zhuǎn)移。該研究也驗證了L1CAM通過IL-6/JAK/STAT信號通路影響血管生成的機(jī)制。

2.3 L1CAM與耐藥性

L1CAM在胰腺癌細(xì)胞中表達(dá)增加能夠提高腫瘤細(xì)胞的耐藥性，促進(jìn)細(xì)胞的增殖。研究表明，NO在腫瘤細(xì)胞的耐藥性中起重要作用。在比較對化療敏感的胰腺癌細(xì)胞系PT45-P1與依托泊苷誘導(dǎo)的耐藥PT45-P1res細(xì)胞系時發(fā)現(xiàn)，后者L1CAM的表達(dá)水平顯著升高，并且具有IL-1β依賴性。而且，敲除L1CAM或轉(zhuǎn)染載有L1CAM的基因后，可增加或降低NO誘導(dǎo)的caspase-3/caspase-7凋亡活性［44］。在上述過程中，L1CAM與α5-integrin的結(jié)合在胰腺癌細(xì)胞的耐藥性中起到重要作用。阻斷或敲除α5-integrin可降低耐藥細(xì)胞系PT45-P1res的耐藥性，而對照組利用siRNA阻斷L1CAM上與α5-integrin結(jié)合位點也可以達(dá)到相同效果［45］。L1CAM結(jié)合α5-integrin后，激活α5-integrin下游的PI3K/ILK通路作用于下游的NF-kB，而NF-kB激活又可以刺激下游細(xì)胞因子IL-6、IL-8、IL-13以及NOS生成，從而作用于NO，誘導(dǎo)細(xì)胞耐藥性［46］。而在上文中提及，NF-kB同時也能夠介導(dǎo)胰腺癌的侵襲與轉(zhuǎn)移。因此，NF-kB同時在胰腺癌耐藥性與侵襲轉(zhuǎn)移中起到重要作用。FOL?FIRI-NOX方案（奧沙利鉑、伊立替康、亞葉酸鹽、5-FU）以及納米白蛋白紫杉醇聯(lián)合吉西他濱被認(rèn)為是當(dāng)前治療轉(zhuǎn)移性胰腺癌的一線治療方案，雖然其大大延長了晚期胰腺癌患者的生存率，但由于胰腺癌細(xì)胞的耐藥性，其總體治療效果并不樂觀。有報道稱，胰腺癌細(xì)胞對5-FU化療敏感性通常與胸苷合成酶（TS）水平呈負(fù)相關(guān)，高水平TS往往表示腫瘤預(yù)后不良。在實驗中，5-FU處理獲得的化療抗性Panc-1細(xì)胞系高表達(dá)TS以及生存素，后者于G2/M期表達(dá)抑制化療藥物產(chǎn)生的細(xì)胞壞死作用。深入研究證明，依賴slug而非β-連環(huán)蛋白作用的L1CAM水平升高在5-FU耐藥性胰腺癌細(xì)胞的侵襲和轉(zhuǎn)移中起到重要作用，敲除slug基因表達(dá)能夠降低L1CAM水平［17］。

除上述3種機(jī)制外，L1CAM通過誘導(dǎo)胰腺癌細(xì)胞周圍免疫耐受細(xì)胞T-reg（主要是CD4+CD25-CD69+T-reg細(xì)胞）的富集產(chǎn)生免疫逃逸從而使癌細(xì)胞避免免疫細(xì)胞的殺傷，延長癌細(xì)胞的生存率，促進(jìn)侵襲轉(zhuǎn)移［47］。

3 總結(jié)與展望

L1CAM作為一種在正常神經(jīng)組織發(fā)育過程中的重要因子，在胰腺癌組織、胰腺癌前病變以及轉(zhuǎn)移癌組織中表達(dá)水平升高，因而成為判斷患者預(yù)后程度的重要指標(biāo)。L1CAM可以通過TGF-β1等途徑在胰腺癌的侵襲轉(zhuǎn)移中起作用，同時也在胰腺癌的異常血管生成方面起重要作用，并且在化療藥物的使用方面，L1CAM表達(dá)水平增高也可導(dǎo)致胰腺癌的化療抗性增加。雖然L1CAM在胰腺癌細(xì)胞轉(zhuǎn)移和EMT方面研究頗多，但迄今為止，使用人胰腺癌組織及人胰腺癌細(xì)胞系證明L1CAM在胰腺癌腫瘤新生血管方面作用的研究卻非常少見。L1CAM誘導(dǎo)癌細(xì)胞免疫耐受的研究也乏善可陳。希望通過大量的研究得以證明L1CAM在胰腺癌發(fā)生發(fā)展中的作用，為更好地進(jìn)行胰腺癌相關(guān)治療診斷提供幫助，同時為今后胰腺癌的化療提供更多的選擇。

[1]Siegel RL,Miller KD,Jemal A.Cancer statistics[J].CA Cancer J Clin, 2017,67(1):7-30.

[2]Chrystoja CC,Diamandis EP,Brand R,et al.Pancreatic cancer[J]. Clin Chem,2013,59(1):41-46.

[3]Kajiwara Y,Ueno H,Hashiguchi Y,et al.Expression of L1 cell adhesion molecule and morphologic features at the invasive front of colorectal cancer[J].Am J Clin Pathol,2011,136(1):138-144.

[4]Sch?fer H,Dieckmann C,Korniienko O,et al.Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma[J].Cancer Lett,2012,319 (1):66-82.

[5]Bao S,Wu Q,Li Z,et al.Targeting cancer stem cells through L1CAM suppresses glioma growth[J].Cancer Res,2008,68(15):6043-6048.

[6]Hai J,Zhu CQ,Bandarchi B,et al.L1 cell adhesion molecule promotestumorigenicity and metastatic potential in non-small cell lung cancer [J].Clin Cancer Res,2012,18(7):1914-1924.

[7]Li S,Jo YS,Lee JH,et al.L1 cell adhesion molecule is a novel independent poor prognostic factor of extrahepatic cholangiocarcinoma[J].Clin Cancer Res,2009,15(23):7345-7351.

[8]Ben QW,Wang JC,Liu J,et al.Positive expression of L1CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma[J].Ann Surg Oncol,2010,17(8):2213-2221.

[9]Schafer H,Dieckmann C,Korniienko O,et al.Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma[J].Cancer Lett, 2012,319(1):66-82.

[10]Hortsch M.The L1 family of neural cell adhesion molecules:old proteins performing new tricks[J].Neuron,1996,17(4):587-593.

[11]Hauser S,Bickel L,Weinspach D,et al.Full-length L1CAM and not its Delta2Delta27 splice variant promotes metastasis through induction of gelatinase expression[J].PLoS One,2011,6(4):e18989.

[12]Thelen K,Kedar V,Panicker AK,et al.The neural cell adhesion molecule L1 potentiates integrin-dependent cell migration to extracellular matrix proteins[J].J Neurosci,2002,22(12):4918-4931.

[13]Weidle UH,Eggle D,Klostermann S.L1-CAM as a target for treatment of cancer with monoclonal antibodies[J].Anticancer Res, 2009,29(12):4919-4931.

[14]Silletti S,Mei F,Sheppard D,et al.Plasmin-sensitive dibasic sequences in the third fibronectin-like domain of L1-cell adhesion molecule(CAM)facilitate homomultimerization and concomitant integrin recruitment[J].J Cell Biol,2000,149(7):1485-1502.

[15]Gavert N,Ben-Shmuel A,Raveh S,et al.L1-CAM in cancerous tissues [J].Expert Opin Biol Ther,2008,8(11):1749-1757.

[16]Lund,K,Dembinski JL,Solberq N,et al.Slug-dependent upregulation of L1CAM is responsible for the increased invasion potential of pancreatic cancer cells following long-term 5-FU treatment[J].PLoS One, 2015,10(4):e0123684.

[17]Trinh-Trang-Tan MM,Bigot S,Picot J,et al.AlphaIIspectrin participates in the surface expression of cell adhesion molecule L1 and neurite outgrowth[J].Exp Cell Res,2014,322(2):365-380.

[18]Mu?oz A,Cabrera-López JC,Santana-Rodríguez A,et al.X-linked hereditary spastic paraplegia due to mutation in the L1CAM gene: three cases reports of CRASH syndrome[J].Rev Neurol,2016,62(5): 218-222.

[19]Raveh S,Gavert N,Ben-Ze'ev A.L1 cell adhesion molecule(L1CAM) in invasive tumors[J].Cancer Lett,2009,282(2):137-145.

[20]Tsutsumi S,Morohashi S,Kudo Y,et al.L1 Cell adhesion molecule (L1CAM)expression at the cancer invasive front is anovel prognostic marker of pancreatic ductal adenocarcinoma[J].2011,103(7):669-673.

[21]Raveh S,Gavert N,Ben-Ze'ev A.L1 cell adhesion molecule(L1CAM) in invasive tumors[J].Cancer Lett,2009,282(2):137-145.

[22]Min JK,Kim JM,Li S,et al.L1 cell adhesion molecule is a novel therapeutic target in intrahepatic cholangiocarcinoma[J].Clin Cancer Res,2010,16(14):3571-3580.

[23]Bergmann F,Wandschneider F,Sipos B,et al.Elevated L1CAM expression in precursor lesions and primary and metastastic tissues of pancreatic ductal adenocarcinoma[J].Oncol Rep,2010,24(4):909-915.

[24]Chen MM,Lee CY,Leland HA,et al.Inside-out regulation of L1 conformation,integrin binding,proteolysis,and concomitant cell migration[J].Mol Biol Cell,2010,21(10):1671-1685.

[25]Siesser PF,Maness PF.L1 cell adhesion molecules as regulators of tumor cell invasiveness[J].Cell Adh Migr,2009,3(3):275-277.

[26]Huszar M,Moldenhauer G,Gschwend V,et al.Expression profile analysis in multiple human tumors identifies L1(CD171)as a molecular marker for differential diagnosis and targeted therapy[J].Hum Pathol,2006,37(8):1000-1008.

[27]Huszar M,Pfeifer M,Schirmer U,et al.Up-regulation of L1CAMis linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas[J].J Pathol,2010,220(5):551-561.

[28]Berqmann F,Wandschneider F,Sipos B,et al.Elevated L1CAM expression in precursor lesions and primary and metastastic tissues of pancreatic ductal adenocarcinoma[J].Oncol Rep,2010,24(4): 909-915.

[29]Ben QW,Wang JC,Liu J,et al.Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma[J].Ann Surg Oncol 2010,17(8):2213-2221.

[30]Banyard J,Bielenberg DR.The role of EMT and MET in cancer dissemination[J].Connect Tissue Res,2015,56(5):403-413.

[31]Geismann C,Morscheck M,koch D,et al.Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1-and slug-dependent:role in malignant transformation of pancreatic cancer[J].Cancer Res,2009,69(10):4517-4526.

[32]Sch?fer H,Geismann C,Heneweer C,et al.Myofibroblast-induced tumorigenicity of pancreatic ductal epithelial cells is L1CAM dependent[J].Carcinogenesis,2012,33(1):84-93.

[33]Geismann C,Arlt A,Bauer I,et al.Binding of the transcription factor Slug to the L1CAM promoter is essential for transforming growth factor-β1(TGF-β)-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells[J].Int J Oncol,2011,38(1):257-266.

[34]Kiefel H,Bondong S,Pfeifer M,et al.EMT-associated up-regulation of L1CAM provides insights into L1CAM-mediated integrin signalling and NF-kappaB activation[J].Carcinogenesis,2012,33(10):1919-1929.

[35]Ben Q,An W,Fei J,et al.Downregulation of L1CAM inhibits proliferation,invasion and arrests cell cycle progression in pancreatic cancer cells in vitro[J].Exp Ther Med,2014,7(4):785-790.

[36]TAKAHASHI H,SHIBUYA M.The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions[J].Clin Sci(Lond),2005,109(3):227-241.

[37]Doi Y,Yashiro M,Yamada N,et al.VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells[J].Ann Surg Oncol,2012,19(8):2733-2743.

[38]Sun Y,Wu C,Ma J,et al.Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling[J].Exp Cell Res,2016, 347(2):274-282.

[39]Tang J,Zhu Y,Xie K,et al.The role of the AMOP domain in MUC4/Y-promoted tumour angiogenesis and metastasis in pancreatic cancer[J].J Exp Clin Cancer Res,2016,35(1):91.

[40]Zhu M,Zhang Q,Wang X,et al.Metformin potentiates anti-tumor effect of resveratrol on pancreatic cancer by down-regulation of VEGFB signaling pathway[J].Oncotarget,2016,7(51):84190-84200.

[41]Hu B,Zhang K,Li S,et al.HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic cancer[J].Cancer Lett,2016,376(2):387-398.

[42]Liu X,Guo X,Li H,et al.Src/STAT3 signaling pathways are involved inKAI1-induced downregulation of VEGF-C expression in pancreatic cancer[J].Mol Med Rep,2016,13(6):4774-4778.

[43]Magrini E,Villa A,Anqiolini F,et al.Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization[J].J Clin Invest,2014,124(10):4335-4350.

[44]Sebens Muerkoster S,Werbing V,Sipos B,et al.Drug-induced expression of the cellular adhesion molecule L1CAM confers antiapoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells[J].Oncogene,2007,26(19):2759-2768.

[45]Sebens Müerk?ster S,Kotteritzsch J,Geismann C,et al.α5-integrin is crucial for L1CAM-mediated chemoresistance in pancreatic adenocarcinoma[J].Int J Oncol,2009,34(1):243-253.

[46]Kiefel H,Bondong S,Erbe-Hoffmann N,et al.L1CAM-integrin interaction induces constitutive NF-kappaB activation in pancreatic adenocarcinoma cells by enhancing IL-1beta expression[J].Oncogene, 2010,29(34):4766-4778.

[47]Grage-GriebenowE,Jerg E,Gorys A,et al.L1CAMpromotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression[J].Mol Oncol,2014,8(5):982-997.

（2016-11-10收稿）

（2017-03-16修回）

（編輯：周曉穎 校對：孫喜佳）

Advances in the mechanism of action of L1CAM in pancreatic cancer invasion and metastasis

Yizhi WANG,Chunlin GE

Chunlin GE;E-mail:gechunlin@139.com
Department of Pancreatic and Biliary Surgery,1st Hospital of China Medical University,Shenyang 110001,China

Pancreatic cancer has the highest mortality among malignant cancers.Known as"the king of ca ncer,"it lacks early symptoms,diagnostic methods and oncologic markers.Early lymph node metastasis could be found in this disease.Moreover,advanced panereatic cancer is incurable by surgery.Due to the limited efficacy of surgery,as well as radiotherapy and chemotherapy tolerance, therapeutic methods for pancreatic cancer are being explored.L1 cell adhesion molecule(L1CAM)is a member of the cell adhesion molecule inmunoglobulin(Ig)super family that is usually expressed in normal developing nervous tissues.L1CAM is highly expressed in pancreatic cancer cells,binds with α5-integrin to activate downstream factors that mediate tumor metastasis and invasion via the TGF-β1/JUK/slug signaling pathway,induces epithelium-mesenchymal transition,and resists chemotherapy drugs.However,L1CAM forms abnormal vessels that increase the invasiveness of pancreatic cancer cells.This abnormal L1CAM expression in pancreatic cancer cells is a new therapeutic target in pancreatic cancer treatment.Therefore,future studies on L1CAM could promote the development of pancreatic cancer therapy and provide new treatment methods.

pancreatic cancer,L1CAM,invasion,metastasis

10.3969/j.issn.1000-8179.2017.07.327

中國醫(yī)科大學(xué)附屬第一醫(yī)院胰膽外科（沈陽市110001）

*本文課題受遼寧省教育廳項目（編號：L2014294）和沈陽市科學(xué)技術(shù)計劃項目（編號：F15-199-1-48）資助

葛春林 gechunlin@139.com

王奕智 專業(yè)方向為胰腺癌相關(guān)分子作用機(jī)制研究。

E-mail：2268549208@qq.com