王湛博，韋立新

（中國人民解放軍總醫(yī)院病理科，北京100853）

膽管癌腫瘤標(biāo)記物研究進(jìn)展

王湛博，韋立新

（中國人民解放軍總醫(yī)院病理科，北京100853）

膽管癌是起源于膽管系統(tǒng)的上皮來源惡性腫瘤，中國膽管癌患者數(shù)量較多，因而膽管癌研究在我國具有特殊意義。手術(shù)切除是首選的治療手段，但早期診斷十分困難，因此尋找膽管癌診斷性標(biāo)志物非常重要。本文介紹了近年出現(xiàn)的幾種對膽管癌早期診斷很有意義的腫瘤標(biāo)記物。

膽管癌；治療；腫瘤標(biāo)記物

膽管系統(tǒng)分肝內(nèi)和肝外兩部分。肝外膽管和膽囊來自肝芽突蒂；肝門部以上的肝內(nèi)膽管則來自門管區(qū)周圍肝母細(xì)胞。膽管癌占肝膽系統(tǒng)腫瘤的10%～15%、消化道腫瘤的2%[1]。目前，膽管癌的發(fā)病率呈上升趨勢[2]。中國人每年新發(fā)病例大約占全世界的55%[3]。2009年AJCC(American joint committee on cancer)將膽管癌分為肝內(nèi)膽管癌、肝外膽管癌兩大類，后者又分為肝門周圍或近端型(Perihilar or proximal groups)和遠(yuǎn)端型(Distal group)。

膽管癌的危險因素具有地域差異性，現(xiàn)已確認(rèn)與膽管癌發(fā)生相關(guān)的因素有慢性病毒感染(乙型及丙型病毒肝炎)、慢性潰瘍性結(jié)腸炎、肝吸蟲感染、原發(fā)性硬化性膽管炎、肝內(nèi)膽管結(jié)石、先天性膽道畸形等。糖尿病和膽腸吻合術(shù)與膽管癌的關(guān)系也很受關(guān)注。中國膽管癌患者10%有膽管結(jié)石病史，西方患者40%有原發(fā)性硬化性膽管炎病史。膽管癌的臨床癥狀特異性不強，出現(xiàn)膽道梗阻時已經(jīng)是進(jìn)展期。治療主要依靠根治切除，切除范圍廣，并發(fā)癥多，預(yù)后較差。近年膽管癌根治切除率上升至64%～71%，但切除后的5年生存率僅提高到21%～30%[4]?；熀透我浦驳戎委熓侄尉焕硐隱5]。因此尋找膽管癌早期診斷的分子標(biāo)志物對患者的預(yù)后就十分重要了。本文現(xiàn)將幾種可能成為膽管癌早期診斷的標(biāo)志物介紹如下：

1 S100A9

S100A9蛋白(CalgranulinB蛋白、MRP14蛋白)屬于鈣結(jié)合蛋白S100蛋白家族，常與S100A8形成同(異)二聚體，甚至四聚體[6]。S100A9可高選擇性和高親和性地結(jié)合Ca2+、Zn2+等離子，具備細(xì)胞外和細(xì)胞內(nèi)調(diào)節(jié)活性，參與細(xì)胞遷移、花生四烯酸代謝、骨髓細(xì)胞成熟等生物學(xué)過程[7]。S100A9表達(dá)水平在炎癥性病變中經(jīng)常升高[8]，在腫瘤的發(fā)生中也起重要作用[9]。有研究表明，S100A8/A9蛋白復(fù)合物通過兩條途徑導(dǎo)致癌細(xì)胞的凋亡：(1)經(jīng)典的線粒體一細(xì)胞色素C旁路途徑；(2)S100A8/A9與zn2+結(jié)合，因為Zn2+是casepase-3的穩(wěn)定劑，當(dāng)細(xì)胞內(nèi)Zn2+濃度降低時，casepase-3被激活，最終導(dǎo)致凋亡[10]。S100A9在甲狀腺癌、肺癌、乳腺癌、肝癌和膀胱癌等中均有上調(diào)表達(dá)，而在食管鱗狀細(xì)胞癌、頭頸部鱗狀細(xì)胞癌等中則下調(diào)表達(dá)。有人報道，S100A9的高表達(dá)與腺癌的侵襲和轉(zhuǎn)移相關(guān)[11]。膽管炎性病變中S100A9血清水平升高，在原發(fā)性硬化性膽管炎中升高更為明顯[12]。有人運用蛋白組學(xué)的方法發(fā)現(xiàn)S100A9可能是一個提示膽道腫瘤的特異性標(biāo)志物[13]。近期，有文獻(xiàn)報道膽管癌中S100A9陽性率高達(dá)92.5%(37/40)[14]。S100A9在膽管癌中的提示作用還需要分別在肝內(nèi)及肝外膽管癌的大樣本實驗中進(jìn)行總結(jié)。

2 S100P

S100P蛋白是S100蛋白家族的1個亞型，由95個氨基酸殘基組成，因從胎盤(Placenta)中分離出來而得名。S100P蛋白作為一種鈣結(jié)合蛋白，與鈣周期結(jié)合蛋白(CacyBP/SIP)、埃茲蛋白(ezrin)、晚期糖基化終末產(chǎn)物(RAGE)、S100P結(jié)合蛋白(S100PBPR)等靶蛋白結(jié)合，參與細(xì)胞信號轉(zhuǎn)導(dǎo)過程，從而在細(xì)胞異常增生、細(xì)胞惡變等腫瘤發(fā)生發(fā)展的病理過程中發(fā)揮重要作用。S100P蛋白在多種腫瘤組織如肺癌、前列腺癌、乳腺癌、結(jié)直腸癌等高表達(dá)，有人認(rèn)為可能和基因的低甲基化有關(guān)[15]。Dowen等[16]發(fā)現(xiàn)，S100P在胰腺癌表達(dá)水平的升高與胰腺上皮內(nèi)瘤變(PanIN)的程度正相關(guān)。吳建國等[17]亦發(fā)現(xiàn)S100P蛋白在高、中、低分化胰腺癌組織中表達(dá)有明顯差異。因此，有人認(rèn)為，S100P蛋白可以作為胰腺癌早期診斷的標(biāo)志物[18]。膽管癌和胰腺癌具有組織學(xué)類型和免疫表型的相似性[19]。Lin等[20]發(fā)現(xiàn)S100P蛋白在胰腺癌和膽管癌中都有診斷價值。Hamada等[21]在一組肝內(nèi)膽管癌病例中發(fā)現(xiàn)S100P陽性率為75.6%，而正常膽管上皮都是陰性表達(dá)。有人發(fā)現(xiàn)膽管上皮從反應(yīng)性增生到上皮內(nèi)瘤變及高分化癌的演變過程中，S100P的表達(dá)率呈逐漸遞升趨勢[22]。Tsai等[23]發(fā)現(xiàn)在伴有結(jié)石形成的肝內(nèi)膽管癌病例中S100P可以100%陽性，而在管內(nèi)型膽管癌中也全部陽性表達(dá)，因此認(rèn)為S100P可能是膽管癌的診斷標(biāo)記物。S100P蛋白的表達(dá)率在肝內(nèi)膽管癌和肝門部膽管癌有差異，說明肝門部膽管癌和肝內(nèi)膽管癌的成瘤機制有區(qū)別。有文獻(xiàn)報道[24]，S100P的表達(dá)還和腫瘤的耐藥性和轉(zhuǎn)移的高風(fēng)險相關(guān)。不過，S100P蛋白表達(dá)不夠特異[20]。在良性膽管上皮病變中，會有灶狀或片狀的陽性表達(dá)，不過此時上皮細(xì)胞胞核陽性，胞漿陰性。而在膽管癌或膽管上皮內(nèi)瘤變區(qū)域，胞核胞漿均為強陽性表達(dá)，此點可作為鑒別[25]。

3 FXYD6

FXYD6蛋白是FXYD家族新成員，人們首先在大鼠腦和腎臟中克隆獲得，染色體定位于ll號染色體長臂(11q23.3)[26]。FXYD蛋白最主要的結(jié)構(gòu)特點是中心為單跨膜節(jié)段的核心結(jié)構(gòu)，兩端是不同的N端和C端，N端位于細(xì)胞外，有時包括一個單肽，C端在細(xì)胞內(nèi)，C端比N端對蛋白的控制作用更強。FXYD蛋白廣泛分布于哺乳動物各器官內(nèi)，特別是在轉(zhuǎn)運流動性液體和溶質(zhì)或有電流產(chǎn)生的器官中表達(dá)尤其顯著，如腎臟、胰腺、前列腺、肝臟、神經(jīng)、肌肉等，但各個成員的表達(dá)都有不同的組織特異性[27]。FXYD6是Na+/K+-ATP酶的組織特異性調(diào)節(jié)蛋白，推測FXYD6可能通過調(diào)節(jié)Na+/K+-ATP酶的活性而影響腫瘤細(xì)胞的分化和增殖[28]。FXYD6蛋白在胰腺癌組織中高表達(dá)，而在正常胰腺組織中不表達(dá)或低表達(dá)，提示FXYD6在胰腺癌的發(fā)病機制中發(fā)揮一定作用，隨著胰腺癌分化程度的由高到低，F(xiàn)XYD6蛋白染色強度逐漸增強；在出現(xiàn)淋巴結(jié)轉(zhuǎn)移的胰腺癌組織中，F(xiàn)XYD6蛋白表達(dá)也明顯增強[29]。有人通過差異顯示PCR方法，發(fā)現(xiàn)FXYD6 mRNA表達(dá)與膽管癌分化程度呈負(fù)相關(guān)，從正常膽管、高分化膽管癌到低分化膽管癌，F(xiàn)XYD6蛋白表達(dá)量依次遞增[30]。FXYD6基因在膽管癌的轉(zhuǎn)化、演進(jìn)過程中可能起重要作用，但還要通過大樣本實驗來驗證。

4 P16

MTS1/Pl6基因位于人第九號染色體短臂，由3個外顯子和兩個內(nèi)含子組成，外顯子序列能編碼細(xì)胞周期素依賴性激酶CDK的抑制蛋白p16。p16蛋白有兩個特點：①在其氨基端有一結(jié)構(gòu)與細(xì)胞周期蛋白P盒子的氨基端同源；②它含有4個特征性的錨蛋白(Ankyrin)重復(fù)序列。CDK4與細(xì)胞周期蛋白(Cyclin D)形成的復(fù)合物促進(jìn)G1-S期轉(zhuǎn)變，從而促進(jìn)細(xì)胞的增生，這可能是腫瘤發(fā)生的重要因素。pl6為CDK4的抑制因子，與CDK4-CyclinD1復(fù)合物結(jié)合，使CDK4不能與Rb磷酸化，阻滯細(xì)胞進(jìn)入G1/S期，導(dǎo)致細(xì)胞增殖抑制而使細(xì)胞生長停滯。因此，一旦p16基因發(fā)生變異，細(xì)胞增殖將無限制進(jìn)行下去，最終導(dǎo)致腫瘤發(fā)生。MTS1/pl6基因的突變和缺失在人類多種腫瘤組織中廣泛存在，主要突變形式是純合缺失和異常甲基化，此外還有雜合缺失、插入點突變和移碼突變等。Yoshida等[31]發(fā)現(xiàn)在膽管癌細(xì)胞株中有p16基因缺失，原發(fā)性膽道癌手術(shù)切除標(biāo)本中63%有p16基因突變并顯著高于p53基因的突變。Ishikawa等[32]根據(jù)膽管上皮內(nèi)瘤變的程度分組后發(fā)現(xiàn)，隨著上皮內(nèi)瘤變級別的升高，p16的表達(dá)率逐漸降低，p16的缺失將會加快細(xì)胞更新、復(fù)制，形成惡性循環(huán)，加快腫瘤的形成。周浩輝等[33]報道，肝內(nèi)膽管癌組織中p16蛋白表達(dá)率為55.4%。中-低分化肝膽管癌P16蛋白陽性表達(dá)顯著低于高分化癌。而正常肝內(nèi)膽管上皮幾乎均表達(dá)p16蛋白(93.3%)，肝膽管結(jié)石癥中增生的膽管上皮p16陽性率為78%。有文獻(xiàn)報道，p16陽性的膽管癌比陰性的膽管癌預(yù)后好，p16的失表達(dá)現(xiàn)象在肝內(nèi)膽管癌比肝外膽管癌中更常見[34]。肝內(nèi)膽管癌中p16啟動子超甲基化導(dǎo)致的失活能促進(jìn)膽管癌的形成與發(fā)展[35]。有人證實，膽管內(nèi)乳頭狀腫瘤和黏液囊性腫瘤都有p16的丟失，說明其可能有共同的腫瘤形成通路[36]。Gonda等[37]強調(diào)，p16作為膽管腫瘤的預(yù)測指標(biāo)時，使用FISH法更準(zhǔn)確。

5 IMP3

IMP3(Insulin like growth factor mRNA-binding protein 3)是胰島素樣生長因子mRNA結(jié)合蛋白家族的一員。最初，IMP3是在胰腺癌的基因篩查中被發(fā)現(xiàn)的，該基因編碼的蛋白被命名為腫瘤中過表達(dá)的K同源區(qū)域包含蛋白(K Homology Domain Containing Protein Overexpressed in Cancer)。該基因定位于7p112，編碼580氨基酸組成的癌胚RNA結(jié)合蛋白。IMP3蛋白在胚胎形成早期有多器官廣泛表達(dá)。在RNA運輸、穩(wěn)定、細(xì)胞生長和遷移中起著重要作用[38]。而在胚胎形成后，該基因保持沉默[39]。在正常成年人，只有胎盤有表達(dá)，偶有淋巴結(jié)生發(fā)中心、卵巢、睪丸、腦、毛發(fā)的毛囊內(nèi)根鞘、小腸黏膜、子宮頸內(nèi)膜局限陽性表達(dá)的報道，不過用普通的免疫組化法很難檢測[40]。目前已經(jīng)證明IMP3在肺癌、胰腺癌、腎癌、宮頸原位腺癌、肝癌、骨肉瘤、膀胱尿路上皮癌和子宮內(nèi)膜漿液性癌等呈高表達(dá)[41]。IMP3作為一種癌胚蛋白(Oncofetal protein)具有刺激和調(diào)節(jié)腫瘤細(xì)胞增殖的重要作用[42]。Yantiss等[43]報道，胰腺癌中IMP3的陽性率為97%。Riener等[44]報道，肝內(nèi)膽管癌中IMP3陽性率約為58.3%。Michael等[45]發(fā)現(xiàn)，IMP3在膽管癌的表達(dá)特異性很好，正常的膽管上皮均為陰性。有文獻(xiàn)報道，IMP3在膽管癌中敏感性達(dá)92%，特異性達(dá)95%[46]。IMP3的表達(dá)與Ki67和p53相關(guān)，可能是膽管癌的獨立預(yù)后因子[47]，在腫瘤的侵襲和轉(zhuǎn)移中發(fā)揮重要作用[48]。不過，IMP3在膽管上皮發(fā)生輕-中度不典型增生時為陰性，在重度不典型增生和原位癌時為陽性表達(dá)，所以，它在判定腫瘤是否發(fā)生浸潤時，價值不大[49]。在陽性表達(dá)的病例中，有50%的病例表達(dá)模式為灶狀陽性，這對結(jié)果的判讀困難很大[50]。

現(xiàn)在，人們熱衷于用蛋白組學(xué)來研究和篩選腫瘤標(biāo)志物。但膽管癌和胰腺導(dǎo)管腺癌類似，很少出現(xiàn)成片的腫瘤細(xì)胞，其癌性間質(zhì)較為豐富，每份腫瘤中的細(xì)胞數(shù)量都不一樣。Sheikh等[51]使用激光顯微切割技術(shù)，在胰腺癌的研究中發(fā)現(xiàn)惡性腫瘤細(xì)胞無S100A9表達(dá)，而腫瘤相關(guān)的間質(zhì)中有S100A9的表達(dá)。膽管癌與胰腺癌特點相似[19]，因此通過蛋白組學(xué)篩選出來的膽管癌腫瘤標(biāo)志物真正應(yīng)用還要建立在病理形態(tài)學(xué)診斷基礎(chǔ)之上，并需要在大樣本的實驗中證實。

[1]Blechacz BR,Gores GJ.Cholangiocarcinoma[J].Clin Liver Dis, 2008,12(1):131-150.

[2]Slattery JM,Sahani DV.What is the current state-of-the-art imaging for detection and staging of cholangiocarcinoma[J].Oncologist, 2006,11(8):913-922.

[3]黃志強.肝膽管外科的發(fā)展方向[J].外科理論與實踐,2011,16: 329-331.

[4]Friman S.Cholangiocarcinoma-current treatment options[J].Scand J Surg,2011,100(1):30-34.

[5]Sirica AE.Cholangiocarcinoma：molecular targeting strategies for chemoprevention and therapy[J].Hepatology,2005,41(1):5-15.

[6]Kornd?rfer IP,Brueckner F,Skerra A.The crystal structure of the human(Sl00A8/S100A9)2 heterotetmmer,calprotectin,illustrates how conformational changes of interacting alpha-helices call determine specific association of two EF－h(huán)and proteins[J].J Mol Biol, 2007,27:370(5):887-898.

[7]Heizmann CW,Ackermann GE,Galichet A.Pathologies involving the S100 proteins and RAGE[J].Subcell Biochem,2007,45: 93-138.

[8]Ma LP,Haugen E,Ikemoto M,et al.S100A8/A9 complex as a new biomarker in prediction of mortality in elderly patients with severe heart failure[J].Int J Cardiol,2012,23,155(1):26-32.

[9]Gebhardt C,Németh J,Angel P,et al.S100A8 and S100A9 in inflammation and cancer[J].Biochem Pharmacol,2006,30:72(11): 1622-1631.

[10]Ghavami S,Kerkhof C,Los M,et a1.Mechanism of apoptosis induced by S100A8/A9 in colon cancer cell lines：the role of ROS and the effect of metal ions[J].J Leukoc Biol,2004,76(1):169-175.

[11]Yong HY,Moon A.Roles of calcium-binding proteins,S100A8 and S100A9,in invasive phenotype of human gastric cancer cells[J]. Arch Pharm Res,2007,30:75-81.

[12]Reinhard L,Rupp C,Riedel HD,et al.S100A9 is a Biliary Protein Marker of Disease Activity in Primary Sclerosing Cholangitis, PLoS One,2012,7(1):29821.

[13]高志慧,呂濤,劉厚寶,等.膽道腫瘤的潛在標(biāo)志物Mrp1[J].中華肝膽外科雜志,2011,l7(9):722-726.

[14]詹茜,沈柏用,施源,等.S100A9與CCT γ在膽管癌中的表達(dá)及其意義[J].外科理論與實踐,2011,16(6):557-561.

[15]Sato N,Fukushima N,Matsubayashi H,et al.Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling[J].Oncogene.2004, 23:1531-1538.

[16]Dowen SE,Crnogorac—Jurcevic T,Gangeswaran R,et a1.Expression of S100P and its novel binding partner S100 PBPR in early pancreatic cancer[J].Am J Pathol,2005,166(1):81-92.

[17]吳建國,李亭,齊海智,等.SlOOp在胰腺癌組織中的表達(dá)及其臨床意義[J].中國普通外科雜志,2010,19(9):1034-1036.

[18]Ohuchida K,Mizumoto K,Egami T,et al.S100P is an early devel-opmental marker of pancreatic carcinogenesis[J].Clin Cancer Res, 2006,12:5411-5416.

[19]Gandou C,Harada K,Sato Y,et al.Hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma share similar histopathologies,immunophenotypes,and development-related molecules[J].Hum Pathol,2012,8177(12):286-289.

[20]Lin F,Shi J,Liu H,et al.Diagnostic utility of S100P and von Hippel-Lindau gene product(pVHL)in pancreatic adenocarcinoma with implication of their roles in early tumorigenesis[J].Am J Surg Pathol,2008,32:78-91.

[21]Hamada S,Satoh K,Hirota M,et al.Calcium-binding protein S100P is a novel diagnostic marker of cholangiocarcinoma[J].Cancer Sci, 2011,102:150-156.

[22]Shinichi A,Nobuhiro F,Yohei M,et al.Different roles of S100P Overexpression in Intrahepatic Cholangiocarcinoma:Carcinogenesis of Perihilar Type and Aggressive Behavior of Peripheral Type [J].Am J Surg Pathol,2011,35:590-598.

[23]Jia-Huei Tsai,1 Wen-Chih Huang,Kuan-Ting Kuo,et al.S100P immunostaining identifies a subset of peripheral-type intrahepatic cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic cholangiocarcinomas[J].Histopathology,2012,61:1106-1116.

[24]Arumugam T,Logsdon CD.S100P:a novel therapeutic target for cancer[J].AminoAcids,2011,41:893-899.

[25]Schmidt MT,Himmelfarb EA,Shafi H,et al.Use of IMP3,S100P, and pVHL Immunopanel to Aid in the Interpretation of Bile Duct Biopsies With Atypical Histology or Suspicious for Malignancy[J]. Appl Immunohistochem Mol Morphol,2012,20(5):478-87.

[26]Pelzann M,Thumher D,Gedlicka C,et a1.Nimesulide andindomethacin induce apoptosis in head and neck e/Ulcer cells[J].J Oral Pathol Med,2004,33(10):607-6l3.

[27]Sweadner KJ,Rael E.The FXYD gone family of snudl itm tratmpert regulators channels:cDNA sequence.protein signature sequence,and expression[J].Genomics,2000,68(1):41-56.

[28]Delprat B,Bibert S,Geering K.FXYD proteins novel regulators of Na,K-ATPase[J].Med Sci(Paris),2006,22:633-638.

[29]劉軍桂,周寧新,夏洪天,等.胰腺癌中FXYD6蛋白的表達(dá)及臨床意義[J].世界華人消化雜志,2008,16(5):540-543.

[30]張效東,周寧新,盧柏松,等.不同分化膽管癌差異表達(dá)基因的分離、克隆和功能研究[J].中華外科雜志,2002,20(5):399.

[31]Yoshida S,Todorki T,Ichikawa Y,et al.Mutation of P16 and P15 gene in biliary tract cancers[J].Cancer Res,1995,55(13):2756-2760.

[32]Ishikawa A,Sasaki M,Sato Y,et a1.Frequent pl6ink4a inactivation san early and frequent event of intraductal papillary neoplasm of the 1iver arising in hepatolithiasis[J].Hum Pathol,2004,35:l505-1514.

[33]周浩輝,陳燕凌,黃長玉,等K i67抗原與P16蛋白在人肝內(nèi)膽管癌中的表達(dá)及其意義[J].醫(yī)學(xué)信息,2010(10):2739-2740.

[34]Karamitopoulou E,Tornillo L,Zlobec I,et al.Clinical Significance of Cell Cycle-and Apoptosis-Related Markers in Biliary Tract Cancer[J].Am J Clin Pathol,2008,130:780-786.

[35]Chinnasri I,Pairojku1 C,Jearanaikoon P,et a1.Preferentially different mechanisms of inactivation of 9p21 gene cluster in liver fluke related cholangiocarcinoma[J].Hunl Pathol,2009,40:817-826.

[36]Matsubara T,Sato Y,Sasaki M,et al.Immunohistochemical characteristics and malignant progression of hepatic cystic neoplasms in comparison with pancreatic counterparts[J].Hum Pathol,2012,43 (12):2177-2186.

[37]Gonda TA,Glick MP,Sethi A,et al.Polysomy and p16 deletion by fluorescence in situ hybridization in the diagnosis of indeterminate biliary strictures[J].Gastrointest Endosc,2012,75(1):74-79.

[38]Nielsen J,C hristiansen J,Lykke Andersen J,et al.A family of insulin like growth factor mRNA binding proteins represses translation in lated evelopment[J].Mol Cell Biol,1999,19(2):1262-1270.

[39]Mueller-Pillasch F,Pohl B,Wilda M,et al.Expression of the highly conserved RNA binding protein KOC in embryogenesis[J].Mech Dev,1999,88:95-99.

[40]Findeis-Hosey JJ,Xu H.The use of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology[J].Hum Pathol,2011,42:303-314.

[41]Jesse H,Meena P,Daniza M,et al.IMP3 Immunocytochemical Staining Increases Sensitivity in the Routine Cytologic Evaluation of Biliary Brush Specimens[J].Diagnostic Cytopathology,2010,4 (40):321-326.

[42]Liao B,H u Y,Herrick D J,et al.The RNA binding protein IMP3 is a translational activator of insulin like growth factor leader 3 mRNA during proliferation of humanK562 leukemia cells[J].J Biol Chem,2005,280(18):18517-18524.

[43]Yantiss RK,Woda BA,Fanger GR,et al.KOC(K-homology domain containing protein overexpressed in cancer).A novel molecular marker that distinguishes between benign and malignant lesions of the pancreas[J].Am J Surg Pathol,2005,29:188-195.

[44]Riener MO,Kristiansen G.S100P,von Hippel-Lindau gene product,and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy[J]. Human Pathology,2011,42(9):1368-1369

[45]Schmidt MT,Himmelfard EA,Shafi H,et al.Use of IMP3,S100P, and pVHL Immunopanel to Aid in the Interpretation of Bile Duct Biopsies With Atypical Histology or Suspicious for Malignancy[J]. Appl Immunohistochem Mol Morphol,2012,20(5):478-487.

[46]Ligato S,Zhao H,Mandich D,er al.KOC(K homology domain containing protein overexpressed in cancer)and S100A4-protein immunoreactivity improves the diagnostic sensitivity of biliary brushing cytology for diagnosing pancreaticobiliary malignancies[J].Diagn Cytopathol,2008,36:561-567.

[47]Riener MO,Fritzsche FR,Clavien PA,et al.IMP3 expression in lesions of the biliary tract:a marker for high-grade dysplasia and an independent prognostic factor in bile duct carcinomas[J].Hum Pathol,2009,40:1377-1383.

[48]Jeng YM,Chang CC,Hu FC,et al.RNA-binding protein insulin-like growth factor II mRNA-binding protein 3 expression promotes tumor invasion and predicts early recurrence and poor prognosis in hepatocellular carcinoma[J].Hepatology,2008,48:1118-1127.

[49]Riener MO,Fritzsche FR,Clavien PA,et al.IMP3 expression in lesions of the biliary tract:a marker for high-grade dysplasia and an independent prognostic factor in bile duct carcinomas[J].Hum Pathol,2009,40:1377-1383.

[50]Levy M,Lin F,Xu H,et al.S100P,von Hippel-Lindau gene product,and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy[J]. Hum Pathol,2010,41:1210-1219.

[51]Sheikh AA,Vimalachandran D,Thompson CC,et al.The expression of S100A8 in pancreatic cancer-associated monocytes is associated with the Smad4 status of pancreatic cancer cells[J].Proteomics, 2007,7(11):1929-1940.

R735.9

A

1003—6350（2013）09—1322—04

10.3969/j.issn.1003-6350.2013.09.0557

2013-02-06)

解放軍總醫(yī)院臨床科研扶持基金（編號：2012FC-TSYS-4008）

韋立新。E-mail:weilx301@263.net