Her-2/neu、TopoIIα在胃癌中的表达及其临床意义
摘要
胃癌是全世界发病率最高的癌症之一,尤其在亚洲和非洲。胃癌的扩散和转移是导致患者死亡的重要原因。虽然胃癌的诊断与治疗研究已经取得很大进展,但是由于各种原因,胃癌患者诊断时多数情况下已经处于晚期,失去了手术机会,这时放、化疗就成为主要的治疗手段。因此提高胃癌的早期诊断率、寻找新的治疗靶点及预后指标,是当前肿瘤研究的重要课题。
目的:
探讨Her-2/neu、TopoIIα在胃癌组织中的表达情况及临床意义,为胃癌的综合治疗寻找新方法。
方法:
1.选取山西医科大学第一医院2005年1月至2007年6月期间经手术治疗的胃癌标本90例作为实验组,30例胃正常组织作为对照组(取自胃、十二指肠溃疡患者手术切除的正常胃组织)。
2.应用免疫组织化学方法(PV-9000法)检测90例胃癌组织、30例胃正常组织中Her-2/neu、TopoIIα的蛋白表达情况。
3.用统计学软件SPSS11.5分析Her-2/neu、TopoIIα蛋白的表达与患者各临床病理参数及二者之间相关性的关系。
结果:
1.实验组90例胃癌组织中Her-2/neu、TopoIIα蛋白阳性率分别为20.0%(18/90)、85.6%(77/90),30例正常胃组织中Her-2/neu、TopoIIα阳性表达率分别为和3.3%(1/30)、60%(18/30),两组之间有显著差异(P<0.05)。
2.胃癌根据Lauren分型分为:肠型、弥漫型、混合型;其Her-2/neu阳性表达率分别是31.8%、9.5%、0%,三者间的差别具有统计学意义(P<0.05),说明Her-2/neu的过表达与胃癌的Lauren病理分型有关。高中、低分化型胃癌组织中Her-2的阳性率分别为10.6%、30.2%,低分化型胃癌阳性率明显高于高、中分化型胃癌,差别具有统计学意义(P<0.05),表明Her-2/neu的过表达与胃癌的分化程度相关。无淋巴转移的癌组织中Her-2/neu的阳性率为2.9%,伴有淋巴转移的胃癌中Her-2/neu的阳性率为30.4%,伴有淋巴结转移的癌组织中Her-2/neu的表达明显高于无淋巴结转移的癌组织,差别具有统计学意义(P<0.05)。但是Her-2/neu的表达与胃癌患者的年龄、性别、部位、大小、临床分期、浸润深度无明显相关性(P>0.05)。
3.TopoIIα在高中、低分化癌组织中阳性表率分别为78.7%、93.0%,TopoIIα在低分化癌中的表达明显高于在高、中分化癌中的表达,差别具有统计学意义(P<0.05)。TopoIIα的表达与胃癌患者的年龄、性别、部位、大小、临床分期、浸润深度、Lauren分型、淋巴转移无关(P>0.05)。
4.在18例Her-2/neu高度表达的胃癌中有(13/18)72.2%伴有TopoIIα的表达,在77例TopoIIα阳性表达的组织中有16.9%(13/77)伴有Her-2/neu的过表达。胃癌中Her-2/neu蛋白的表达与TopoIIα蛋白的表达无明显相关性(P>0.05),但是二者的共同表达率相对较高。
结论:
1.Her-2/neu在胃癌组织中呈高表达,在胃的良性病变组织中呈低表达,Her-2/neu的表达与Lauren病理分型、分化程度、淋巴转移有关,而与患者的年龄、性别、肿瘤大小、部位、临床分期、浸润深度无关,提示Her-2/neu在胃癌的发生发展过程中可能起重要作用。
2.TopoIIα在胃癌组织中高表达,而在正常组织中呈低表达,TopoIIα的表达与癌组织的分化程度有关,而与患者的年龄、性别、部位、大小、临床分期、浸润深度、Lauren分型无关,提示TopoIIα在胃癌组织中的表达增高,可能与肿瘤的恶性细胞增生有关。
3.在胃癌组织中,Her-2/neu蛋白与TopoIIα蛋白的表达无明显相关性,但是二者的共同表达率相对较高,研究二者在胃癌中的表达可以为探讨胃癌新的治疗方法提供理论基础。
The gastric carcinoma is one of the highest disease rates of cancer, especially in Asia and Africa. Diffusion and metastasis is the important cause of cancer-related death. In China, at least 160 000 people died of gastric carcinoma, with the highest death rate for all cancer. Though obvious improvement has been achieved in diagnostic and therapeutic research of gastric cancer, most of gastric carcinoma patients were diagnosed as advanced stage. The treatment of appeasable surgery and chemo-radiotherapy did not significantly improve survival time of advanced gastric carcinoma patients. It is a key task for cancer research to search novel prognostic marker, improve early diagnostic rate, and new target of molecular targeted therapy of gastric carcinoma.
Objectives :
To study the expression and clinical significance of Her-2/neu、TopoIIαin gastric carcinoma tissue,which provided a theoretical basis on the combined therapy to gastric carcinoma.
Methods:
1. To collect 90 cases of gastric carcinoma and 30 cases of normal gastric tissue from First Hospital Affiliated to Shan Xi Medical University.
2. To detect Her-2/neu and TopoIIαexpression in gastric carcinoma and normal gastric tissue by immunohistochemistry assay(PV-9000).
3. To statistically analyze the relationship between Her-2/neu and TopoIIαexpression and various clinicopathologic parameters using SPSS 11.5.
Results:
1. In 90 specimens of gastric cancer,the positive expression rates of Her-2、TopoIIαwere 20.0%(18/90)、85.6%(77/90) respectively.In 30 specimens of normal gastric tissue , the positive expression rates of Her-2、TopoIIαwere 3.3%(1/30)、60%(18/30) respectively. There are the significant difference between two groups(P<0.05).
2. According to Lauren type , gastric carcinoma is divided into intestine type、suffusion type、mixed type. the positive expression rates of Her-2/neu were 31.8%、9.5%、0% respectively, there are the significant difference between three types(P<0.05).It indicates that the over-expression of Her-2/neu has relation to the Lauren type of gastric carcinoma. In well and moderately differentiated、poorly differentiated gastric carcinoma,the positive expression rates of Her-2 were 10.6%、30.2% respectively,difference was significant. It indicates that the over-expression of Her-2/neu has relation to the differentiation of gastric carcinoma.The over-expression of Her-2/neu in gastric carcinoma without lymphatic node metastasis were 2.9%, and that with lymphatic node metastasis were 30.4%, difference was significant. However, the expression of Her-2/neu in gastric carcinoma were not related to age, sex, position, clinical stage, invasion depth.
3. The expression of TopoIIαhad related to the differentiation degree of gastric carcinoma, while there was no relationship with age,sex,position,size,clinical stage, invasion depth,Lauren type, lymphatic node metastasis.
4. 72.2%(13/18) of Her-2/neu amplification had concomitant TopoIIαamplication. 72.2%(13/18) of Her-2/neu amplification had concomitant TopoIIαamplication. There was no relationship between Her-2/neu and TopoIIα, but their co-expression rate was relatively high.
Conclusions:
The overexpression of Her-2/neu and TopoIIαmay play a role in the pathogenesis of gastric carcinoma, combined detection would be of benefit in selecting chemotherapeutic agents and evaluating prognosis in gastric carcinoma.
目的:
探讨Her-2/neu、TopoIIα在胃癌组织中的表达情况及临床意义,为胃癌的综合治疗寻找新方法。
方法:
1.选取山西医科大学第一医院2005年1月至2007年6月期间经手术治疗的胃癌标本90例作为实验组,30例胃正常组织作为对照组(取自胃、十二指肠溃疡患者手术切除的正常胃组织)。
2.应用免疫组织化学方法(PV-9000法)检测90例胃癌组织、30例胃正常组织中Her-2/neu、TopoIIα的蛋白表达情况。
3.用统计学软件SPSS11.5分析Her-2/neu、TopoIIα蛋白的表达与患者各临床病理参数及二者之间相关性的关系。
结果:
1.实验组90例胃癌组织中Her-2/neu、TopoIIα蛋白阳性率分别为20.0%(18/90)、85.6%(77/90),30例正常胃组织中Her-2/neu、TopoIIα阳性表达率分别为和3.3%(1/30)、60%(18/30),两组之间有显著差异(P<0.05)。
2.胃癌根据Lauren分型分为:肠型、弥漫型、混合型;其Her-2/neu阳性表达率分别是31.8%、9.5%、0%,三者间的差别具有统计学意义(P<0.05),说明Her-2/neu的过表达与胃癌的Lauren病理分型有关。高中、低分化型胃癌组织中Her-2的阳性率分别为10.6%、30.2%,低分化型胃癌阳性率明显高于高、中分化型胃癌,差别具有统计学意义(P<0.05),表明Her-2/neu的过表达与胃癌的分化程度相关。无淋巴转移的癌组织中Her-2/neu的阳性率为2.9%,伴有淋巴转移的胃癌中Her-2/neu的阳性率为30.4%,伴有淋巴结转移的癌组织中Her-2/neu的表达明显高于无淋巴结转移的癌组织,差别具有统计学意义(P<0.05)。但是Her-2/neu的表达与胃癌患者的年龄、性别、部位、大小、临床分期、浸润深度无明显相关性(P>0.05)。
3.TopoIIα在高中、低分化癌组织中阳性表率分别为78.7%、93.0%,TopoIIα在低分化癌中的表达明显高于在高、中分化癌中的表达,差别具有统计学意义(P<0.05)。TopoIIα的表达与胃癌患者的年龄、性别、部位、大小、临床分期、浸润深度、Lauren分型、淋巴转移无关(P>0.05)。
4.在18例Her-2/neu高度表达的胃癌中有(13/18)72.2%伴有TopoIIα的表达,在77例TopoIIα阳性表达的组织中有16.9%(13/77)伴有Her-2/neu的过表达。胃癌中Her-2/neu蛋白的表达与TopoIIα蛋白的表达无明显相关性(P>0.05),但是二者的共同表达率相对较高。
结论:
1.Her-2/neu在胃癌组织中呈高表达,在胃的良性病变组织中呈低表达,Her-2/neu的表达与Lauren病理分型、分化程度、淋巴转移有关,而与患者的年龄、性别、肿瘤大小、部位、临床分期、浸润深度无关,提示Her-2/neu在胃癌的发生发展过程中可能起重要作用。
2.TopoIIα在胃癌组织中高表达,而在正常组织中呈低表达,TopoIIα的表达与癌组织的分化程度有关,而与患者的年龄、性别、部位、大小、临床分期、浸润深度、Lauren分型无关,提示TopoIIα在胃癌组织中的表达增高,可能与肿瘤的恶性细胞增生有关。
3.在胃癌组织中,Her-2/neu蛋白与TopoIIα蛋白的表达无明显相关性,但是二者的共同表达率相对较高,研究二者在胃癌中的表达可以为探讨胃癌新的治疗方法提供理论基础。
The gastric carcinoma is one of the highest disease rates of cancer, especially in Asia and Africa. Diffusion and metastasis is the important cause of cancer-related death. In China, at least 160 000 people died of gastric carcinoma, with the highest death rate for all cancer. Though obvious improvement has been achieved in diagnostic and therapeutic research of gastric cancer, most of gastric carcinoma patients were diagnosed as advanced stage. The treatment of appeasable surgery and chemo-radiotherapy did not significantly improve survival time of advanced gastric carcinoma patients. It is a key task for cancer research to search novel prognostic marker, improve early diagnostic rate, and new target of molecular targeted therapy of gastric carcinoma.
Objectives :
To study the expression and clinical significance of Her-2/neu、TopoIIαin gastric carcinoma tissue,which provided a theoretical basis on the combined therapy to gastric carcinoma.
Methods:
1. To collect 90 cases of gastric carcinoma and 30 cases of normal gastric tissue from First Hospital Affiliated to Shan Xi Medical University.
2. To detect Her-2/neu and TopoIIαexpression in gastric carcinoma and normal gastric tissue by immunohistochemistry assay(PV-9000).
3. To statistically analyze the relationship between Her-2/neu and TopoIIαexpression and various clinicopathologic parameters using SPSS 11.5.
Results:
1. In 90 specimens of gastric cancer,the positive expression rates of Her-2、TopoIIαwere 20.0%(18/90)、85.6%(77/90) respectively.In 30 specimens of normal gastric tissue , the positive expression rates of Her-2、TopoIIαwere 3.3%(1/30)、60%(18/30) respectively. There are the significant difference between two groups(P<0.05).
2. According to Lauren type , gastric carcinoma is divided into intestine type、suffusion type、mixed type. the positive expression rates of Her-2/neu were 31.8%、9.5%、0% respectively, there are the significant difference between three types(P<0.05).It indicates that the over-expression of Her-2/neu has relation to the Lauren type of gastric carcinoma. In well and moderately differentiated、poorly differentiated gastric carcinoma,the positive expression rates of Her-2 were 10.6%、30.2% respectively,difference was significant. It indicates that the over-expression of Her-2/neu has relation to the differentiation of gastric carcinoma.The over-expression of Her-2/neu in gastric carcinoma without lymphatic node metastasis were 2.9%, and that with lymphatic node metastasis were 30.4%, difference was significant. However, the expression of Her-2/neu in gastric carcinoma were not related to age, sex, position, clinical stage, invasion depth.
3. The expression of TopoIIαhad related to the differentiation degree of gastric carcinoma, while there was no relationship with age,sex,position,size,clinical stage, invasion depth,Lauren type, lymphatic node metastasis.
4. 72.2%(13/18) of Her-2/neu amplification had concomitant TopoIIαamplication. 72.2%(13/18) of Her-2/neu amplification had concomitant TopoIIαamplication. There was no relationship between Her-2/neu and TopoIIα, but their co-expression rate was relatively high.
Conclusions:
The overexpression of Her-2/neu and TopoIIαmay play a role in the pathogenesis of gastric carcinoma, combined detection would be of benefit in selecting chemotherapeutic agents and evaluating prognosis in gastric carcinoma.
引文
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[1] Hohenberger P,Gretschel S.Gastric cancer[J]. Lancet, 2003; 362(9380):305-315
[2] Greenlee RT, Murray T,Bolden S, et al. Cancer statistics 2000[J]. CA Cancer J Clin, 2000; 50(1):7-33
[3]杨玲,李连弟,陈育德,等.中国2000年及2005年恶性肿瘤发病死亡的估计与预测[J].中国卫生统计, 2005; 22(4):218-21
[4] Casaretto L, Sousa PL, Mari JJ.Chemotherapy versus support cancer treatment in advanced gastric cancer: a meta-analysis[J]. Braz J Med Biol Res, 2006; 39(4):431-440
[5] Lin W,Kao HW, Robinson D, et al. Tyrosine kinases and gastric cancer [J]. Oncogene, 2000; 19 (49):5680-9
[6] Otsuji E, Yamaguchi T, Sawai K, et al. Recent advances in surgical treatment have improved the survival of patients with gastric carcinoma [J]. Cancer, 1998; 82(7):1233-7
[7] Lawrence W Jr. Our operative approach to cancer has been modified by scientific innovations:is this true for gastrointestinal cancer [J]. J Surg Oncol, 2002; 79(4):205-8
[8] Kono K, Takahashi A, Ichihara F, et al. Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer [J]. Cancer Res, 2002; 62(20):5813-5817
[9]吕峰,胡云章,姜述德.表皮生长因了受体抑制剂在肿瘤治疗方面的研究进展[J].中国肿瘤生物治疗杂志, 2004; 11(1):75-77
[10]邓静,陈余清.表皮生长因子受体抑制剂靶治疗癌症的新进展[J].国外医学内科学分册, 2004; 31( 7):277-279
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[13]De Peter CR. The neu oncogene more than a prognostic indicator ? Hun pathol [J], 1994; 25:1264
[14]Jeffrey SR, Jonathan AF. HER-2/neu (c-erbB-2) gene and protein in breast CanCer.Am J Clin Pathol [J], 1999; 112(Sup):S 53
[15]曾志武,易继林.HER一2/NEU基因在肿瘤组织中的表达及其临床价值.消化外科[J],2003; 2(3):221-224
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[1] Hohenberger P,Gretschel S.Gastric cancer[J]. Lancet, 2003; 362(9380):305-315
[2] Greenlee RT, Murray T,Bolden S, et al. Cancer statistics 2000[J]. CA Cancer J Clin, 2000; 50(1):7-33
[3]杨玲,李连弟,陈育德,等.中国2000年及2005年恶性肿瘤发病死亡的估计与预测[J].中国卫生统计, 2005; 22(4):218-21
[4] Casaretto L, Sousa PL, Mari JJ.Chemotherapy versus support cancer treatment in advanced gastric cancer: a meta-analysis[J]. Braz J Med Biol Res, 2006; 39(4):431-440
[5] Lin W,Kao HW, Robinson D, et al. Tyrosine kinases and gastric cancer [J]. Oncogene, 2000; 19 (49):5680-9
[6] Otsuji E, Yamaguchi T, Sawai K, et al. Recent advances in surgical treatment have improved the survival of patients with gastric carcinoma [J]. Cancer, 1998; 82(7):1233-7
[7] Lawrence W Jr. Our operative approach to cancer has been modified by scientific innovations:is this true for gastrointestinal cancer [J]. J Surg Oncol, 2002; 79(4):205-8
[8] Kono K, Takahashi A, Ichihara F, et al. Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer [J]. Cancer Res, 2002; 62(20):5813-5817
[9]吕峰,胡云章,姜述德.表皮生长因了受体抑制剂在肿瘤治疗方面的研究进展[J].中国肿瘤生物治疗杂志, 2004; 11(1):75-77
[10]邓静,陈余清.表皮生长因子受体抑制剂靶治疗癌症的新进展[J].国外医学内科学分册, 2004; 31( 7):277-279
[11]曾志武,易继林.HER-2/neu基因在肿瘤组织中的表达及其临床价值[J].消化外科, 2003;2(3):221-4
[12] Jeffrey SR, Jonathan AF.The HER-2/NEU Oncogene in breast cancer prognostic factor predictive and target for therapy[J].Stem Cell, 1998; 16:413
[13]De Peter CR. The neu oncogene more than a prognostic indicator ? Hun pathol [J], 1994; 25:1264
[14]Jeffrey SR, Jonathan AF. HER-2/neu (c-erbB-2) gene and protein in breast CanCer.Am J Clin Pathol [J], 1999; 112(Sup):S 53
[15]曾志武,易继林.HER一2/NEU基因在肿瘤组织中的表达及其临床价值.消化外科[J],2003; 2(3):221-224
[16]Sony Yang Z, Shoelson SE, Chaudhuri M, et al. Shz-Domain recognize specific phosphopetide sequences.Cell, 1993; 72:767
[17]Wang DP, Konishi I, Koshiyama M, et al. Immunohistochemisal loction of c-erbB-2 protein and EGF receptor in normal surfance epithelium inclusion systs and common epithelial tumors of the ovary. Vrch Pathol Anat, 1992;421:393
[18]Yu D, Hamada JI,Zhang H, et al. Mechanisms of neu oncogene induced metastasis and abrogation of metastatic properties by the adenovirus 5EIA gene products. Oncogene, 1992;7:2263
[19] Yonemura Ohoyama S, Kimura H, et al. The expression of proliferative-associted nuclear antigen p105 in gastric carcinoma.Cancer, 1991; 67:2523-2528
[20]山际裕史,马玉峰.胃的上皮化生及分化型腺癌EGFR,PCNA,C-erbB-2,P53,Kras的免疫组化染色研究[J].国外医学,分子生物学分册, 1994; 16(60):283-284
[21]陈存远,叶锋.胃癌c-erbB-2基因表达及其临床意义探讨[J].中华消化杂志,1993,13(4):208-210
[22]孙秀梅,刘国泉.C-erbB-2癌基因产物在胃癌中表达及预后意义的免疫组织化学研[J].中华病理学杂志,1994,23
[23]李宁,祝庆孚.C-erbB-2和P53基因产物增强表达与胃癌生物学行为和预后关系[J].中华外科杂志.1994; 32(9):558
[24] Sliwkowski MX,Lofgren JA, Lewis GD,et al. Nonclinical studies addressing the mechanism of action of trastuzumab(Herceptin) [J]. Semin Oncol, 1999; 26 (4 Suppl):60-70
[25] Wang SC, Hung MC. Her-2 overexpression and cancer targeting [J]. Semin Oncol, 2001;28 (5 Suppl 16):115-124
[26]Shak S. For the Herceptin multinational investigator study group. Overview of the trastuzumab (Herceptin) anti-HER-2 monoclonal antibody clinical program in HER-2 overexpressing metastatic breast cancer[J]. Semin Oncol,1999; 26(4 Suppl 12):71-77
[27]Villman K, Stahl E, Liljegren G, et al. Topoisomerase II alpha expression in different cellcycle phases in fresh human breast carcinomas[J]. Mod Pathol, 2002;15(5 ):486-491
[28]Zini N, Santi S, Ognibene A, et al. Disrete localization of different DNA topoisomerases in Hela and K562 cell nuclei and subnuclear fraction. Exp Cell Res , 1994; 210:336
[29] Adachi N, Miyaike M, Kato S, et al. Cellular distribution of mammalian DNA topoisomerase is determined by its catalytically dispensable C-terminal domain Nucleic Acids Res,1997;25(15):3135-42
[30] Freudenreich CH, Kreuzer KN. Mutational analysis of a type topoisomerase cleavage, site:distinct requirement for enzyme and inhibitors.EMBO J ,1993;12(5):2085-97
[31]张威,邹寿椿,赵仲生等.拓朴异构酶在胃癌中的表达及临床意义[J].Surg Concepts, 2001; 6(1):58-60
[32]杨东萍,乔玉环.人表皮生长因子2及拓扑异构酶IIα在卵巢上皮肿瘤的表达及相关性检测.肿瘤基础与临床, 2006;19(3):196-198
[33] Di Leo A, Gancberg D, Larsimont D,et al. HER-2 amplification and Topoisomerase II alpha gene aberrations as predictive markers in nde-posotov breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophamide, methotrexate, and 5-fluorouracil. Clin Cancer Res, 2002; 8(5):1107-1116
[34] Simon R, Atefy R, Wagner U, et a1. HER-2 and TopoIIαcoamplification in urinary bladder cancer. Int J Cancer, 2003; 107(5):764-772
[35] Mano MS,Awada A,DiLeo A,et a1.Rates of TOPOⅡ-alpha and HER-2 gene amplification and expression in epithelial ovarian carcinoma[J].Gynecologic Oncology,2004;92(6):887—895
[36] Tanner B,Pilch H,Schaffer U,et a1.Expression of c-erbB-2 and TopoisomeraseⅡalpha in relation to chemoresistance in ovarian cancer[J].Zentralbl Gynakol, 2002; 124(3):176-183.
[37] Ciardiello F, Caputo R, Pomatico G, et al. Resistance to taxanes is induced by c-erbB-2 overexpression in human MCF-l0A mammary epithelial cells and is blocked by combined treatment with an antisense oligonucleotide targeting type protein kinase[J], A. Int. J. Cancer, 2000; 85(5):710-715
[38] Rebischung C, Barnoud R, Stefani L, et al. The effectiveness of trastuzumab (Herceptin) combined with chemotherapy for gastric carcinoma with overexpression of the c-erbB-2 protein. Gastric Cancer. 2005; 8(4):249-52