人肝细胞肝癌组织中Smad4、Fascin、Cortactin蛋白的表达及其对临床预后判断价值的研究
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摘要
目的
检测肝细胞肝癌组织及正常肝组织中Smad4、Fascin、Cortactin蛋白表达,研究三者的相关性及其与临床病理特征、患者生存期的关系,探讨它们在肝癌的发生发展及转移过程中的作用及其对临床预后判断价值。
方法
收集肝细胞肝癌手术切除组织标本117例,正常肝组织7例。采用免疫组化技术检测肝癌组织及正常肝组织中Smad4、Fascin、Cortactin蛋白表达情况;同时随访患者,对有有效生存资料的74例肝细胞肝癌患者进行Kaplan-Meier生存分析,应用Cox回归模型分析预后因素,采用SPSS13.0统计软件包进行统计学处理。
结果
1. Smad4蛋白在肝癌组织及正常肝组织的表达阳性率分别为31.6%和85.7%,两者之间差异显著(χ2=6.310,P=0.012);Smad4蛋白表达与术前血清AFP水平、分化程度、是否发生转移、UICC T分期和我国肝癌分期系统有关。
2. Fascin蛋白在肝癌组织及正常肝组织的表达阳性率分别为69.2%和14.3%,两者之间差异显著(χ2=6.618,P=0.010);Fascin蛋白表达与分化程度、是否发生转移及我国肝癌分期系统有关。
3. Cortactin蛋白在肝癌组织及正常肝组织的表达阳性率分别为62.4%、和14.3%,两者之间差异显著(χ2=4.510,P=0.034)。Cortactin蛋白表达与分化程度、是否发生转移、UICC T分期和我国肝癌分期系统有关。
4. Smad4阴性组Fascin阳性率(77.5%)高于Smad4阳性组Fascin阳性率(51.35%),差异显著,相关系数r=-0.263;Smad4阴性组Cortactin阳性率(78.75%)高于Smad4阳性组中Cortactin阳性率(27.03%),差异显著,相关系数r=-0.497;Fascin阳性组Cortactin阳性率(81.48%)与阴性组Cortactin阳性率(19.44%)间差异显著,相关系数r=0.591。5. Kaplan-Meier法单因素生存分析结果显示Smad4阴性表达、Fascin阳性表达、Cortactin阳性表达、分化程度、是否发生转移和肿瘤直径与肝癌患者的生存期有关;Cox多因素回归分析示Smad4表达情况和分化程度是影响患者生存期的独立预后因素。
结论
1.肝癌组织Smad4低表达,正常肝组织Smad4高表达;肝癌组织Fascin、Cortactin高表达,正常肝组织Fascin、Cortactin低表达。
2. Smad4低表达、Fascin阳性表达及Cortactin的阳性表达与肝细胞肝癌转移情况、分化程度、我国肝癌分期系统等密切相关;联合检测Smad4、Fascin和Cortactin可能有助于判断肝癌恶性程度及转移情况,评估患者预后。
3.肝癌中Smad4与Fascin、Cortactin的表达均呈负相关,Fascin与Cortactin的表达呈正相关。提示Smad4在肝细胞肝癌中可能通过某种机制影响Fascin、Cortactin的表达。
4.肝癌Smad4、Fascin和Cortactin表达情况、肿瘤直径、分化程度、转移情况、UICC T分期、我国肝癌分期系统与肝癌患者的生存期有关;Smad4表达情况和分化程度是独立的预后因素。Smad4、Fascin和Cortactin可能可以作为判断肝癌恶性程度及转移的重要标志,有助于对肝细胞肝癌患者预后的判断。
OBJECTIVE
To evaluate the expression of Smad4, Fascin, Cortactin protein in hepatocellular carcinoma, combine with some clinical pathological factors to discuss the relationship between expressions of Smad4, Fascin, Cortactin and the progress, metastasis and prognosis of hepatocellular carcinoma.
METHODS
The expressions of Smad4, Fascin, Cortactin proteins were examined in 117 hepatocellular carcinoma tissues by immunhistochemical staining. The association between the clinicopathologic features with Smad4, Fascin, Cortactin expression were evaluated. Part of patients were visited, 74 clincopathology and the survival time of the patients were analyzed. SPSS 13.0 statistical software was used for the analysis.
RESULTS
1. Expression of Smad4 was demonstrated in 31.6% of hepatocellular carcinoma and 85.7% of healthy controls, (χ2=6.310, P=0.012). Expression of Smad4 significantly correlated with serum AFP level, histological differentiation, metastasis, T stage (UICC) and Chinese staging systems.
2. Expression of Fascin was demonstrated in 69.2% of hepatocellular carcinoma and 14.3% of healthy controls, (χ2=6.618, P=0.010). Expression of Fascin significantly correlated with histological differentiation, metastasis, and Chinese staging systems.
3. Expression of Cortactin was demonstrated in 62.4% of hepatocellular carcinoma and 14.3% of healthy controls, (χ2=4.510, P=0.034). Expression of Cortactin significantly correlated with tumor size, histological differentiation, metastasis, T stage (UICC) and Chinese staging systems.
4. The positive rate of Fascin in Smad4 negative group (77.5%) was higher than that in Smad4 positive group (51.35%), coefficient of correlation r=-0.263. The positive rate of Cortactin in Smad4 negative group (78.75%) was higher than that in Smad4 positive group (27.03%), coefficient of correlation r=-0.497. The positive rate of Cortactin in Fascin positive group (81.48%) was higher than that in Fascin negative group (19.44%), coefficient of correlation r=0.591.
5. Kaplan-Meier survival curves showed that Smad4 negative expression, Fascin positive expression, Cortactin positive expression, histological differentiation, metastasis, and tumor size effect on the patients survival time. Cox multiple regression showed that the partial regression coefficient of histological differentiation and Smad4 were -1.099,-1.722. The confidence interval of 95% were (0.123, 0.906) and (0.034, 0.946).
CONCLUTIONS
1. Smad4 was low expression in hepatocellular carcinoma; Fascin and Cortactin were high expression in hepatocellular carcinoma.
2. Negative expression of Smad4 and positive expression of Fascin, Cortactin were closely related to histological differentiation, metastasis, and Chinese staging systems. Smad4, Fascin, and Cortactin can be important indicator of the metastasis and prognosis.
3. Positive correlations were observed between the expression of Smad4, Fascin and Cortactin in hepatocellular carcinoma tissues. It suggested that Smad4 could influence the expression of Fascin and Cortactin in hepatocellular carcinoma tissues through some mechanisms.
4. Smad4 negative expression, Fascin positive expression, Cortactin positive expression, tumor size, histological differentiation, metastasis, T stage (UICC) and Chinese staging systems effect on patients’survival. Histological differentiation and Smad4 can be used as independent prognostic factors. Smad4, Fascin, Cortactin can be important indicators of the metastasis and prognosis to the HCC patients.
检测肝细胞肝癌组织及正常肝组织中Smad4、Fascin、Cortactin蛋白表达,研究三者的相关性及其与临床病理特征、患者生存期的关系,探讨它们在肝癌的发生发展及转移过程中的作用及其对临床预后判断价值。
方法
收集肝细胞肝癌手术切除组织标本117例,正常肝组织7例。采用免疫组化技术检测肝癌组织及正常肝组织中Smad4、Fascin、Cortactin蛋白表达情况;同时随访患者,对有有效生存资料的74例肝细胞肝癌患者进行Kaplan-Meier生存分析,应用Cox回归模型分析预后因素,采用SPSS13.0统计软件包进行统计学处理。
结果
1. Smad4蛋白在肝癌组织及正常肝组织的表达阳性率分别为31.6%和85.7%,两者之间差异显著(χ2=6.310,P=0.012);Smad4蛋白表达与术前血清AFP水平、分化程度、是否发生转移、UICC T分期和我国肝癌分期系统有关。
2. Fascin蛋白在肝癌组织及正常肝组织的表达阳性率分别为69.2%和14.3%,两者之间差异显著(χ2=6.618,P=0.010);Fascin蛋白表达与分化程度、是否发生转移及我国肝癌分期系统有关。
3. Cortactin蛋白在肝癌组织及正常肝组织的表达阳性率分别为62.4%、和14.3%,两者之间差异显著(χ2=4.510,P=0.034)。Cortactin蛋白表达与分化程度、是否发生转移、UICC T分期和我国肝癌分期系统有关。
4. Smad4阴性组Fascin阳性率(77.5%)高于Smad4阳性组Fascin阳性率(51.35%),差异显著,相关系数r=-0.263;Smad4阴性组Cortactin阳性率(78.75%)高于Smad4阳性组中Cortactin阳性率(27.03%),差异显著,相关系数r=-0.497;Fascin阳性组Cortactin阳性率(81.48%)与阴性组Cortactin阳性率(19.44%)间差异显著,相关系数r=0.591。5. Kaplan-Meier法单因素生存分析结果显示Smad4阴性表达、Fascin阳性表达、Cortactin阳性表达、分化程度、是否发生转移和肿瘤直径与肝癌患者的生存期有关;Cox多因素回归分析示Smad4表达情况和分化程度是影响患者生存期的独立预后因素。
结论
1.肝癌组织Smad4低表达,正常肝组织Smad4高表达;肝癌组织Fascin、Cortactin高表达,正常肝组织Fascin、Cortactin低表达。
2. Smad4低表达、Fascin阳性表达及Cortactin的阳性表达与肝细胞肝癌转移情况、分化程度、我国肝癌分期系统等密切相关;联合检测Smad4、Fascin和Cortactin可能有助于判断肝癌恶性程度及转移情况,评估患者预后。
3.肝癌中Smad4与Fascin、Cortactin的表达均呈负相关,Fascin与Cortactin的表达呈正相关。提示Smad4在肝细胞肝癌中可能通过某种机制影响Fascin、Cortactin的表达。
4.肝癌Smad4、Fascin和Cortactin表达情况、肿瘤直径、分化程度、转移情况、UICC T分期、我国肝癌分期系统与肝癌患者的生存期有关;Smad4表达情况和分化程度是独立的预后因素。Smad4、Fascin和Cortactin可能可以作为判断肝癌恶性程度及转移的重要标志,有助于对肝细胞肝癌患者预后的判断。
OBJECTIVE
To evaluate the expression of Smad4, Fascin, Cortactin protein in hepatocellular carcinoma, combine with some clinical pathological factors to discuss the relationship between expressions of Smad4, Fascin, Cortactin and the progress, metastasis and prognosis of hepatocellular carcinoma.
METHODS
The expressions of Smad4, Fascin, Cortactin proteins were examined in 117 hepatocellular carcinoma tissues by immunhistochemical staining. The association between the clinicopathologic features with Smad4, Fascin, Cortactin expression were evaluated. Part of patients were visited, 74 clincopathology and the survival time of the patients were analyzed. SPSS 13.0 statistical software was used for the analysis.
RESULTS
1. Expression of Smad4 was demonstrated in 31.6% of hepatocellular carcinoma and 85.7% of healthy controls, (χ2=6.310, P=0.012). Expression of Smad4 significantly correlated with serum AFP level, histological differentiation, metastasis, T stage (UICC) and Chinese staging systems.
2. Expression of Fascin was demonstrated in 69.2% of hepatocellular carcinoma and 14.3% of healthy controls, (χ2=6.618, P=0.010). Expression of Fascin significantly correlated with histological differentiation, metastasis, and Chinese staging systems.
3. Expression of Cortactin was demonstrated in 62.4% of hepatocellular carcinoma and 14.3% of healthy controls, (χ2=4.510, P=0.034). Expression of Cortactin significantly correlated with tumor size, histological differentiation, metastasis, T stage (UICC) and Chinese staging systems.
4. The positive rate of Fascin in Smad4 negative group (77.5%) was higher than that in Smad4 positive group (51.35%), coefficient of correlation r=-0.263. The positive rate of Cortactin in Smad4 negative group (78.75%) was higher than that in Smad4 positive group (27.03%), coefficient of correlation r=-0.497. The positive rate of Cortactin in Fascin positive group (81.48%) was higher than that in Fascin negative group (19.44%), coefficient of correlation r=0.591.
5. Kaplan-Meier survival curves showed that Smad4 negative expression, Fascin positive expression, Cortactin positive expression, histological differentiation, metastasis, and tumor size effect on the patients survival time. Cox multiple regression showed that the partial regression coefficient of histological differentiation and Smad4 were -1.099,-1.722. The confidence interval of 95% were (0.123, 0.906) and (0.034, 0.946).
CONCLUTIONS
1. Smad4 was low expression in hepatocellular carcinoma; Fascin and Cortactin were high expression in hepatocellular carcinoma.
2. Negative expression of Smad4 and positive expression of Fascin, Cortactin were closely related to histological differentiation, metastasis, and Chinese staging systems. Smad4, Fascin, and Cortactin can be important indicator of the metastasis and prognosis.
3. Positive correlations were observed between the expression of Smad4, Fascin and Cortactin in hepatocellular carcinoma tissues. It suggested that Smad4 could influence the expression of Fascin and Cortactin in hepatocellular carcinoma tissues through some mechanisms.
4. Smad4 negative expression, Fascin positive expression, Cortactin positive expression, tumor size, histological differentiation, metastasis, T stage (UICC) and Chinese staging systems effect on patients’survival. Histological differentiation and Smad4 can be used as independent prognostic factors. Smad4, Fascin, Cortactin can be important indicators of the metastasis and prognosis to the HCC patients.
引文
[1] Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin, 2005,55:74-108.
[2] Tang ZY. Small hepatocellular carcinoma: current status and prospects. Hepatobiliary Pancreat Dis Int, 2002,1:349-353.
[3] Pollard TD,et al. Cellular motility driven by assembly and disassembly of actin filaments. Cell 2003; 112: 453-465.
[4] Liu N,et al. Reversal of the malignant phenotype of gastric cancer cells by inhibition of RhoA expression and activity. Clin Cancer Res. 2004; 10: 6239-6247.
[5] Pan Y,et al. Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun. 2004; 315: 686-691.
[6] Massague J. TGFbeta in Cancer. Cell, 2008,134:215-230.
[7] Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003,425:577-584.
[8] Jazag A, Ijichi H, Kanai F, et al. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene, 2005;24:662-671.
[9] Huang S, Zhang F, Ji G, et al. Lentiviral-mediated Smad4 RNAi induced anti-proliferation by p16 up-regulation and apoptosis by caspase 3 down-regulation in hepatoma SMMC-7721 cells. Oncol Rep, 2008;20:1053-1059.
[10] Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 1996;271:350-353.
[11] De Caesteckr MP, Yahata T, Wang D, et al. The Smad4 actibation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain. J Biol Chem, 2000,275:2115-2122.
[12] Kim RH, Wang D, Tsang M, et al. A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Gene Dev, 2000, 14:1605-1616.
[13] Zawei L. G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: phenotypes reversed by a tumorigenic mutation. Mol Cell, 1998,1:611-617.
[14] Bryan J, Kane RE. Separation and interaction of the major component of sea urchin actin gel. J Mol Biol, 1978, 125:207-224.
[15] Ono S, Yamakita Y, Yamashi m S, et al. Dentification of an actin binding region and a protein kinase C phoephorylation site on human Fascin. J Biol Chem, 1997, 272: 2527-2533.
[16] Adams JC, Clelland JD, Collett GD, et al. Cell-matrix adhesions differentially regulate Fascin phosphorylation. Mol Biol Cell,1999, 10: 4177-4190.
[17] Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol, 2004, 5: 816-826.
[18] Kureishy N, Sapountzi V, Prag S. Fascins, and their roles in cell structure and function. Bioessays, 2002, 24: 350-361.
[19] Yamashiro S, Yamakita Y, Ono S, et al. Fascin, an actin-bundling protein, induces membrane protrusions and increases cell motility of epithelial cells. Mol Biol Cell, 1998, 9: 993-1006.
[20] Wu H, Reynolds AB, Kanner SB, et al. Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Mol Cell Biol, 1991, 11: 5113-5124.
[21] Zhang LH, Tian B, Diao LR, et al. Dominant expression of 85-kDa form of Cortactin in colorectal cancer. J Cancer Res Clin Oncol,2006,132:113-120
[22] van Damme H, Brok H, Schuuring-Scholtes E, et al. The redistribution of Cortactin into cell-matrix contact sites in human carcinoma cells with 11q13 amplification is associated with both overexpression and post-translational modification. J Biol Chem, 1997, 272: 7374-7380.
[23] Ka’lma’n Somogyi, Pernille Rorth. Cortactin modulates cell migration and ring canal morphogenesis during Drosophila oogenesis. Mech Dev, 2004, 121: 57-64.
[24] Yuan BZ, Zhou X, Zi monjic DB, et al. Amplification and over expression of the EMS1 oncogene, a possible p rognostic marker, in human hepatocellular carcinoma. J Mol Diagn, 2003, 1: 48-53.
[25] Schuuring E, Verhoeven E, Mooi WJ, et al. Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene, 1992, 7:355-361.
[26] Rodrigo JP, Garcia LA, Ramos S, et al. EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res, 2000, 6:3177-3182.
[27] Zhang F, Ren G, Lu Y, et al. Identification of TRAK1 (Trafficking protein, kinesin-binding 1) as MGb2-Ag: a novel cancer biomarker. Cancer Lett, 2009,274:250-258.
[28] Greene FL, Page DL, Fleming ID, et al. American joint committee on cancer staging manual. 6th ed. New York, NY: Springer, 2002,131-144.
[29]中国抗癌协会肝癌专业委员会.原发性肝癌的临床诊断与分期标准.实用癌症杂志, 2001,16:672.
[30] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell, 2000,7,100:57.
[31] Liotta LA, Kohn EC. Cancer’s deadly signature. Nat Genet,2003,33:10.
[32] Woodhouse EC, Chuaqui RF, Liotta LA. General mechanisms of metastasis. Cancer, 1997,80:1529.
[33] Liotta LA. Cancer cell invasion and metastasis. Sci Am, 1992,266:54-62.
[34] Tanaka T, Watanabe T, Kazama Y, et al. Loss of Smad4 protein expression and 18qLOH as molecular markers indicating lymph node metastasis in colorectal cancer--a study matched for tumor depth and pathology. J Surg Oncol, 2008, 97:69-73.
[35] Kim YH, Lee HS, Lee HJ, et al. Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. Ann Oncol, 2004,15:574-580.
[36] Natsugoe S, Xiangming C, Matsumoto M, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res, 2002,8:1838-1842.
[37] Wiseman BS, Werb A. Stromal effects on mammary gland debelopment and breast cancer. Science,2002,296:1046.
[38] Bissell MK, Radisky D. Putting tumours in context. Nat Rev Cancer, 2001,1:46.
[39] Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998,279:509-514.
[40] Hashimoto Y, Ito T, Inoue H, et al. Prognostic significance of Fascin over expression in human esophageal squamous cell carcinoma. Clin Cancer Res, 2005,11:2597-2605.
[41] Hashimoto Y, Shimada Y, Kawamura J, et al. The prognostic relevance of Fascin expression in human gastric carcinoma. Oncology,2004,67:262-270.
[42] Yoder BJ, Tso E, Skacel M, et al. The expression of Fascin, an actin-bundling motility protein, correlates with hormone receptor-negative breast cancer and a more aggressive clinical course. Clin Cancer Res, 2005,11:186-192.
[43] Lee TK, Poon RT, Man K, et al. Fascin over-expression is associated with aggressiveness of oral squamous cell carcinoma. Cancer Lett,2007,254:308-315.
[44] Chuma M, Sakamoto M, yasuda J, et al. Overexpression of Cortactin is involved in motility and metastasis of hepatocellular carcinoma. J Hepatol, 2004,41:629-636.
[45] Zhang LH, Tian B, Diao LR, et al. Dominant expression of 85-kDa form of Cortactin in colorectal cancer. J cancer Res Clin Oncol, 2006,132:113-120.
[1]DerynckR,ZhangYE.Smad-dependentandSmad-independentpathwaysinTGF-betafamilysignalling.Nature,2003;425:577-584.
[2]MassaguéJ.TGFbetainCancer.Cell,2008;134:215-230.
[3]GordonKJ,BlobeGC.Roleoftransforminggrowthfactor-betasuperfamilysignalingpathwaysinhumandisease.BiochimBiophysActa,2008;1782:197-228.
[4]WangLH,KimSH,LeeJH,ChoiYL,KimYC,ParkTS,HongYC,WuCF,ShinYK.InactivationofSMAD4tumorsuppressorgeneduringgastriccarcinomaprogression.ClinCancerRes,2007;13:102-110.
[5]ZhaoS,VenkatasubbaraoK,LazorJW,SperryJ,JinC,CaoL,FreemanJW.InhibitionofSTAT3Tyr705phosphorylationbySmad4suppressestransforminggrowthfactorbeta-mediatedinvasionandmetastasisinpancreaticcancercells.CancerRes,2008;68:4221-4228.
[6]WangH,RajanS,LiuG,ChakrabartyS.Transforminggrowthfactorbetasuppressesbeta-catenin/WntsignalingandstimulatesanadhesionresponseinhumancoloncarcinomacellsinaSmad4/DPC4independentmanner.CancerLett,2008;264:281-287.
[7]BarrosR,PereiraB,DulucI,AzevedoM,MendesN,CamiloV,JacobsRJ,PauloP,Santos-SilvaF,vanSeuningenI,vandenBrinkGR,DavidL,FreundJN,AlmeidaR.KeyelementsoftheBMP/SMADpathwayco-localizewithCDX2inintestinalmetaplasiaandregulateCDX2expressioninhumangastriccelllines.JPathol,2008;215:411-420.
[8]HuangS,ZhangF,MiaoL,ZhangH,FanZ,WangX,JiG.Lentiviral-mediatedSmad4RNAiinducedanti-proliferationbyp16up-regulationandapoptosisbycaspase3down-regulationinhepatomaSMMC-7721cells.OncolRep,2008;20:1053-1059.
[9]JiGZ,WangXH,MiaoL,LiuZ,ZhangP,ZhangFM,YangJB.Roleoftransforminggrowthfactor-beta1-smadsignaltransductionpathwayinpatientswithhepatocellularcarcinoma.WorldJGastroenterol,2006;12:644-648.
[10]季国忠,王学浩.转化生长因子β-Smad信号通路在肿瘤发生中的作用.医学研究生学报, 2005;18:542-545.
[11] Souchelnytskyi S, Tamaki K, Engstr?m U, Wernstedt C, ten Dijke P, Heldin CH. Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem, 1997;272:28107-28115.
[12] Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature, 2004;430:226-231.
[13] Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 1996;271:350-353.
[14] Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev, 2006;20:3130-3146.
[15] Ijichi H, Ikenoue T, Kato N, Mitsuno Y, Togo G, Kato J, Kanai F, Shiratori Y, Omata M. Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells. Biochem Biophys Res Commun, 2001;289:350-357.
[16] Pizzi S, Azzoni C, Bassi D, Bottarelli L, Milione M, Bordi C. Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. Cancer, 2003;98:1273-1282.
[17] Xie W, Rimm DL, Lin Y, Shih WJ, Reiss M. Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis. Cancer J, 2003;9:302-312.
[18] Shiou SR, Singh AB, Moorthy K, Datta PK, Washington MK, Beauchamp RD, Dhawan P. Smad4 regulates claudin-1 expression in a transforming growth factor-beta-independent manner in colon cancer cells. Cancer Res, 2007;67:1571-1579.
[19] Xiao DS, Wen JF, Li JH, Hu ZL, Zheng H, Fu CY. Effect of deleted pancreatic cancer locus 4 gene transfection on biological behaviors of human colorectal carcinoma cells. World J Gastroenterol, 2005;11:348-352.
[20] Losi L, Bouzourene H, Benhattar J. Loss of Smad4 expression predicts liver metastasis in human colorectal cancer. Oncol Rep, 2007;17:1095-1099.
[21] Kim YH, Lee HS, Lee HJ, Hur K, Kim WH, Bang YJ, Kim SJ, Lee KU, Choe KJ, Yang HK. Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. Ann Oncol, 2004;15:574-580.
[22]徐岩,王振宁,徐惠绵,陈亚男,罗阳.胃癌癌变过程中Smad4表达的变化及其与临床病理特征的关系.世界华人消化杂志,2007;15:1510-1515.
[23] Okano H, Shinohara H, Miyamoto A, Takaori K, Tanigawa N. Concomitant overexpression of cyclooxygenase-2 in HER-2-positive on Smad4-reduced human gastric carcinomas is associated with a poor patient outcome. Clin Cancer Res. 2004;15:6938-6945.
[24] Torbenson M, Marinopoulos S, Dang DT, Choti M, Ashfaq R, Maitra A, Boitnott J, Wilentz RE. Smad4 overexpression in hepatocellular carcinoma is strongly associated with transforming growth factor beta II receptor immunolabeling. Hum Pathol, 2002; 33:871-876.
[25] Longerich T, Breuhahn K, Odenthal M, Petmecky K, Schirmacher P. Factors of transforming growth factor beta signalling are co-regulated in human hepatocellular carcinoma. Virchows Arch, 2004;445:589-596.
[26] Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene, 1999;18:4879-4883.
[27] Tannapfel A, Anhalt K, H?usermann P, Sommerer F, Benicke M, Uhlmann D, Witzigmann H, Hauss J, Wittekind C. Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol, 2003;201:238-249.
[28]季国忠,张发明,翟惠虹,范志宁,樊代明,王学浩. Smad4基因RNAi慢病毒载体的构建与鉴定.第四军医大学学报, 2005;27:600-602.
[29] Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, Ishigami S, Baba M, Takao S, Aikou T. Smad4 and transforming growth factorbeta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res, 2002;8:1838-1842.
[30] Popovi? Hadzija M, Hras?an R, Bosnar MH, Zeljko Z, Hadzija M, Cadez J, Paveli? K, Kapitanovi? S. Infrequent alteration of the DPC4 tumor suppressor gene in renal cell carcinoma. Urol Res, 2004;32:229-235.
[31] Baldus SE, Schwarz E, Lohrey C, Zapatka M, Landsberg S, Hahn SA, Schmidt D, Dienes HP, Schmiegel WH, Schwarte-Waldhoff I. Smad4 deficiency in cervical carcinoma cells. Oncogene, 2005;24:810-819.
[32] Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC, Moses HL. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell, 2008;13:23-35.
[33] Nagatake M, Takagi Y, Osada H, Uchida K, Mitsudomi T, Saji S, Shimokata K, Takahashi T, Takahashi T. Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancers. Cancer Res, 1996;56:2718-2720.
[34] Aitchison AA, Veerakumarasivam A, Vias M, Kumar R, Hamdy FC, Neal DE, Mills IG. Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. Prostate, 2008;68:661-674.
[35] Tanaka T, Watanabe T, Kazama Y, Tanaka J, Kanazawa T, Kazama S, Nagawa H. Loss of Smad4 protein expression and 18qLOH as molecular markers indicating lymph node metastasis in colorectal cancer--a study matched for tumor depth and pathology. J Surg Oncol, 2008;97:69-73.
[36] Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B, Ohta M, Imamura J, Tanaka Y, Tateishi K, Ikenoue T, Kawakami T, Arakawa Y, Miyagishi M, Taira K, Kawabe T, Omata M. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene, 2005;24:662-671.
[37] Zhang F, Ren G, Lu Y, Jin B, Wang J, Chen X, Liu Z, Li K, Nie Y, Wang X, Fan D. Identification of TRAK1 (Trafficking protein, kinesin-binding 1) as MGb2-Ag: a novel cancer biomarker. Cancer Lett. 2009;274:250-258.
[38] Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, Aoki M, Oshima M, Hattori M, Takabayashi A, Minato N, Taketo MM.SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet, 2007;39:467-475.
[39] Imamichi Y, Waidmann O, Hein R, Eleftheriou P, Giehl K, Menke A. TGF beta-induced focal complex formation in epithelial cells is mediated by activated ERK and JNK MAP kinases and is independent of Smad4. Biol Chem, 2005;386:225-236.
[40] Ellenrieder V, Hendler SF, Ruhland C, Boeck W, Adler G, Gress TM. TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer, 2001;93:204-211.
[41] Pardali K, Moustakas A. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta, 2007;1775:21-62.
[42] Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol, 2005;17:548-558.
[43] Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene, 2005;24:7443-7454.
[1] Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell, 2009,139(5):871-890.
[2] Guarino M. Epithelial-mesenchymal transition and tumour invasion[J]. Int J Biochem Cell Biol, 2007,39(12):2153-2160.
[3] Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells[J]. J Cell Biol, 1982,95(1):333-339.
[4] Thiery JP. Epithelial-mesenchymal transitions in development and pathologies[J]. Curr Opin Cell Biol, 2003,15(6):740-746.
[5] Lu Z, Ghosh S, Wang Z, et al. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion[J]. Cancer Cell, 2003,4(6):499-515.
[6] Savagner P. Leaving the neighborhood: molecular mechanisms involved duringepithelial-mesenchymal transition[J]. Bioessays, 2001,23(10):912-923.
[7] Xu Z, Shen MX, Ma DZ, et al. TGF-beta1-promoted epithelial-to-mesenchymal transformation and cell adhesion contribute to TGF-beta1-enhanced cell migration in SMMC-7721 cells[J]. Cell Res, 2003,13(5):343-350.
[8] Bates RC, DeLeo MJ 3rd,Mercurio AM. The epithelial-mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis[J]. Exp Cell Res, 2004,299(2):315-324.
[9] Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation[J]. Kidney Int, 2002,61(5):1714-1728.
[10] Kong W, Yang H, He L, et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA[J]. Mol Cell Biol, 2008,28(22):6773-6784.
[11] Graham TR, Zhau HE, Odero-Marah VA, et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells[J]. Cancer Res, 2008,68(7):2479-2488.
[12] Lee MY, Chou CY, Tang MJ, et al. Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation[J]. Clin Cancer Res, 2008,14(15):4743-4750.
[13] Valcourt U, Kowanetz M, Niimi H, et al. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition[J]. Mol Biol Cell, 2005,16(4):1987-2002.
[14] Edme N, Downward J, Thiery JP, et al. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways[J]. J Cell Sci, 2002,115(Pt 12):2591-2601.
[15] Janda E, Lehmann K, Killisch I, et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways[J]. J Cell Biol, 2002,156(2):299-313.
[16] Bhowmick NA, Zent R, Ghiassi M, et al. Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity[J]. J Biol Chem, 2001,276(50):46707-46713.
[17] Guarino M. Src signaling in cancer invasion[J]. J Cell Physiol, 2010,223(1):14-26.
[18] Wheeler DL, Iida M,Dunn EF. The role of Src in solid tumors[J]. Oncologist, 2009,14(7):667-678.
[19] Karlsson R, Pedersen ED, Wang Z, et al. Rho GTPase function in tumorigenesis[J]. Biochim Biophys Acta, 2009,1796(2):91-98.
[20] Symons M, Segall JE. Rac and Rho driving tumor invasion: who's at the wheel?[J]. Genome Biol, 2009,10(3):213.
[21] Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways[J]. Oncogene, 2005,24(50):7443-7454.
[22] Grille SJ, Bellacosa A, Upson J, et al. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines[J]. Cancer Res, 2003,63(9):2172-2178.
[23] Satdarshan P, Singh M. Wnt signaling in liver physiology and pathology[J]. Journal of Medical Postgraduates, 2009,22(2):113-114.
[24] Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis[J]. Cell, 2004,118(3):277-279.
[25] Peinado H, Olmeda D,Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?[J]. Nat Rev Cancer, 2007,7(6):415-428.
[26] Min C, Eddy SF, Sherr DH, et al. NF-kappaB and epithelial to mesenchymal transition of cancer[J]. J Cell Biochem, 2008,104(3):733-744.
[27] Chua HL, Bhat-Nakshatri P, Clare SE, et al. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2[J]. Oncogene,2007,26(5):711-724.
[28] Zuo YH, Shi X.Update of the metastatic mechanisms of malignant tumors[J]. Journal of Medical Postgraduates, 2008,21(3):293-297.
[29] Geiger TR, Peeper DS. Metastasis mechanisms[J]. Biochim Biophys Acta, 2009,1796(2):293-308.
[30] Brabletz T, Jung A, Reu S, et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment[J]. Proc Natl Acad Sci U S A, 2001,98(18):10356-10361.
[31] Gjerdrum C, Tiron C, Hoiby T, et al. Axl is an essential epithelial-to- mesenchymal transition-induced regulator of breast cancer metastasis and patient survival[J]. Proc Natl Acad Sci USA, 2010,107(3):1124-1129.
[32] Zhau HE, Odero-Marah V, Lue HW, et al. Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model[J]. Clin Exp Metastasis, 2008,25(6):601-610.
[33] Yang MH, Chen CL, Chau GY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma[J]. Hepatology, 2009,50(5):1464-1474.
[34] Hugo H, Ackland ML, Blick T, et al. Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression[J]. J Cell Physiol, 2007,213(2):374-383.
[2] Tang ZY. Small hepatocellular carcinoma: current status and prospects. Hepatobiliary Pancreat Dis Int, 2002,1:349-353.
[3] Pollard TD,et al. Cellular motility driven by assembly and disassembly of actin filaments. Cell 2003; 112: 453-465.
[4] Liu N,et al. Reversal of the malignant phenotype of gastric cancer cells by inhibition of RhoA expression and activity. Clin Cancer Res. 2004; 10: 6239-6247.
[5] Pan Y,et al. Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun. 2004; 315: 686-691.
[6] Massague J. TGFbeta in Cancer. Cell, 2008,134:215-230.
[7] Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003,425:577-584.
[8] Jazag A, Ijichi H, Kanai F, et al. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene, 2005;24:662-671.
[9] Huang S, Zhang F, Ji G, et al. Lentiviral-mediated Smad4 RNAi induced anti-proliferation by p16 up-regulation and apoptosis by caspase 3 down-regulation in hepatoma SMMC-7721 cells. Oncol Rep, 2008;20:1053-1059.
[10] Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 1996;271:350-353.
[11] De Caesteckr MP, Yahata T, Wang D, et al. The Smad4 actibation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain. J Biol Chem, 2000,275:2115-2122.
[12] Kim RH, Wang D, Tsang M, et al. A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Gene Dev, 2000, 14:1605-1616.
[13] Zawei L. G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: phenotypes reversed by a tumorigenic mutation. Mol Cell, 1998,1:611-617.
[14] Bryan J, Kane RE. Separation and interaction of the major component of sea urchin actin gel. J Mol Biol, 1978, 125:207-224.
[15] Ono S, Yamakita Y, Yamashi m S, et al. Dentification of an actin binding region and a protein kinase C phoephorylation site on human Fascin. J Biol Chem, 1997, 272: 2527-2533.
[16] Adams JC, Clelland JD, Collett GD, et al. Cell-matrix adhesions differentially regulate Fascin phosphorylation. Mol Biol Cell,1999, 10: 4177-4190.
[17] Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol, 2004, 5: 816-826.
[18] Kureishy N, Sapountzi V, Prag S. Fascins, and their roles in cell structure and function. Bioessays, 2002, 24: 350-361.
[19] Yamashiro S, Yamakita Y, Ono S, et al. Fascin, an actin-bundling protein, induces membrane protrusions and increases cell motility of epithelial cells. Mol Biol Cell, 1998, 9: 993-1006.
[20] Wu H, Reynolds AB, Kanner SB, et al. Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Mol Cell Biol, 1991, 11: 5113-5124.
[21] Zhang LH, Tian B, Diao LR, et al. Dominant expression of 85-kDa form of Cortactin in colorectal cancer. J Cancer Res Clin Oncol,2006,132:113-120
[22] van Damme H, Brok H, Schuuring-Scholtes E, et al. The redistribution of Cortactin into cell-matrix contact sites in human carcinoma cells with 11q13 amplification is associated with both overexpression and post-translational modification. J Biol Chem, 1997, 272: 7374-7380.
[23] Ka’lma’n Somogyi, Pernille Rorth. Cortactin modulates cell migration and ring canal morphogenesis during Drosophila oogenesis. Mech Dev, 2004, 121: 57-64.
[24] Yuan BZ, Zhou X, Zi monjic DB, et al. Amplification and over expression of the EMS1 oncogene, a possible p rognostic marker, in human hepatocellular carcinoma. J Mol Diagn, 2003, 1: 48-53.
[25] Schuuring E, Verhoeven E, Mooi WJ, et al. Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene, 1992, 7:355-361.
[26] Rodrigo JP, Garcia LA, Ramos S, et al. EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res, 2000, 6:3177-3182.
[27] Zhang F, Ren G, Lu Y, et al. Identification of TRAK1 (Trafficking protein, kinesin-binding 1) as MGb2-Ag: a novel cancer biomarker. Cancer Lett, 2009,274:250-258.
[28] Greene FL, Page DL, Fleming ID, et al. American joint committee on cancer staging manual. 6th ed. New York, NY: Springer, 2002,131-144.
[29]中国抗癌协会肝癌专业委员会.原发性肝癌的临床诊断与分期标准.实用癌症杂志, 2001,16:672.
[30] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell, 2000,7,100:57.
[31] Liotta LA, Kohn EC. Cancer’s deadly signature. Nat Genet,2003,33:10.
[32] Woodhouse EC, Chuaqui RF, Liotta LA. General mechanisms of metastasis. Cancer, 1997,80:1529.
[33] Liotta LA. Cancer cell invasion and metastasis. Sci Am, 1992,266:54-62.
[34] Tanaka T, Watanabe T, Kazama Y, et al. Loss of Smad4 protein expression and 18qLOH as molecular markers indicating lymph node metastasis in colorectal cancer--a study matched for tumor depth and pathology. J Surg Oncol, 2008, 97:69-73.
[35] Kim YH, Lee HS, Lee HJ, et al. Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. Ann Oncol, 2004,15:574-580.
[36] Natsugoe S, Xiangming C, Matsumoto M, et al. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res, 2002,8:1838-1842.
[37] Wiseman BS, Werb A. Stromal effects on mammary gland debelopment and breast cancer. Science,2002,296:1046.
[38] Bissell MK, Radisky D. Putting tumours in context. Nat Rev Cancer, 2001,1:46.
[39] Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998,279:509-514.
[40] Hashimoto Y, Ito T, Inoue H, et al. Prognostic significance of Fascin over expression in human esophageal squamous cell carcinoma. Clin Cancer Res, 2005,11:2597-2605.
[41] Hashimoto Y, Shimada Y, Kawamura J, et al. The prognostic relevance of Fascin expression in human gastric carcinoma. Oncology,2004,67:262-270.
[42] Yoder BJ, Tso E, Skacel M, et al. The expression of Fascin, an actin-bundling motility protein, correlates with hormone receptor-negative breast cancer and a more aggressive clinical course. Clin Cancer Res, 2005,11:186-192.
[43] Lee TK, Poon RT, Man K, et al. Fascin over-expression is associated with aggressiveness of oral squamous cell carcinoma. Cancer Lett,2007,254:308-315.
[44] Chuma M, Sakamoto M, yasuda J, et al. Overexpression of Cortactin is involved in motility and metastasis of hepatocellular carcinoma. J Hepatol, 2004,41:629-636.
[45] Zhang LH, Tian B, Diao LR, et al. Dominant expression of 85-kDa form of Cortactin in colorectal cancer. J cancer Res Clin Oncol, 2006,132:113-120.
[1]DerynckR,ZhangYE.Smad-dependentandSmad-independentpathwaysinTGF-betafamilysignalling.Nature,2003;425:577-584.
[2]MassaguéJ.TGFbetainCancer.Cell,2008;134:215-230.
[3]GordonKJ,BlobeGC.Roleoftransforminggrowthfactor-betasuperfamilysignalingpathwaysinhumandisease.BiochimBiophysActa,2008;1782:197-228.
[4]WangLH,KimSH,LeeJH,ChoiYL,KimYC,ParkTS,HongYC,WuCF,ShinYK.InactivationofSMAD4tumorsuppressorgeneduringgastriccarcinomaprogression.ClinCancerRes,2007;13:102-110.
[5]ZhaoS,VenkatasubbaraoK,LazorJW,SperryJ,JinC,CaoL,FreemanJW.InhibitionofSTAT3Tyr705phosphorylationbySmad4suppressestransforminggrowthfactorbeta-mediatedinvasionandmetastasisinpancreaticcancercells.CancerRes,2008;68:4221-4228.
[6]WangH,RajanS,LiuG,ChakrabartyS.Transforminggrowthfactorbetasuppressesbeta-catenin/WntsignalingandstimulatesanadhesionresponseinhumancoloncarcinomacellsinaSmad4/DPC4independentmanner.CancerLett,2008;264:281-287.
[7]BarrosR,PereiraB,DulucI,AzevedoM,MendesN,CamiloV,JacobsRJ,PauloP,Santos-SilvaF,vanSeuningenI,vandenBrinkGR,DavidL,FreundJN,AlmeidaR.KeyelementsoftheBMP/SMADpathwayco-localizewithCDX2inintestinalmetaplasiaandregulateCDX2expressioninhumangastriccelllines.JPathol,2008;215:411-420.
[8]HuangS,ZhangF,MiaoL,ZhangH,FanZ,WangX,JiG.Lentiviral-mediatedSmad4RNAiinducedanti-proliferationbyp16up-regulationandapoptosisbycaspase3down-regulationinhepatomaSMMC-7721cells.OncolRep,2008;20:1053-1059.
[9]JiGZ,WangXH,MiaoL,LiuZ,ZhangP,ZhangFM,YangJB.Roleoftransforminggrowthfactor-beta1-smadsignaltransductionpathwayinpatientswithhepatocellularcarcinoma.WorldJGastroenterol,2006;12:644-648.
[10]季国忠,王学浩.转化生长因子β-Smad信号通路在肿瘤发生中的作用.医学研究生学报, 2005;18:542-545.
[11] Souchelnytskyi S, Tamaki K, Engstr?m U, Wernstedt C, ten Dijke P, Heldin CH. Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem, 1997;272:28107-28115.
[12] Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature, 2004;430:226-231.
[13] Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 1996;271:350-353.
[14] Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev, 2006;20:3130-3146.
[15] Ijichi H, Ikenoue T, Kato N, Mitsuno Y, Togo G, Kato J, Kanai F, Shiratori Y, Omata M. Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells. Biochem Biophys Res Commun, 2001;289:350-357.
[16] Pizzi S, Azzoni C, Bassi D, Bottarelli L, Milione M, Bordi C. Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. Cancer, 2003;98:1273-1282.
[17] Xie W, Rimm DL, Lin Y, Shih WJ, Reiss M. Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis. Cancer J, 2003;9:302-312.
[18] Shiou SR, Singh AB, Moorthy K, Datta PK, Washington MK, Beauchamp RD, Dhawan P. Smad4 regulates claudin-1 expression in a transforming growth factor-beta-independent manner in colon cancer cells. Cancer Res, 2007;67:1571-1579.
[19] Xiao DS, Wen JF, Li JH, Hu ZL, Zheng H, Fu CY. Effect of deleted pancreatic cancer locus 4 gene transfection on biological behaviors of human colorectal carcinoma cells. World J Gastroenterol, 2005;11:348-352.
[20] Losi L, Bouzourene H, Benhattar J. Loss of Smad4 expression predicts liver metastasis in human colorectal cancer. Oncol Rep, 2007;17:1095-1099.
[21] Kim YH, Lee HS, Lee HJ, Hur K, Kim WH, Bang YJ, Kim SJ, Lee KU, Choe KJ, Yang HK. Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. Ann Oncol, 2004;15:574-580.
[22]徐岩,王振宁,徐惠绵,陈亚男,罗阳.胃癌癌变过程中Smad4表达的变化及其与临床病理特征的关系.世界华人消化杂志,2007;15:1510-1515.
[23] Okano H, Shinohara H, Miyamoto A, Takaori K, Tanigawa N. Concomitant overexpression of cyclooxygenase-2 in HER-2-positive on Smad4-reduced human gastric carcinomas is associated with a poor patient outcome. Clin Cancer Res. 2004;15:6938-6945.
[24] Torbenson M, Marinopoulos S, Dang DT, Choti M, Ashfaq R, Maitra A, Boitnott J, Wilentz RE. Smad4 overexpression in hepatocellular carcinoma is strongly associated with transforming growth factor beta II receptor immunolabeling. Hum Pathol, 2002; 33:871-876.
[25] Longerich T, Breuhahn K, Odenthal M, Petmecky K, Schirmacher P. Factors of transforming growth factor beta signalling are co-regulated in human hepatocellular carcinoma. Virchows Arch, 2004;445:589-596.
[26] Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene, 1999;18:4879-4883.
[27] Tannapfel A, Anhalt K, H?usermann P, Sommerer F, Benicke M, Uhlmann D, Witzigmann H, Hauss J, Wittekind C. Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol, 2003;201:238-249.
[28]季国忠,张发明,翟惠虹,范志宁,樊代明,王学浩. Smad4基因RNAi慢病毒载体的构建与鉴定.第四军医大学学报, 2005;27:600-602.
[29] Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, Ishigami S, Baba M, Takao S, Aikou T. Smad4 and transforming growth factorbeta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res, 2002;8:1838-1842.
[30] Popovi? Hadzija M, Hras?an R, Bosnar MH, Zeljko Z, Hadzija M, Cadez J, Paveli? K, Kapitanovi? S. Infrequent alteration of the DPC4 tumor suppressor gene in renal cell carcinoma. Urol Res, 2004;32:229-235.
[31] Baldus SE, Schwarz E, Lohrey C, Zapatka M, Landsberg S, Hahn SA, Schmidt D, Dienes HP, Schmiegel WH, Schwarte-Waldhoff I. Smad4 deficiency in cervical carcinoma cells. Oncogene, 2005;24:810-819.
[32] Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC, Moses HL. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell, 2008;13:23-35.
[33] Nagatake M, Takagi Y, Osada H, Uchida K, Mitsudomi T, Saji S, Shimokata K, Takahashi T, Takahashi T. Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancers. Cancer Res, 1996;56:2718-2720.
[34] Aitchison AA, Veerakumarasivam A, Vias M, Kumar R, Hamdy FC, Neal DE, Mills IG. Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. Prostate, 2008;68:661-674.
[35] Tanaka T, Watanabe T, Kazama Y, Tanaka J, Kanazawa T, Kazama S, Nagawa H. Loss of Smad4 protein expression and 18qLOH as molecular markers indicating lymph node metastasis in colorectal cancer--a study matched for tumor depth and pathology. J Surg Oncol, 2008;97:69-73.
[36] Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B, Ohta M, Imamura J, Tanaka Y, Tateishi K, Ikenoue T, Kawakami T, Arakawa Y, Miyagishi M, Taira K, Kawabe T, Omata M. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene, 2005;24:662-671.
[37] Zhang F, Ren G, Lu Y, Jin B, Wang J, Chen X, Liu Z, Li K, Nie Y, Wang X, Fan D. Identification of TRAK1 (Trafficking protein, kinesin-binding 1) as MGb2-Ag: a novel cancer biomarker. Cancer Lett. 2009;274:250-258.
[38] Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, Aoki M, Oshima M, Hattori M, Takabayashi A, Minato N, Taketo MM.SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet, 2007;39:467-475.
[39] Imamichi Y, Waidmann O, Hein R, Eleftheriou P, Giehl K, Menke A. TGF beta-induced focal complex formation in epithelial cells is mediated by activated ERK and JNK MAP kinases and is independent of Smad4. Biol Chem, 2005;386:225-236.
[40] Ellenrieder V, Hendler SF, Ruhland C, Boeck W, Adler G, Gress TM. TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer, 2001;93:204-211.
[41] Pardali K, Moustakas A. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta, 2007;1775:21-62.
[42] Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol, 2005;17:548-558.
[43] Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene, 2005;24:7443-7454.
[1] Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell, 2009,139(5):871-890.
[2] Guarino M. Epithelial-mesenchymal transition and tumour invasion[J]. Int J Biochem Cell Biol, 2007,39(12):2153-2160.
[3] Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells[J]. J Cell Biol, 1982,95(1):333-339.
[4] Thiery JP. Epithelial-mesenchymal transitions in development and pathologies[J]. Curr Opin Cell Biol, 2003,15(6):740-746.
[5] Lu Z, Ghosh S, Wang Z, et al. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion[J]. Cancer Cell, 2003,4(6):499-515.
[6] Savagner P. Leaving the neighborhood: molecular mechanisms involved duringepithelial-mesenchymal transition[J]. Bioessays, 2001,23(10):912-923.
[7] Xu Z, Shen MX, Ma DZ, et al. TGF-beta1-promoted epithelial-to-mesenchymal transformation and cell adhesion contribute to TGF-beta1-enhanced cell migration in SMMC-7721 cells[J]. Cell Res, 2003,13(5):343-350.
[8] Bates RC, DeLeo MJ 3rd,Mercurio AM. The epithelial-mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis[J]. Exp Cell Res, 2004,299(2):315-324.
[9] Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation[J]. Kidney Int, 2002,61(5):1714-1728.
[10] Kong W, Yang H, He L, et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA[J]. Mol Cell Biol, 2008,28(22):6773-6784.
[11] Graham TR, Zhau HE, Odero-Marah VA, et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells[J]. Cancer Res, 2008,68(7):2479-2488.
[12] Lee MY, Chou CY, Tang MJ, et al. Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation[J]. Clin Cancer Res, 2008,14(15):4743-4750.
[13] Valcourt U, Kowanetz M, Niimi H, et al. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition[J]. Mol Biol Cell, 2005,16(4):1987-2002.
[14] Edme N, Downward J, Thiery JP, et al. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways[J]. J Cell Sci, 2002,115(Pt 12):2591-2601.
[15] Janda E, Lehmann K, Killisch I, et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways[J]. J Cell Biol, 2002,156(2):299-313.
[16] Bhowmick NA, Zent R, Ghiassi M, et al. Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity[J]. J Biol Chem, 2001,276(50):46707-46713.
[17] Guarino M. Src signaling in cancer invasion[J]. J Cell Physiol, 2010,223(1):14-26.
[18] Wheeler DL, Iida M,Dunn EF. The role of Src in solid tumors[J]. Oncologist, 2009,14(7):667-678.
[19] Karlsson R, Pedersen ED, Wang Z, et al. Rho GTPase function in tumorigenesis[J]. Biochim Biophys Acta, 2009,1796(2):91-98.
[20] Symons M, Segall JE. Rac and Rho driving tumor invasion: who's at the wheel?[J]. Genome Biol, 2009,10(3):213.
[21] Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways[J]. Oncogene, 2005,24(50):7443-7454.
[22] Grille SJ, Bellacosa A, Upson J, et al. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines[J]. Cancer Res, 2003,63(9):2172-2178.
[23] Satdarshan P, Singh M. Wnt signaling in liver physiology and pathology[J]. Journal of Medical Postgraduates, 2009,22(2):113-114.
[24] Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis[J]. Cell, 2004,118(3):277-279.
[25] Peinado H, Olmeda D,Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?[J]. Nat Rev Cancer, 2007,7(6):415-428.
[26] Min C, Eddy SF, Sherr DH, et al. NF-kappaB and epithelial to mesenchymal transition of cancer[J]. J Cell Biochem, 2008,104(3):733-744.
[27] Chua HL, Bhat-Nakshatri P, Clare SE, et al. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2[J]. Oncogene,2007,26(5):711-724.
[28] Zuo YH, Shi X.Update of the metastatic mechanisms of malignant tumors[J]. Journal of Medical Postgraduates, 2008,21(3):293-297.
[29] Geiger TR, Peeper DS. Metastasis mechanisms[J]. Biochim Biophys Acta, 2009,1796(2):293-308.
[30] Brabletz T, Jung A, Reu S, et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment[J]. Proc Natl Acad Sci U S A, 2001,98(18):10356-10361.
[31] Gjerdrum C, Tiron C, Hoiby T, et al. Axl is an essential epithelial-to- mesenchymal transition-induced regulator of breast cancer metastasis and patient survival[J]. Proc Natl Acad Sci USA, 2010,107(3):1124-1129.
[32] Zhau HE, Odero-Marah V, Lue HW, et al. Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model[J]. Clin Exp Metastasis, 2008,25(6):601-610.
[33] Yang MH, Chen CL, Chau GY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma[J]. Hepatology, 2009,50(5):1464-1474.
[34] Hugo H, Ackland ML, Blick T, et al. Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression[J]. J Cell Physiol, 2007,213(2):374-383.