Glypcian-3在原发性肝癌中的检测及与AFP联合检测的诊断价值
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摘要
目的
检测原发性肝癌(PHC)患者血清中Glypican-3(GPC3)与甲胎蛋白(AFP)的水平,探讨PHC患者血清中GPC3的表达和临床意义及与AFP联合检测在原发性肝癌中的诊断价值。
方法
选取吉林大学中日联谊医院门诊和住院收治的原发性肝癌(PHC)患者64例、肝硬化(LC)患者63例和健康体检者54例空腹血清标本。Glypcian-3采用酶联免疫吸附试验(ELISA)方法,AFP采用微粒子酶免化学发光分析法,分别检测原发性肝癌组、肝硬化组和正常对照组血清Glypcian-3及AFP含量并进行相关因素的分析。
结果
64例PHC患者、63例LC患者和54例健康体检者血清中的Glypcian-3阳性表达率分别为75.00%、0%、0%。Glypcian-3对PHC诊断的敏感性75.00%,特异性100%。Glypcian-3与TNM分期呈明显正相关(P<0.01),随着分期的增加,Glypcian-3的检出率增加;而与性别、年龄、肿瘤直径、癌结节数目、门脉癌栓、肝功能分级及AFP水平无相关性(P>0.05)。在AFP阴性的PHC患者中Glypcian-3阳性检出率为76.47%,Glypcian-3与AFP联合检测的敏感性为93.75%。
结论
1. Glypican-3在原发性肝癌患者血清中高表达,在肝硬化患者及正常组血清中不表达或低表达,可作为原发性肝癌诊断的肿瘤标志物,有助于鉴别良、恶性肝病。
2. Glypcian-3与TNM分期明显正相关,而与性别、年龄、肿瘤直径、癌结节数目、有无门脉癌栓、肝功能分级及AFP水平无相关,提示疾病的初始就有Glypcian-3的表达,有助于判断病情轻重及预后。
3. Glypican-3在AFP阴性的原发性肝癌患者血清中有较高的检出率,与AFP联合检测可提高原发性肝癌的检测敏感性,对AFP阴性及低浓度的原发性肝癌的筛选均有一定的临床诊断和鉴别诊断价值,有助于提高原发性肝癌的早期诊断率,减少漏诊。
Primary hepatic carcinoma (PHC) is one of most frequent malignant tumor in the world.It has characteristics of high malignant degree and bad prognosis. Advanced stage PHC has high recurrence rate and is easy to metastasize after exsection. Early diagnosis and early treatment are the most significant methods of elevating the survival rate of hepatoma. At present,we diagnose hepatoma mostly by the discovery of imageology and the detection from the tumor markers(TM) of blood serum. As an important blood-serum marker of PHC,Alpha fetoprotein(AFP) is one of most significant indicatrix in serology to diagnose hepatoma and generally used for screening of PHC , observation of curative effect and analyses of prognosis. However ,due to the effect of the differentiation degree of hepatoma carcinoma cell, the masculine rate is approximately 60 to 70 per cents,as 30 per cents of PHC sufferer has slight advance or non-advance. In some cases such as Pregnancy, some gastric carcinoma, hepatic metastasis of alimentary canal, active hepatitis and procreate embryo tumor,AFP also can heighten to influence the specificity of diagnosing hepatoma. If we do clinical diagnosis and extensive survey of hepatoma only by AFP,it may result in missed diagnosis or misdiagnosis. Therefore,the diagnosis for this part hepatoma patients is more important, especially for microhepatia tumor.
Glypican-3(GPC3) is a member of heparan sulfate proteoglycan (HSPG) family.As a new type of genes, GPC3 considered to be closely connect with the occurrence and development of hepatoma, has important effect on the regulation of growth.The research of the dependability between GPC3 and hepatoma becomes a hot spot,scine Pilia .etc have cloned GPC3 gene successfully in 1996.Some research indicates that masculine rate of GPC3 protein is high in the serum of hepatoma patient.It’s paid close attention whether GPC3 will be a satisfactory serum marker for PHC. Accordingly,we will discuss the expression and cilinic significance of GPC3 protein in the serum of hepatoma patient,from the detection of GPC3 protein in the serum of hepatoma patient.
Objective:
To approach the expression and cilinic significance of GPC3 in the serum of hepatoma patient and the diagnostic value for PHC combined with AFP detection.
Methods:
We collected the serum of outpatients clinic and inpatients hospital with an empty stomach in China-Japan Union Hospital of JiLin University, including 64 of PHC,63 of LC and 54 of healthy blood donor.In PHC group:male:54 persons,female:10 personson the ages of 24-81equally (58.06±12.13).In LC group: male:45 persons,female:18 persons,on the ages of 24-80equally (53.92±11.67). The final diagnosis of all the PHC patiens is consistent with clinical diagnosis and staging standard of PHC which was revised in sep,2001 by China Anticancer Association of Professional Com- mittee of liver cancer. In 64 PHC patiens,there is 6 inⅠs tage(9.38%),28 inⅡ(43.75%),26 inⅢ(40.63%),4 inⅣ(6.25%);while 26 with carcino-epistom in portal vein (40.63%), 28 with cancer diameter≥5cm(43.75%),24 with 2 or more cancer tubercle(37.5%),and in Hepatic function Child-pugh Staging: 22 in A degree(34.38%),14 in B degree(21.88%),28 in C degree(12.50%). In LC group: male:45 persons,female:18 persons,on the ages of 24-80 equally (53.92±11.67).The diagnosis is consistent with diagnostic criteria of prevention and cure program for viral hepatitis which is revised by Xi'an conference of Chinese Medical Association in 2000.In normal group: male 41 persons,female 13 persons,on the ages of 35-79(equally54.17±12.67).We determine GPC3 by the methods of ELISA,with the kit provided by ADL(Adlitteram Diagnostic laboratories)in American.AFP is determined by microparticle enzyme chemi- luminometry,and AXSYM automatic immunity analysator and kit is provided by Abbott Laboratories in American.
Results:
1. Comparing with LC group and normal control ,the detection of GPC3 in the serum from PHC patients advances obviously, with significant difference (p<0.01). Comparing with LC group and normal control ,the detection of AFP in the serum from PHC patients advances obviously,with significant difference (p<0.01). Comparing with LC group and normal control,the detection of GPC3 and AFP , with no significant difference(p>0.05).
2.The masculine rate of GPC3 and AFP in PHC and LC patients is obviously higher than normal control, with significant difference (p<0.01). The detection rate of GPC3 in AFP negative is 76.47%.The difference of masculine comparison is quiet comparing between AFP masculine and negative (P>0.05).
3.GPC3 is correlatedwith Clinical TNM Staging,but not with sexuality、age、the diameter of cancer、number of cancer tubercle、carcino-epistom、Hepatic function Child-pugh Staging and level of AFP(P>0.05).
4.In the serum of hepatoma patient whose AFP is negative, GPC3 is detected highly by 76.47%.The sensibility will be elevated to 93.75%,as well as missed diagnosis rate dropped to 6.25%,by associated detection of GPC3 and AFP.It has significant deviation, comparing with solitude detection of GPC3 and AFP.
Conclusion:
As a new gene, Glypcian-3 has important effectiveness for growth regulation.It may be important reason that the mutation of gene induce overbalance of cell multiplication and apoptosis. Generous researches show that Glypcian-3 is be overexpressed in PHC cells,while lowexpressed or non-expressed in normal adult tissue, laterocancer tissue, hepatitis and hepatic cirrhosis tissue.By estimate analysis of diagnosis text, GPC3 in serum has high sensibility(75.00%), specificity(100%) and low misdiagnosis rate(25.00%) in the method of ELISA.It is not found in serum of hepatic cirrhosis patients and health adult.So, antidiastole value is high.In the reseach,it also show that expression of GPC3 protein has no significant dependablity with sexuality、age、the diameter of cancer、number of cancer tubercle、carcino- epistom、Hepatic function Child-pugh Staging and level of AFP,but,with significant dependability with TNM Staging(P<0.01).It’s indicate that GPC3 protein ,as a specific tumor marker,may be expressed steadily in incipient cell canceration, being a earlier period occurrence of HCC development,with important value for forecast of malignancy degree, pathogenetic condition and prognosis.As marker for PHC early diagnosis,GPC3 protein has high mascu- line rate in serum of PHC patients with AFP negative. GPC3 combined with AFP detection can elevate detection rate of PHC, has clinical diagnosis and antidiastole value to PHC with AFP negative or low degree and will elevate early diagnosis rate of PHC as well as reduce missed diagnosis of PHC. Therefore,we should employ combining detection to elevate early diagnosis rate of PHC.
检测原发性肝癌(PHC)患者血清中Glypican-3(GPC3)与甲胎蛋白(AFP)的水平,探讨PHC患者血清中GPC3的表达和临床意义及与AFP联合检测在原发性肝癌中的诊断价值。
方法
选取吉林大学中日联谊医院门诊和住院收治的原发性肝癌(PHC)患者64例、肝硬化(LC)患者63例和健康体检者54例空腹血清标本。Glypcian-3采用酶联免疫吸附试验(ELISA)方法,AFP采用微粒子酶免化学发光分析法,分别检测原发性肝癌组、肝硬化组和正常对照组血清Glypcian-3及AFP含量并进行相关因素的分析。
结果
64例PHC患者、63例LC患者和54例健康体检者血清中的Glypcian-3阳性表达率分别为75.00%、0%、0%。Glypcian-3对PHC诊断的敏感性75.00%,特异性100%。Glypcian-3与TNM分期呈明显正相关(P<0.01),随着分期的增加,Glypcian-3的检出率增加;而与性别、年龄、肿瘤直径、癌结节数目、门脉癌栓、肝功能分级及AFP水平无相关性(P>0.05)。在AFP阴性的PHC患者中Glypcian-3阳性检出率为76.47%,Glypcian-3与AFP联合检测的敏感性为93.75%。
结论
1. Glypican-3在原发性肝癌患者血清中高表达,在肝硬化患者及正常组血清中不表达或低表达,可作为原发性肝癌诊断的肿瘤标志物,有助于鉴别良、恶性肝病。
2. Glypcian-3与TNM分期明显正相关,而与性别、年龄、肿瘤直径、癌结节数目、有无门脉癌栓、肝功能分级及AFP水平无相关,提示疾病的初始就有Glypcian-3的表达,有助于判断病情轻重及预后。
3. Glypican-3在AFP阴性的原发性肝癌患者血清中有较高的检出率,与AFP联合检测可提高原发性肝癌的检测敏感性,对AFP阴性及低浓度的原发性肝癌的筛选均有一定的临床诊断和鉴别诊断价值,有助于提高原发性肝癌的早期诊断率,减少漏诊。
Primary hepatic carcinoma (PHC) is one of most frequent malignant tumor in the world.It has characteristics of high malignant degree and bad prognosis. Advanced stage PHC has high recurrence rate and is easy to metastasize after exsection. Early diagnosis and early treatment are the most significant methods of elevating the survival rate of hepatoma. At present,we diagnose hepatoma mostly by the discovery of imageology and the detection from the tumor markers(TM) of blood serum. As an important blood-serum marker of PHC,Alpha fetoprotein(AFP) is one of most significant indicatrix in serology to diagnose hepatoma and generally used for screening of PHC , observation of curative effect and analyses of prognosis. However ,due to the effect of the differentiation degree of hepatoma carcinoma cell, the masculine rate is approximately 60 to 70 per cents,as 30 per cents of PHC sufferer has slight advance or non-advance. In some cases such as Pregnancy, some gastric carcinoma, hepatic metastasis of alimentary canal, active hepatitis and procreate embryo tumor,AFP also can heighten to influence the specificity of diagnosing hepatoma. If we do clinical diagnosis and extensive survey of hepatoma only by AFP,it may result in missed diagnosis or misdiagnosis. Therefore,the diagnosis for this part hepatoma patients is more important, especially for microhepatia tumor.
Glypican-3(GPC3) is a member of heparan sulfate proteoglycan (HSPG) family.As a new type of genes, GPC3 considered to be closely connect with the occurrence and development of hepatoma, has important effect on the regulation of growth.The research of the dependability between GPC3 and hepatoma becomes a hot spot,scine Pilia .etc have cloned GPC3 gene successfully in 1996.Some research indicates that masculine rate of GPC3 protein is high in the serum of hepatoma patient.It’s paid close attention whether GPC3 will be a satisfactory serum marker for PHC. Accordingly,we will discuss the expression and cilinic significance of GPC3 protein in the serum of hepatoma patient,from the detection of GPC3 protein in the serum of hepatoma patient.
Objective:
To approach the expression and cilinic significance of GPC3 in the serum of hepatoma patient and the diagnostic value for PHC combined with AFP detection.
Methods:
We collected the serum of outpatients clinic and inpatients hospital with an empty stomach in China-Japan Union Hospital of JiLin University, including 64 of PHC,63 of LC and 54 of healthy blood donor.In PHC group:male:54 persons,female:10 personson the ages of 24-81equally (58.06±12.13).In LC group: male:45 persons,female:18 persons,on the ages of 24-80equally (53.92±11.67). The final diagnosis of all the PHC patiens is consistent with clinical diagnosis and staging standard of PHC which was revised in sep,2001 by China Anticancer Association of Professional Com- mittee of liver cancer. In 64 PHC patiens,there is 6 inⅠs tage(9.38%),28 inⅡ(43.75%),26 inⅢ(40.63%),4 inⅣ(6.25%);while 26 with carcino-epistom in portal vein (40.63%), 28 with cancer diameter≥5cm(43.75%),24 with 2 or more cancer tubercle(37.5%),and in Hepatic function Child-pugh Staging: 22 in A degree(34.38%),14 in B degree(21.88%),28 in C degree(12.50%). In LC group: male:45 persons,female:18 persons,on the ages of 24-80 equally (53.92±11.67).The diagnosis is consistent with diagnostic criteria of prevention and cure program for viral hepatitis which is revised by Xi'an conference of Chinese Medical Association in 2000.In normal group: male 41 persons,female 13 persons,on the ages of 35-79(equally54.17±12.67).We determine GPC3 by the methods of ELISA,with the kit provided by ADL(Adlitteram Diagnostic laboratories)in American.AFP is determined by microparticle enzyme chemi- luminometry,and AXSYM automatic immunity analysator and kit is provided by Abbott Laboratories in American.
Results:
1. Comparing with LC group and normal control ,the detection of GPC3 in the serum from PHC patients advances obviously, with significant difference (p<0.01). Comparing with LC group and normal control ,the detection of AFP in the serum from PHC patients advances obviously,with significant difference (p<0.01). Comparing with LC group and normal control,the detection of GPC3 and AFP , with no significant difference(p>0.05).
2.The masculine rate of GPC3 and AFP in PHC and LC patients is obviously higher than normal control, with significant difference (p<0.01). The detection rate of GPC3 in AFP negative is 76.47%.The difference of masculine comparison is quiet comparing between AFP masculine and negative (P>0.05).
3.GPC3 is correlatedwith Clinical TNM Staging,but not with sexuality、age、the diameter of cancer、number of cancer tubercle、carcino-epistom、Hepatic function Child-pugh Staging and level of AFP(P>0.05).
4.In the serum of hepatoma patient whose AFP is negative, GPC3 is detected highly by 76.47%.The sensibility will be elevated to 93.75%,as well as missed diagnosis rate dropped to 6.25%,by associated detection of GPC3 and AFP.It has significant deviation, comparing with solitude detection of GPC3 and AFP.
Conclusion:
As a new gene, Glypcian-3 has important effectiveness for growth regulation.It may be important reason that the mutation of gene induce overbalance of cell multiplication and apoptosis. Generous researches show that Glypcian-3 is be overexpressed in PHC cells,while lowexpressed or non-expressed in normal adult tissue, laterocancer tissue, hepatitis and hepatic cirrhosis tissue.By estimate analysis of diagnosis text, GPC3 in serum has high sensibility(75.00%), specificity(100%) and low misdiagnosis rate(25.00%) in the method of ELISA.It is not found in serum of hepatic cirrhosis patients and health adult.So, antidiastole value is high.In the reseach,it also show that expression of GPC3 protein has no significant dependablity with sexuality、age、the diameter of cancer、number of cancer tubercle、carcino- epistom、Hepatic function Child-pugh Staging and level of AFP,but,with significant dependability with TNM Staging(P<0.01).It’s indicate that GPC3 protein ,as a specific tumor marker,may be expressed steadily in incipient cell canceration, being a earlier period occurrence of HCC development,with important value for forecast of malignancy degree, pathogenetic condition and prognosis.As marker for PHC early diagnosis,GPC3 protein has high mascu- line rate in serum of PHC patients with AFP negative. GPC3 combined with AFP detection can elevate detection rate of PHC, has clinical diagnosis and antidiastole value to PHC with AFP negative or low degree and will elevate early diagnosis rate of PHC as well as reduce missed diagnosis of PHC. Therefore,we should employ combining detection to elevate early diagnosis rate of PHC.
引文
1.马寄晓,刘秀杰.实用临床核医学.第1版.北京:原子能出版社. 2002;464.
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5.Lindsay S , Ireland M ,O’Brien O , et al . Large scaledeletions in the GPC3 gene may account for a minority of cases of Simpson Golabi Behmel syndrome. JMed Genet ,1997;34 :480.
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14.Hsu HC, Cheng W, Lai PL. Cloning and expressionof a developmentally regulated transcript MXR7 inhepatocellular carcinoma:biological signi- ficanceand temporospatial distribution. Cancer Res,1997;57: 5179- 5184.
15.Zhu ZW, Friess H, Wang L, et al. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut, 2001, 48: 558-564.
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21.Murthy SS, Shen T,De Rienzo A,Lee WC,Ferriola PC,Jhanwar SC, Mossman BT,Filmus J,TestaJR.Expression of GPC3,an X-linked recessive over growth gene, is silenced in malignant mesothelioma. On cogene,2000; 19: 410-416.
22.Toretsky JA, Zitomersky NL, Eskenazi AE, VoigtRW, Strauch ED, Sun CC, Huber R, Meltzer SJ,Schlessinger D. Glypican-3 expression in Wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol,2001;23: 496-499.
23.LuZL,LuoDZ,WenJM.Expression an dsignificance of tumor related genes in HCC.World Jgastroenterol,2005;11: 3850-3854.
24.缪辉来, 温继育, 陈念平, 陈明, 包仕廷 Glypican-3 蛋白在肝细胞癌患者血 清 和 组 织 中 的 表 达 及 意 义 [J]. 世 界 华 人 消 化 杂 志 ,2007; 15(21):2311-2315.
25.Francoise Degos MD, et al.Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas[J]. Human Pathology 2006;37:1435-1441.
26.方芳;王红阳;吴秀菊;周赟.聚糖蛋白抗体的制备及其在肝癌组织及细胞系蛋白表达检测中的应用[J].中华实验外科杂志,2007; 4(18):293-295.
27.Hippo Y,Watanabe K,Watanabe A, et al.Identification of soluble terminal fragment of glypican-3 as a serological marker for early-stage hepatocellul-ar carcinoma [J]. Cancer Res, 2004; 64 (7) :2418 - 2423.
28.柏凯,梁平.原发性肝癌患者外周血 GPC-3 mRNA 的表达与微转移的关系[J].消化外科杂志,2006;5(2):115-118
29.CapurroM, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.Gastroenterology, 2003; 125: 89297.
30.Yamauchi N,Watanabe A, Hishinuman M, et al. The glypican-3 on cofetal protein is a promising diagnostic marker for hepetocellular carcinoma[J]. Mod Pathol, 2005;18(12): 1591-1598.
31.Filmus J, Capurro M. Glypican-3 and alph-afetoprotein as diagnostic tests for hepatocellular carcinoma[J].Mol Diagn,2004;8(4):207-212.
32.Dreijerink K, Braga E , Kuzmin I , et al .The candidate tumor suppressor gene,RASSF1A,from human chromosome 3p21.3 is involved in kidney tumorigenesis. Proc Natl Acad Sci USA ,2001;98 (13) :7504.
33.Dammann R ,Li C ,Yoon J H ,et al. Epigenetic inactivation of a Ras association do main family protein from the lung tumour suppressor locus 3p21. 3. Nat Genet ,2000;25:315-319.
34.Dammann R,Schagdarsurengin U,Strunnikova M,et al.Histol Histopa thol, 2003;18:665～677.
35.Pfeifer GP, Yoon JH, Liu L, et al. Methylation of the RASSF1A gene in human cancers[J]. Biol Chem, 2002;383 (6):907 - 914.
36.Zhong S,Yeo W,Tang MW,et al.Clin Cancer Res,2003;9:3376-3382.
37.Schagdarsurengin U, Wilkens L, Steinemann D, et al.ncogene,2003;22: 1866-1871.
38.HoqueMO, Begum S, Topaloglu O, et al. Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine,and serum DNA ofpatients with renal cancer [J]. Cancer Res,2004;64 (15) : 5511 - 5517.
39.Kang GH, Lee S, Lee HJ, Hwang KS. Aberrant CpG island hypermethy- lation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia[J]. J Pathol, 2004;202 (2):233 - 240.
40.Muller HM, Widschwendter A, Fiegl H, et al. DNA methylation inserum of breast cancer patients: An independent prognostic marker[J]. Cancer Res, 2003;63 (22) : 7641 - 7645.
41.Liebman HA , Furie BC , Tong MJ , et al . Des-γ-carboxy (abnormal) pro- thrombin as a serum marker of primary hepatocellular carcinoma. NEng J Med , 1984;310 :1427-1431.
42.TangW ,K okudoN ,Su gawaraY ,G uoQ ImamuraH Sano K, Karako H Qu X, Nakata M, MakuuchiM. Desgammacar-boxyprothrombin expression incancer and/or non-cancer liver tissues:associationwith survival of patients with resectable hepatocellular carcinoma.Oncol Rep,2005;13: 25-30.
43.SuzukiM ,Sh irahaH ,Fu jikawaT ,Ta kaokaN ,U edaN, Nakanishi Y, Koike K, Takaki A, Shiratori Y.Desgamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma.j Biolchem,2005; 280: 64 09-6415.
44.Dohmen K,Shigematsu H,Irie K,Ishibashi H.Clinic alcharacteristics among patients with hepatocellular carcinoma according to the serum levels ofalpha-fetoprotein and desycarboxy prothrombin.Hepatogastroenterology ,2003;50:2072-2078.
45.Nagaoka S, Yatsuhashi H, Hamada H, Yano K,Matsumoto T, Daikoku M, Arisawa K, Ishibashi H,KogaM ,Sa taM ,Y anoM.The des-gamma-carboxy prothrombin index is a new prognostic indicator for hepatocellular carcino- ma. Cancer,2003; 98:2671-2677.
46.谢斌.肝细胞癌标志物去γ-羧基凝血酶原研究进展[J].国外医学肿瘤学分册,2004;31(2).
47.段永强,王梅林,汪晓龙,等.TSGF测定在肺癌中的临床应用[J].临床肿瘤学杂志,2004;9(6):644-645
48.肖永棋.肿瘤特异性生长因子检测在原发性肝癌诊断中的应用[J].广西医学,2004;26(1):77-78.
49.Hirakawa H, Nawata S, Sueoka K, Murakami A, Takeda O,Numa F, Kato H, Sugino N. Regulation of squamous cell carcinoma antigen production by E-cadherin mediated cell-celadhesion in squamous cell carcinoma cell line. Oncol Rep,2004;11:415-419.
50.Suminami Y,Nagashima S ,Murakami A,Nawata S ,Gondo T,Hirakawa H,Numa F, Silverman GA,Kato H.Suppression of asquamouscel carcinoma (SCC)-related serpin,SCCA ntigen,inhibits tumor growth with increased intratumo infiltration of natural killer cells.Cancer Res,2001;61:1176- 1180.
51.Pontisso P, Calabrese F, Benvegnu L, Lise M, Belluco C,Ruvoletto MG, Marino M, Valente M, Nitti D, Gatta A,Fassina G. Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma. Br I Cancer,2004;90:833-837.
52.Beneduce L, Castaldi F, Marino M, Quarta S, Ruvoletto M,Benvegnu L, Calabrese F, Gatta A, Pontisso P, Fassina G.Squamous Cell Carcinoma Antigen Immunoglobulin M Complexes as Novel Biomarkers for epatocell- ular Carcinoma.Cancer,2005;103:2558-2565.
53.Giannelli G, Marinosci F, Sgarra C, Lupo L, Dentico P,Antonaci S. Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcino- ma. Int I Cancer,2005;116:579-583.
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14.Hsu HC, Cheng W, Lai PL. Cloning and expressionof a developmentally regulated transcript MXR7 inhepatocellular carcinoma:biological signi- ficanceand temporospatial distribution. Cancer Res,1997;57: 5179- 5184.
15.Zhu ZW, Friess H, Wang L, et al. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut, 2001, 48: 558-564.
16.Farooq M, Hwang SY, Park MK, et al. Blocking endogenous glypican-3 expression releases Hep-B cells from Garrest[J]. Mol Cells,2003;15(3): 356-360.
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22.Toretsky JA, Zitomersky NL, Eskenazi AE, VoigtRW, Strauch ED, Sun CC, Huber R, Meltzer SJ,Schlessinger D. Glypican-3 expression in Wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol,2001;23: 496-499.
23.LuZL,LuoDZ,WenJM.Expression an dsignificance of tumor related genes in HCC.World Jgastroenterol,2005;11: 3850-3854.
24.缪辉来, 温继育, 陈念平, 陈明, 包仕廷 Glypican-3 蛋白在肝细胞癌患者血 清 和 组 织 中 的 表 达 及 意 义 [J]. 世 界 华 人 消 化 杂 志 ,2007; 15(21):2311-2315.
25.Francoise Degos MD, et al.Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas[J]. Human Pathology 2006;37:1435-1441.
26.方芳;王红阳;吴秀菊;周赟.聚糖蛋白抗体的制备及其在肝癌组织及细胞系蛋白表达检测中的应用[J].中华实验外科杂志,2007; 4(18):293-295.
27.Hippo Y,Watanabe K,Watanabe A, et al.Identification of soluble terminal fragment of glypican-3 as a serological marker for early-stage hepatocellul-ar carcinoma [J]. Cancer Res, 2004; 64 (7) :2418 - 2423.
28.柏凯,梁平.原发性肝癌患者外周血 GPC-3 mRNA 的表达与微转移的关系[J].消化外科杂志,2006;5(2):115-118
29.CapurroM, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.Gastroenterology, 2003; 125: 89297.
30.Yamauchi N,Watanabe A, Hishinuman M, et al. The glypican-3 on cofetal protein is a promising diagnostic marker for hepetocellular carcinoma[J]. Mod Pathol, 2005;18(12): 1591-1598.
31.Filmus J, Capurro M. Glypican-3 and alph-afetoprotein as diagnostic tests for hepatocellular carcinoma[J].Mol Diagn,2004;8(4):207-212.
32.Dreijerink K, Braga E , Kuzmin I , et al .The candidate tumor suppressor gene,RASSF1A,from human chromosome 3p21.3 is involved in kidney tumorigenesis. Proc Natl Acad Sci USA ,2001;98 (13) :7504.
33.Dammann R ,Li C ,Yoon J H ,et al. Epigenetic inactivation of a Ras association do main family protein from the lung tumour suppressor locus 3p21. 3. Nat Genet ,2000;25:315-319.
34.Dammann R,Schagdarsurengin U,Strunnikova M,et al.Histol Histopa thol, 2003;18:665～677.
35.Pfeifer GP, Yoon JH, Liu L, et al. Methylation of the RASSF1A gene in human cancers[J]. Biol Chem, 2002;383 (6):907 - 914.
36.Zhong S,Yeo W,Tang MW,et al.Clin Cancer Res,2003;9:3376-3382.
37.Schagdarsurengin U, Wilkens L, Steinemann D, et al.ncogene,2003;22: 1866-1871.
38.HoqueMO, Begum S, Topaloglu O, et al. Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine,and serum DNA ofpatients with renal cancer [J]. Cancer Res,2004;64 (15) : 5511 - 5517.
39.Kang GH, Lee S, Lee HJ, Hwang KS. Aberrant CpG island hypermethy- lation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia[J]. J Pathol, 2004;202 (2):233 - 240.
40.Muller HM, Widschwendter A, Fiegl H, et al. DNA methylation inserum of breast cancer patients: An independent prognostic marker[J]. Cancer Res, 2003;63 (22) : 7641 - 7645.
41.Liebman HA , Furie BC , Tong MJ , et al . Des-γ-carboxy (abnormal) pro- thrombin as a serum marker of primary hepatocellular carcinoma. NEng J Med , 1984;310 :1427-1431.
42.TangW ,K okudoN ,Su gawaraY ,G uoQ ImamuraH Sano K, Karako H Qu X, Nakata M, MakuuchiM. Desgammacar-boxyprothrombin expression incancer and/or non-cancer liver tissues:associationwith survival of patients with resectable hepatocellular carcinoma.Oncol Rep,2005;13: 25-30.
43.SuzukiM ,Sh irahaH ,Fu jikawaT ,Ta kaokaN ,U edaN, Nakanishi Y, Koike K, Takaki A, Shiratori Y.Desgamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma.j Biolchem,2005; 280: 64 09-6415.
44.Dohmen K,Shigematsu H,Irie K,Ishibashi H.Clinic alcharacteristics among patients with hepatocellular carcinoma according to the serum levels ofalpha-fetoprotein and desycarboxy prothrombin.Hepatogastroenterology ,2003;50:2072-2078.
45.Nagaoka S, Yatsuhashi H, Hamada H, Yano K,Matsumoto T, Daikoku M, Arisawa K, Ishibashi H,KogaM ,Sa taM ,Y anoM.The des-gamma-carboxy prothrombin index is a new prognostic indicator for hepatocellular carcino- ma. Cancer,2003; 98:2671-2677.
46.谢斌.肝细胞癌标志物去γ-羧基凝血酶原研究进展[J].国外医学肿瘤学分册,2004;31(2).
47.段永强,王梅林,汪晓龙,等.TSGF测定在肺癌中的临床应用[J].临床肿瘤学杂志,2004;9(6):644-645
48.肖永棋.肿瘤特异性生长因子检测在原发性肝癌诊断中的应用[J].广西医学,2004;26(1):77-78.
49.Hirakawa H, Nawata S, Sueoka K, Murakami A, Takeda O,Numa F, Kato H, Sugino N. Regulation of squamous cell carcinoma antigen production by E-cadherin mediated cell-celadhesion in squamous cell carcinoma cell line. Oncol Rep,2004;11:415-419.
50.Suminami Y,Nagashima S ,Murakami A,Nawata S ,Gondo T,Hirakawa H,Numa F, Silverman GA,Kato H.Suppression of asquamouscel carcinoma (SCC)-related serpin,SCCA ntigen,inhibits tumor growth with increased intratumo infiltration of natural killer cells.Cancer Res,2001;61:1176- 1180.
51.Pontisso P, Calabrese F, Benvegnu L, Lise M, Belluco C,Ruvoletto MG, Marino M, Valente M, Nitti D, Gatta A,Fassina G. Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma. Br I Cancer,2004;90:833-837.
52.Beneduce L, Castaldi F, Marino M, Quarta S, Ruvoletto M,Benvegnu L, Calabrese F, Gatta A, Pontisso P, Fassina G.Squamous Cell Carcinoma Antigen Immunoglobulin M Complexes as Novel Biomarkers for epatocell- ular Carcinoma.Cancer,2005;103:2558-2565.
53.Giannelli G, Marinosci F, Sgarra C, Lupo L, Dentico P,Antonaci S. Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcino- ma. Int I Cancer,2005;116:579-583.
54.王自正.现代医学标记免疫学[J].第1版北京:人民军医出版社出版,2000;56.
55.ShixL,ZhouY,XiaoL.Clinical evaluation of several tumor markers in the diagnosis of primary hepatic cancer[J].中华肿瘤杂志,1998;29(6):437.
56.赵开春.三种肿瘤标记物联检对原发性肝癌诊治的评价[J].淮海医药,2002;20(4)1.
57.卢加荪,徐笑红,卢忠.血清糖抗原19-9和242在肝癌的临床应用[J].上海医学检验杂志,2000;15 (2).
58.颜登国,区庆嘉.联合检测血AFP、CA-199和CA-125对原发性肝癌的诊断意义[J].实用肿瘤学杂志,2001;15(1):17.
59.黄宏思,黄卫彤,何延专.血清AFP、CA125、CA199、CEA联检对原发性肝癌的诊断价值[J].右江民族医学院学报,2006;28 (5):759-760.
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