芯片技术筛选肝癌早期复发相关基因及对SOX4、CD24验证实验研究
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摘要
原发性肝癌是世界范围内最常见的恶性肿瘤之一,我国是全球肝癌发病率最高的地区,肝癌术后高的复发率是影响患者预后的最主要因素。目前开展的针对肝癌生物学特性的研究,有可能为肝癌患者的临床治疗带来新的希望。基因芯片是近年来出现的一种高通量、快速、平行核酸序列测定及定量分析技术。基因芯片技术的出现,为在全基因组范围内寻找与肿瘤发生、发展相关的基因变化提供了一个强有力的手段,它只用一次实验、一次杂交反应就能在全基因组范围内同时分析待测样本中成千上万个基因的表达情况及其相互关系,这一巨大优势是其他分子生物学技术所无法比拟的。
2003年1月开始,我们开始建立和维护一个信息化管理的符合基因组学研究的肝癌数据标本库,接受肝癌切除手术的患者在签署知情同意书后,进入肝癌数据标本库资料收集系统。至2009年12月,共有304例患者组织标本,126例血液样本,114例石蜡标本进入肝癌数据标本库资料收集系统。对标本定期随机抽样进行RNA提取鉴定符合相关分子生物学研究的要求。信息化管理的肝癌数据标本库为多个科研项目提供支持。
我们从建立的肝癌标本库中各随机选取10例早期复发组和10例非早期复发组患者中进入本研究。我们利用Affymetrix基因芯片技术在全基因组范围内分析比较早期复发和非早期复发肝癌患者基因表达谱差异,进而通过数据挖掘筛选与肝癌早期复发相关基因。肝癌早期复发是一个多步骤、多因素参与的复杂过程,是多基因协同作用的结果。筛选到与肝癌早期复发密切相关的分子靶标,为肝癌的生物治疗提供新的靶点和思路,以此建立一组与肝癌早期复发密切相关的分子标签,进行更准确的分子学分类分型,并将为患者提供预后的判断和个体化的治疗。
进一步利用免疫组化验证差异表达基因SOX4和CD24在早期复发组和非早期复发组肝癌之间的表达水平的差异,发现SOX4和CD24基因与肝癌的早期复发密切相关,SOX4和CD24基因高表达有可能促进了肝癌的侵袭和转移,并可能作为预防和治疗肝癌早期复发的分子靶标。
PartⅠEstablishment and maintenance of HCC tissue and data bank by information management
Objective: To explore how to establish and maintenance HCC data bank of information management.Methods:HCC patients after operation were entered into HCC data bank, after signed informed consent. Fresh tissues were stored in liquid nitrogenSome tissue embedded in paraffin and the blood samples were collected. The collected clinical data and specimens is of information management.Resultes:304 cases of tissue specimens, 126 cases of blood samples, 114 cases of paraffin specimens of HCC were entered into HCC data bank. HCC data bank showed be suitable for molecular biologic research.Through information management, HCC data bank provide support for many research projects.Conclusion: Through establish and maintenance HCC data bank of information management, a good foundation is made for study of HCC.
Part II Identification of differentially expressed genes associated with early recurrence of HCC using genechip technology
Objective: To identify the differential expression genes associated with early recurrence after curative resection for HCC using genechip technology.Methods: 20 cases selected from ER group and nER group randomly were entered into this study. The cRNAs were hybridized with Affymetrix genechip. The picture signals were analyzed with GCOS1.2. GeneSpring 10.0 analysis software screened differential gene. The differential expression genes identified by GO analysis, cluster analysis, principal component analysis and pathway analysis.Resultes: There is 2214 differential expression genes analyzed by the GeneSpring software. GO analysis found the differential expression genes were associated with 28 GO terms.The 20 cases could be divided into ER and nER correctly by using clustering analysis and principal component analysis. Pathway analysis showed that differential expression genes participated in apoptosis, transcription, proliferation, processes, and differential expression genes and may be involved in the process of tumor recurrence.Conclusion: The application of Affymetrix genechip technique is a powerful strategy to identify differential expression genes associated with early recurrence for HCC. The further study of the differential expression genes may found molecular mechanism of early recurrence of HCC and screen some new potential therapeutic targets for HCC.
PartⅢExpression of SOX4 and CD24 and early recurrence of hepatocellular carcinoma: validation of their relationship and clinical significance
Objective: To explore study the relationship between expression of SOX4 and CD24 gene and early recurrence after curative resection of HCC, and its clinical significance.Methods: SOX4 and CD24 expression of HCC in 60 patients and normal liver was studied with the methods of immunohisto- chemisty. Resultes: The positive expression of SOX4 and CD24 in HCC was higher than in normal liver. The positive expression of SOX4 and CD24 in HCC of ER after curative resection was higher than HCC of nER. Conclusion: SOX4 and CD24 was confirmed be associated with early recurrence of HCC after curative resection. Up-regulation of SOX4 and CD24may contribute to early recurrence potential of HCC. SOX4 and CD24 may be developed as a new and effective molecular target for HCC in future. The detection of SOX4 in HCC might sever as an important parameter for estimating the prognosis.
2003年1月开始,我们开始建立和维护一个信息化管理的符合基因组学研究的肝癌数据标本库,接受肝癌切除手术的患者在签署知情同意书后,进入肝癌数据标本库资料收集系统。至2009年12月,共有304例患者组织标本,126例血液样本,114例石蜡标本进入肝癌数据标本库资料收集系统。对标本定期随机抽样进行RNA提取鉴定符合相关分子生物学研究的要求。信息化管理的肝癌数据标本库为多个科研项目提供支持。
我们从建立的肝癌标本库中各随机选取10例早期复发组和10例非早期复发组患者中进入本研究。我们利用Affymetrix基因芯片技术在全基因组范围内分析比较早期复发和非早期复发肝癌患者基因表达谱差异,进而通过数据挖掘筛选与肝癌早期复发相关基因。肝癌早期复发是一个多步骤、多因素参与的复杂过程,是多基因协同作用的结果。筛选到与肝癌早期复发密切相关的分子靶标,为肝癌的生物治疗提供新的靶点和思路,以此建立一组与肝癌早期复发密切相关的分子标签,进行更准确的分子学分类分型,并将为患者提供预后的判断和个体化的治疗。
进一步利用免疫组化验证差异表达基因SOX4和CD24在早期复发组和非早期复发组肝癌之间的表达水平的差异,发现SOX4和CD24基因与肝癌的早期复发密切相关,SOX4和CD24基因高表达有可能促进了肝癌的侵袭和转移,并可能作为预防和治疗肝癌早期复发的分子靶标。
PartⅠEstablishment and maintenance of HCC tissue and data bank by information management
Objective: To explore how to establish and maintenance HCC data bank of information management.Methods:HCC patients after operation were entered into HCC data bank, after signed informed consent. Fresh tissues were stored in liquid nitrogenSome tissue embedded in paraffin and the blood samples were collected. The collected clinical data and specimens is of information management.Resultes:304 cases of tissue specimens, 126 cases of blood samples, 114 cases of paraffin specimens of HCC were entered into HCC data bank. HCC data bank showed be suitable for molecular biologic research.Through information management, HCC data bank provide support for many research projects.Conclusion: Through establish and maintenance HCC data bank of information management, a good foundation is made for study of HCC.
Part II Identification of differentially expressed genes associated with early recurrence of HCC using genechip technology
Objective: To identify the differential expression genes associated with early recurrence after curative resection for HCC using genechip technology.Methods: 20 cases selected from ER group and nER group randomly were entered into this study. The cRNAs were hybridized with Affymetrix genechip. The picture signals were analyzed with GCOS1.2. GeneSpring 10.0 analysis software screened differential gene. The differential expression genes identified by GO analysis, cluster analysis, principal component analysis and pathway analysis.Resultes: There is 2214 differential expression genes analyzed by the GeneSpring software. GO analysis found the differential expression genes were associated with 28 GO terms.The 20 cases could be divided into ER and nER correctly by using clustering analysis and principal component analysis. Pathway analysis showed that differential expression genes participated in apoptosis, transcription, proliferation, processes, and differential expression genes and may be involved in the process of tumor recurrence.Conclusion: The application of Affymetrix genechip technique is a powerful strategy to identify differential expression genes associated with early recurrence for HCC. The further study of the differential expression genes may found molecular mechanism of early recurrence of HCC and screen some new potential therapeutic targets for HCC.
PartⅢExpression of SOX4 and CD24 and early recurrence of hepatocellular carcinoma: validation of their relationship and clinical significance
Objective: To explore study the relationship between expression of SOX4 and CD24 gene and early recurrence after curative resection of HCC, and its clinical significance.Methods: SOX4 and CD24 expression of HCC in 60 patients and normal liver was studied with the methods of immunohisto- chemisty. Resultes: The positive expression of SOX4 and CD24 in HCC was higher than in normal liver. The positive expression of SOX4 and CD24 in HCC of ER after curative resection was higher than HCC of nER. Conclusion: SOX4 and CD24 was confirmed be associated with early recurrence of HCC after curative resection. Up-regulation of SOX4 and CD24may contribute to early recurrence potential of HCC. SOX4 and CD24 may be developed as a new and effective molecular target for HCC in future. The detection of SOX4 in HCC might sever as an important parameter for estimating the prognosis.
引文
[1]汤钊猷,21世纪初肝脏外科展望,中华肝胆外科杂志,2005;11(2):75-76.
[2]叶胜龙;秦叔逵;吴孟超;等,原发性肝癌规范化诊治的专家共识,临床肝胆病杂志. 2009;25(2):83-92.
[3]Lau H,Fan ST ,Ng IO ,et al. Long term prognosis after hepatectomy for hepatocellular carcinoma : a survival analysis of 204 consecutive patients. Cancer ,1998 ;83(11) : 2302-2311.
[4]卢欣;赵海涛;毛一雷;等,肝细胞肝癌患者术后早期复发情况,中国医学科学院学报2008,30 (4):415-420.
[5]Regimbeau JM, Abdalla EK, Vauthey JN, et al.Risk factors for early death due to recurrence after liver resection for hepatocellular carcinoma: results of a multicenter study. J Surg Oncol. 2004;85(1):36-41.
[6]张博恒;汤钊猷;余耀,等.影响肝细胞癌术后长期生存的相关因素,癌症进展杂志2005; 3(1):21-25.
[7]Poon RT , Fan ST , Ng IO ,et al. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer , 2000 ,89 (3) : 500-507.
[8]季锡清;李朝龙;刘兴国,等.影响原发性肝癌根治术后近期和远期复发的临床病理因素.西南国防医药,2004;14(2):140-143
[9]张博恒,影响肝癌术后复发因素探讨,中国实用外科杂志,2000;20(3):134-135.
[10]Yasuhiro Y, Kanematsu T ,Matsumata T ,et al. Surgical margin and recurrence after resection of hepatocellular carcinoma in patients with cirrhosis : further evaluation of limited hepatic resection. Ann Surg ,1989 ;209 (4) :297–301.
[11]Poon RT, Fan ST, Ng IO, et al. Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal. Ann Surg, 2000; 231(4): 544-551.
[12] Mathurin P,Raynard B,Dharancy S,et al.Meta-analysis:evaluation of adjunvant therapy after curative liver resection for hepatocellular carcinoma.Aliment Phaimacol Ther,2003,17:1247-1261.
[13]Lai EC, Lo CM, Fan ST, et al. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg, 1998, 133: 183-188.
[14]Endo K,Ueda T,Ueyama J,et al.Immunoreactive E-cadherin, al-pha-catein, beta-catenin,and gamma-catenin proteins in hepato-cellular carcinoma: relation- ships with tumor grade,clinicopatho-logic parameters,and patient' s survival.Hum Pathol,2000,31:558-565.
[15]郭荣平;钟崇;石明;等,血管内皮生长因子和基质金属蛋白酶-2在肝细胞肝癌中的表达及临床意义,中华肿瘤杂志2006,28(4):285-288.
[16]刘智敏;严律南;汤宇;等,血管内皮生长因子和基质金属蛋白酶-9在肝细胞癌中的表达及其意义.中国普外基础与临床杂志, 2002; 9 (6)∶421-423.
[17]Poon RT,Ng IO,Lau C,et al.Serum vascular endothelial growth factor predict s venous invasion in hepatocellular carcinoma : a prospective study. Ann Surg , 2001;233 (2)∶227-235.
[18]Qin LX, Tang ZY, Sham JS, et al. The association of chromosome 8p deletion and tumor metastasis in human hepatocellular carcinoma. Cancer Res,1999,59 (22): 5662-5665.
[19]Ye QH,Qin LX,Forgues M,et al.Predicting hepatitis B virus- positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning.Nat Med,2003;9 (4)∶416-423.
[20]Iizuka N, Oka M, Yamada-Okabe H,et al. Oligonucleotidemicroarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet,2003,361(9361):923-929.
1.温增庆,吴孟超,杨甲梅等。巨大肝癌手术切除的临床疗效。实用癌症杂志,2001,16(2):189-190。
2. Izumi R,Shimizu K,Iyobe T,et al.Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs with hepatocellular carcinoma. Hepatology ,1994 , 20:295-301.
3. Ercolani G,Grazi GL,Ravaioli M,et al.Liver resection for hepatocellular carcinoma on cirrhosis:Univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg,2003,237:536.
4. Poon RT,Fan ST. Hepatectomy for hepatocellular carcinoma: Patient selection and postoperative outcome. Liver Transpl, 2004,10:S39.
5. Brentani RR,Carraro DM,Verjovski-Almeida S,et al.Gene expression arrays in cancer research: methods and applications [J]. Crit Revin Oncol Hematol,2005,54(2):95-105.
6. Yano K,Miki Y. Perspectives on postgenome medicine Cancer [J]. Nippon Rinsho,2001,59(1):31-37.
7. Ye QH , Qin LX , Forgues M , et al . Predicting hepatitis B virus- positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med , 2003 ; 9 (4)∶416-423.
8.陈伟,林叶,侯宝华,等.规范化网络信息系统支持的肝癌标本库建立探讨.实用医学杂志, 2007, 23 (6) : 826 - 827.
9. AminW, ParwaniAV, SchmandtL, et al. National Mesothelioma Virtual Bank: A standard based biospecimen and clinical data resource to enhance translational research. BMC Cancer, 2008,8: 236.
10. Marinelli RJ, Montgomery K, Liu CL, et al. The Stanford TissueMicroarray Database. Nucleic Acids Res, 2008, 36 (Databaseissue) : D871 - D877.
11. Whyte B. National tumor bank set up in United Kindom. J Natal Cancer Inst,2003,95:706
12. Tschulik A,Zatloukal K. The increasing importance of tumor and tissue banks in the light of genomic and proteomic research. Pathology,2001,22:310-315.
13.张智坚,杨甲梅,吴孟超等。肝癌根治性切除手术标准的探讨。肝胆外科杂杂志,1999,7:180-182。
14.黄志强。肝切除范围与肝癌复发。见黄志强著:肝脏外科手术学,179-181。北京:人民军医出版社,1996。
15.叶青海,汤钊猷,钦伦秀等.基因芯片技术在肝癌转移相关基因筛选中的应用[J].中华肝胆外科杂志,2004,10(10):679.
16. Liu LX,Jiang HC,Liu ZH,et al. Integrin gene expression profiles of human hepatocellular carcinoma [J]. World J Gastroenterol, 2002, 8(4): 631.
17. Li Y,Tang Z,Ye S,et al. Gene expression profile of human hepatocellular carcinoma cell lines with different metastatic potentials.中华肿瘤杂志,2002,24(6):533.
18. Lizuka N,Oka M,Nishida M,et al.Oligonucleotide microarray for predicition of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet,2003,361:923
19. Wilson ME, Yang KY, Kalousova A, et al. The HMG box transcription factor SoX4 contributes to the development of the endocrine pancreas. Diabetes, 2005, 54 (12) :3402?3409.
20. Sinner D , Jennifer J , Kordich S , et al . Sox17 and Sox4 differentially regulateβ- catenin/ T- cell factor activity and proliferation of colon carcinoma cells. Mol Cellular Biol ,2007 ,27(22) :7802 - 7815.
21. Ahn SG, Kim HS , Jeong SW, et al . Sox-4 is a positive regulator of Hep3B and HepG2 cells' apoptosis induced by prostaglandin (PG)A(2) and delta(12)-PGJ(2).Exp Mol Med ,2002 ,34(3) :243 - 249.
22. Liu P , Ramachandran S , Ali Seyed M, et al . Sex - determining region Y box 4 is a transforming oncogene in human prostate cancer cells.Cancer Res ,2006 ,66(8) :4011 - 4019.
23. Liao YL, Sun YM, Chau GY,et al . Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma. Oncogene. 2008, 27, 5578–5589.
24. Surowiak P ,Materna V , Gyorffy B ,et al . Multivariate Analysis of Oest rogen Receptor Alpha , pS2 , Metallot hionein and CD24 Expression in Invasive Breast Cancers. Br J Cancer ,2006 ,95 :3392-346
25. Surowiak P ,Materna V , Kaplenko I ,et al . Unfavorable Prognostic Value of CD24 Expression in Sections f rom Primary and Relapsed Ovarian Cancer Tissue. Int J Gynecol Cancer ,2006 ,16 :515-521.
26. Jung KC,Seo JN ,KimT W,et al . CD24 Expressionin Gastric adenocarcinomais associated wit h Tumor Invasivenes. Korean J Pat hol ,2004 ,38 (6) :388-393.
27. Sagiv E , Kazanov D ,Arber N ,et al . CD24 Plays an Important Role in the carcinogenesis Proces of t he Pancreas . Biomed Pharmacot her ,2006 ,60 (6) :280-284.
28. Songun I, Lit vinov SV, Van de velde CJ,et al. Loss of EP-cam (CO17-1A) expression predicts survival in patientswith gastric cancer.BrJCancer, 2005, 92 (9): 1767-1772.
29. Seligson DB,Horvath S, Shi T,et al. G.lobal histone modification patterns predict risk of prostate cancer recurrence.Nature,2005, 435(7046): 1262-1266.
30.丁光伟,徐秋霞,杨玉秀等.肝硬化和肝癌差异基因表达的对比研究[J].胃肠病学和肝病学杂志,2006,15(3):260.
31. Kennedy MT, Jordan RC, Berean KW, et al. Expression attern of CK7, CK20, CDX22, and villin in intstinal type sinonasal adenocarcinoma [ J ]. J Clin Pathol, 2004, 57(9) : 932
32.赵成波,周成军,郭建强,绒毛蛋白在胃癌及癌前病变中的表达及意义,山东大学学报(医学版),2009年,47(2):46-49.
33.徐忠东,吴琴,微管蛋白的研究进展,安徽教育学院学报,1999,2:73-74.
34. Sinclair AH, Berta P, Palmer MS, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990. 346(6281): 240-4.
35. Wilson ME, Yang KY, Kalousova A, et al. The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas. Diabetes. 2005. 54(12): 3402-9.
36. Boyd KE, Xiao YY, Fan K, et al. Sox4 cooperates with Evi1 in AKXD-23 myeloid tumors via transactivation of proviral LTR. Blood. 2006. 107(2): 733-41.
37. Springer T, Galfre G, Secher DS, Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978. 8(8): 539-51.
38. Kim HJ, Kim JB, Lee KM, et al. Isolation of CD24(high) and CD24(low/-) cells from MCF-7: CD24 expression is positively related with proliferation, adhesion and invasion in MCF-7. Cancer Lett. 2007. 258(1): 98-108.
39. Baumann P, Cremers N, Kroese F, et al. CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res. 2005. 65(23): 10783-93.
40. Smith SC, Oxford G, Wu Z, et al. The metastasis-associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer. CancerRes. 2006. 66(4): 1917-22.
41. Runz S, Mierke CT, Joumaa S, Behrens J, Fabry B, Altevogt P. CD24 induces localization of beta1 integrin to lipid raft domains. Biochem Biophys Res Commun. 2008. 365(1): 35-41.
42.庄建良,苏子剑,许荣誉. CD24与肿瘤侵袭转移的关系.国际病理科学与临床杂志. 2006. (05): 387-390.
43. Jacob J, Bellach J, Grutzmann R, et al. Expression of CD24 in adenocarcinomas of the pancreas correlates with higher tumor grades. Pancreatology. 2004. 4(5): 454-60.
44. Sagiv E, Memeo L, Karin A, et al. CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis. Gastroenterology. 2006. 131(2): 630-9.
45. Weichert W, Denkert C, Burkhardt M, et al. Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival. Clin Cancer Res. 2005. 11(18): 6574-81.
46. Bircan S, Kapucuoglu N, Baspinar S, Inan G, Candir O. CD24 expression in ductal carcinoma in situ and invasive ductal carcinoma of breast: an immuno-工团histochemistry-based pilot study. Pathol Res Pract. 2006. 202(8): 569-76.
47. Kristiansen G, Winzer KJ, Mayordomo E, et al. CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res. 2003. 9(13): 4906-13.
48. Huang LR, Hsu HC. Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation. Cancer Res. 1995. 55(20): 4717-21.
[2]叶胜龙;秦叔逵;吴孟超;等,原发性肝癌规范化诊治的专家共识,临床肝胆病杂志. 2009;25(2):83-92.
[3]Lau H,Fan ST ,Ng IO ,et al. Long term prognosis after hepatectomy for hepatocellular carcinoma : a survival analysis of 204 consecutive patients. Cancer ,1998 ;83(11) : 2302-2311.
[4]卢欣;赵海涛;毛一雷;等,肝细胞肝癌患者术后早期复发情况,中国医学科学院学报2008,30 (4):415-420.
[5]Regimbeau JM, Abdalla EK, Vauthey JN, et al.Risk factors for early death due to recurrence after liver resection for hepatocellular carcinoma: results of a multicenter study. J Surg Oncol. 2004;85(1):36-41.
[6]张博恒;汤钊猷;余耀,等.影响肝细胞癌术后长期生存的相关因素,癌症进展杂志2005; 3(1):21-25.
[7]Poon RT , Fan ST , Ng IO ,et al. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer , 2000 ,89 (3) : 500-507.
[8]季锡清;李朝龙;刘兴国,等.影响原发性肝癌根治术后近期和远期复发的临床病理因素.西南国防医药,2004;14(2):140-143
[9]张博恒,影响肝癌术后复发因素探讨,中国实用外科杂志,2000;20(3):134-135.
[10]Yasuhiro Y, Kanematsu T ,Matsumata T ,et al. Surgical margin and recurrence after resection of hepatocellular carcinoma in patients with cirrhosis : further evaluation of limited hepatic resection. Ann Surg ,1989 ;209 (4) :297–301.
[11]Poon RT, Fan ST, Ng IO, et al. Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal. Ann Surg, 2000; 231(4): 544-551.
[12] Mathurin P,Raynard B,Dharancy S,et al.Meta-analysis:evaluation of adjunvant therapy after curative liver resection for hepatocellular carcinoma.Aliment Phaimacol Ther,2003,17:1247-1261.
[13]Lai EC, Lo CM, Fan ST, et al. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg, 1998, 133: 183-188.
[14]Endo K,Ueda T,Ueyama J,et al.Immunoreactive E-cadherin, al-pha-catein, beta-catenin,and gamma-catenin proteins in hepato-cellular carcinoma: relation- ships with tumor grade,clinicopatho-logic parameters,and patient' s survival.Hum Pathol,2000,31:558-565.
[15]郭荣平;钟崇;石明;等,血管内皮生长因子和基质金属蛋白酶-2在肝细胞肝癌中的表达及临床意义,中华肿瘤杂志2006,28(4):285-288.
[16]刘智敏;严律南;汤宇;等,血管内皮生长因子和基质金属蛋白酶-9在肝细胞癌中的表达及其意义.中国普外基础与临床杂志, 2002; 9 (6)∶421-423.
[17]Poon RT,Ng IO,Lau C,et al.Serum vascular endothelial growth factor predict s venous invasion in hepatocellular carcinoma : a prospective study. Ann Surg , 2001;233 (2)∶227-235.
[18]Qin LX, Tang ZY, Sham JS, et al. The association of chromosome 8p deletion and tumor metastasis in human hepatocellular carcinoma. Cancer Res,1999,59 (22): 5662-5665.
[19]Ye QH,Qin LX,Forgues M,et al.Predicting hepatitis B virus- positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning.Nat Med,2003;9 (4)∶416-423.
[20]Iizuka N, Oka M, Yamada-Okabe H,et al. Oligonucleotidemicroarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet,2003,361(9361):923-929.
1.温增庆,吴孟超,杨甲梅等。巨大肝癌手术切除的临床疗效。实用癌症杂志,2001,16(2):189-190。
2. Izumi R,Shimizu K,Iyobe T,et al.Postoperative adjuvant hepatic arterial infusion of Lipiodol containing anticancer drugs with hepatocellular carcinoma. Hepatology ,1994 , 20:295-301.
3. Ercolani G,Grazi GL,Ravaioli M,et al.Liver resection for hepatocellular carcinoma on cirrhosis:Univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg,2003,237:536.
4. Poon RT,Fan ST. Hepatectomy for hepatocellular carcinoma: Patient selection and postoperative outcome. Liver Transpl, 2004,10:S39.
5. Brentani RR,Carraro DM,Verjovski-Almeida S,et al.Gene expression arrays in cancer research: methods and applications [J]. Crit Revin Oncol Hematol,2005,54(2):95-105.
6. Yano K,Miki Y. Perspectives on postgenome medicine Cancer [J]. Nippon Rinsho,2001,59(1):31-37.
7. Ye QH , Qin LX , Forgues M , et al . Predicting hepatitis B virus- positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med , 2003 ; 9 (4)∶416-423.
8.陈伟,林叶,侯宝华,等.规范化网络信息系统支持的肝癌标本库建立探讨.实用医学杂志, 2007, 23 (6) : 826 - 827.
9. AminW, ParwaniAV, SchmandtL, et al. National Mesothelioma Virtual Bank: A standard based biospecimen and clinical data resource to enhance translational research. BMC Cancer, 2008,8: 236.
10. Marinelli RJ, Montgomery K, Liu CL, et al. The Stanford TissueMicroarray Database. Nucleic Acids Res, 2008, 36 (Databaseissue) : D871 - D877.
11. Whyte B. National tumor bank set up in United Kindom. J Natal Cancer Inst,2003,95:706
12. Tschulik A,Zatloukal K. The increasing importance of tumor and tissue banks in the light of genomic and proteomic research. Pathology,2001,22:310-315.
13.张智坚,杨甲梅,吴孟超等。肝癌根治性切除手术标准的探讨。肝胆外科杂杂志,1999,7:180-182。
14.黄志强。肝切除范围与肝癌复发。见黄志强著:肝脏外科手术学,179-181。北京:人民军医出版社,1996。
15.叶青海,汤钊猷,钦伦秀等.基因芯片技术在肝癌转移相关基因筛选中的应用[J].中华肝胆外科杂志,2004,10(10):679.
16. Liu LX,Jiang HC,Liu ZH,et al. Integrin gene expression profiles of human hepatocellular carcinoma [J]. World J Gastroenterol, 2002, 8(4): 631.
17. Li Y,Tang Z,Ye S,et al. Gene expression profile of human hepatocellular carcinoma cell lines with different metastatic potentials.中华肿瘤杂志,2002,24(6):533.
18. Lizuka N,Oka M,Nishida M,et al.Oligonucleotide microarray for predicition of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet,2003,361:923
19. Wilson ME, Yang KY, Kalousova A, et al. The HMG box transcription factor SoX4 contributes to the development of the endocrine pancreas. Diabetes, 2005, 54 (12) :3402?3409.
20. Sinner D , Jennifer J , Kordich S , et al . Sox17 and Sox4 differentially regulateβ- catenin/ T- cell factor activity and proliferation of colon carcinoma cells. Mol Cellular Biol ,2007 ,27(22) :7802 - 7815.
21. Ahn SG, Kim HS , Jeong SW, et al . Sox-4 is a positive regulator of Hep3B and HepG2 cells' apoptosis induced by prostaglandin (PG)A(2) and delta(12)-PGJ(2).Exp Mol Med ,2002 ,34(3) :243 - 249.
22. Liu P , Ramachandran S , Ali Seyed M, et al . Sex - determining region Y box 4 is a transforming oncogene in human prostate cancer cells.Cancer Res ,2006 ,66(8) :4011 - 4019.
23. Liao YL, Sun YM, Chau GY,et al . Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma. Oncogene. 2008, 27, 5578–5589.
24. Surowiak P ,Materna V , Gyorffy B ,et al . Multivariate Analysis of Oest rogen Receptor Alpha , pS2 , Metallot hionein and CD24 Expression in Invasive Breast Cancers. Br J Cancer ,2006 ,95 :3392-346
25. Surowiak P ,Materna V , Kaplenko I ,et al . Unfavorable Prognostic Value of CD24 Expression in Sections f rom Primary and Relapsed Ovarian Cancer Tissue. Int J Gynecol Cancer ,2006 ,16 :515-521.
26. Jung KC,Seo JN ,KimT W,et al . CD24 Expressionin Gastric adenocarcinomais associated wit h Tumor Invasivenes. Korean J Pat hol ,2004 ,38 (6) :388-393.
27. Sagiv E , Kazanov D ,Arber N ,et al . CD24 Plays an Important Role in the carcinogenesis Proces of t he Pancreas . Biomed Pharmacot her ,2006 ,60 (6) :280-284.
28. Songun I, Lit vinov SV, Van de velde CJ,et al. Loss of EP-cam (CO17-1A) expression predicts survival in patientswith gastric cancer.BrJCancer, 2005, 92 (9): 1767-1772.
29. Seligson DB,Horvath S, Shi T,et al. G.lobal histone modification patterns predict risk of prostate cancer recurrence.Nature,2005, 435(7046): 1262-1266.
30.丁光伟,徐秋霞,杨玉秀等.肝硬化和肝癌差异基因表达的对比研究[J].胃肠病学和肝病学杂志,2006,15(3):260.
31. Kennedy MT, Jordan RC, Berean KW, et al. Expression attern of CK7, CK20, CDX22, and villin in intstinal type sinonasal adenocarcinoma [ J ]. J Clin Pathol, 2004, 57(9) : 932
32.赵成波,周成军,郭建强,绒毛蛋白在胃癌及癌前病变中的表达及意义,山东大学学报(医学版),2009年,47(2):46-49.
33.徐忠东,吴琴,微管蛋白的研究进展,安徽教育学院学报,1999,2:73-74.
34. Sinclair AH, Berta P, Palmer MS, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990. 346(6281): 240-4.
35. Wilson ME, Yang KY, Kalousova A, et al. The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas. Diabetes. 2005. 54(12): 3402-9.
36. Boyd KE, Xiao YY, Fan K, et al. Sox4 cooperates with Evi1 in AKXD-23 myeloid tumors via transactivation of proviral LTR. Blood. 2006. 107(2): 733-41.
37. Springer T, Galfre G, Secher DS, Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978. 8(8): 539-51.
38. Kim HJ, Kim JB, Lee KM, et al. Isolation of CD24(high) and CD24(low/-) cells from MCF-7: CD24 expression is positively related with proliferation, adhesion and invasion in MCF-7. Cancer Lett. 2007. 258(1): 98-108.
39. Baumann P, Cremers N, Kroese F, et al. CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res. 2005. 65(23): 10783-93.
40. Smith SC, Oxford G, Wu Z, et al. The metastasis-associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer. CancerRes. 2006. 66(4): 1917-22.
41. Runz S, Mierke CT, Joumaa S, Behrens J, Fabry B, Altevogt P. CD24 induces localization of beta1 integrin to lipid raft domains. Biochem Biophys Res Commun. 2008. 365(1): 35-41.
42.庄建良,苏子剑,许荣誉. CD24与肿瘤侵袭转移的关系.国际病理科学与临床杂志. 2006. (05): 387-390.
43. Jacob J, Bellach J, Grutzmann R, et al. Expression of CD24 in adenocarcinomas of the pancreas correlates with higher tumor grades. Pancreatology. 2004. 4(5): 454-60.
44. Sagiv E, Memeo L, Karin A, et al. CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis. Gastroenterology. 2006. 131(2): 630-9.
45. Weichert W, Denkert C, Burkhardt M, et al. Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival. Clin Cancer Res. 2005. 11(18): 6574-81.
46. Bircan S, Kapucuoglu N, Baspinar S, Inan G, Candir O. CD24 expression in ductal carcinoma in situ and invasive ductal carcinoma of breast: an immuno-工团histochemistry-based pilot study. Pathol Res Pract. 2006. 202(8): 569-76.
47. Kristiansen G, Winzer KJ, Mayordomo E, et al. CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res. 2003. 9(13): 4906-13.
48. Huang LR, Hsu HC. Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation. Cancer Res. 1995. 55(20): 4717-21.