AR,Rb,cyclinD1在胃癌组织中的表达及其与预后的关系
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摘要
目的 研究AR，Rb和cyclinD1在胃癌组织中的表达及其相关性，同时探讨它们与临床病理因素的关系及其预后意义。方法 选取安徽医科大学第一附属医院1990～1999年经手术切除并经病理证实的早、进展期胃癌73例，并对其蜡块进行免疫组化SP法染色，检测AR，Rb和cyclinD1在胃癌组织中的表达，应用SPSS 10.0for Windows软件，统计分析它们之间的关系及其与临床病理指标、预后的关系。
结果 (1)胃癌发病年龄高峰为40～59岁；40岁之前女性胃癌发病略高于男性，而40岁以后，男性胃癌发病率显著高于女性(P＜0.05)；(2)胃癌组织中存在AR(阳性率为39.73％)；(3)胃癌组织中AR与Rb呈正相关，它们与cyclinD1无相关性；(4)AR与胃癌大小、分化程度呈负相关；Rb与胃癌浸润深度、淋巴结转移及病期呈正相关；AR，Rb与术后5年生存时间有关(P＜0.05)；cyclinD1与临床病理因素无关；(5)单变量分析显示：AR，Rb的表达、肿瘤大小、病期、淋巴结转移、浸润深度、及远处转移均影响胃癌预后；多变量分析表明，只有淋巴结转移和浸润深度是显著独立的预后指标。结论 (1)胃癌的发生随年龄增长而上升及男女在胃癌年龄分布的差异，提示除环境因素外，性激素与胃癌存在某种内在联系；(2)胃癌具有雄性激素依赖性肿瘤的特性，雄激素通过其受体对胃癌的病因、生长和控制过程起某种作用；(3)AR，Rb在胃癌的形成和发展起协同促进作用；cyclinD1可能是重要的胃癌促发因素；(4)cyclinD1的表达调控着AR，Rb对胃癌的作用；AR和Rb的过度表达协同影响胃癌生长、分化，参与胃癌进展和转移；(5)淋巴结转移、浸润深度显著影响胃癌预后；AR，Rb在一定程度上影响胃癌的预后，cyclinD1与预后无关；(6)AR阳性的胃癌为抗雄激素内分泌治疗提供参考；对于Rb阳性胃癌，术中须加强清扫淋巴结，以期彻底切除病灶；cyclinD1的异常表达可能作为潜在的早期诊断分子指标。
Objective To investigate the expression of androgen receptor, retinoblastoma and cyclinDl for the purpose to evaluate their prognostic function in gastric cancer relationship. Methods Samples from 73 patients with early and advanced gastric cancer, who underwent surgical resection at First Affiliated Hospital, Anhui Medical University from 1990 to 1999, were used for this study. limmunohistochemical technique was used to detect the expression of AR, Rb and cyclinDl with SP method. The software of SPSS 10.0 was used to analyze the relationship between the expression of AR, Rb and cyclinDl with clinical parameters. Results (1) The range of the patients with gastric cancer was 40-59 years old. The incidence in female was higher than that in male with the age under 40 years, but the reverse condition presented when the age was over 40 years (P<0.05); (2) The expression of AR could be found in gastric cancer with 39.73% positive ratio; (3) The positive correlation between the expression of AR and Rb was significa
nt, but there was no different with the expression of cyclinDl; (4) The expression of AR was negatively related to the tumor size and the grade of differentiation (P<0.05); Rb was positively related to lymph node metastasis, depth of tumor invasion and disease course (P<0.05); but there was no difference between the expression of cyclinDl and their clinical parameters; (5) Single-variate analysis indicated that all the factors including the expression of AR and Rb, lymph node metastasis, depth of tumor invasion, disease course, type of histology, size of carcinoma and far metastasis were related to the prognosis of gastric cancer; moreover, multivariate analysis indicated that lymph node metastasis and depth of tumor invasion could be use as independent prognostic
factors. Conclusion (1) The incidence of gastric cancer will go up along with the factors of age and sex, which hints that the sex hormone may related to the cause of gastric cancer besides entironment factor; (2) Gastric cancer have a character of male hormone dependence, which can accelerate the formation and progression of gastric cancer by its receptor; (3) The positive relationship between the expression of AR and Rb suggests that they might accelerate the formation and progression of gastric cancer synergistically. Their overexpression relate to the advance of gastric carcinoma. cyclinD1 may be a important factor to form gastric cancer; (4) The overexpression of cyclinDl can decrease the exression of AR and Rb; The overexpression of AR and Rb can accelerate the formation and differentiation of gastric cancer synergistically, and concern with the development and metastasis of gastric carncer. (5) Lymph node metastasis and depth of tumor invasion obviously affect the prognosis of gastric cancer, the expr
ession of AR and Rb may become the prognosis factor of gastric cancer on a certain degree; the expression of cyclinDl can not be used as a prognosis factor on gastric cancer. (6) The expression of AR could be use as a reference for incretion therapy to resist the sex hormone; for the patient with positive expression of Rb, the clearance of lymph node should be pay attention during the operation; The overexpression of cyclinDl may be a early event in gastric
cancer.
结果 (1)胃癌发病年龄高峰为40～59岁；40岁之前女性胃癌发病略高于男性，而40岁以后，男性胃癌发病率显著高于女性(P＜0.05)；(2)胃癌组织中存在AR(阳性率为39.73％)；(3)胃癌组织中AR与Rb呈正相关，它们与cyclinD1无相关性；(4)AR与胃癌大小、分化程度呈负相关；Rb与胃癌浸润深度、淋巴结转移及病期呈正相关；AR，Rb与术后5年生存时间有关(P＜0.05)；cyclinD1与临床病理因素无关；(5)单变量分析显示：AR，Rb的表达、肿瘤大小、病期、淋巴结转移、浸润深度、及远处转移均影响胃癌预后；多变量分析表明，只有淋巴结转移和浸润深度是显著独立的预后指标。结论 (1)胃癌的发生随年龄增长而上升及男女在胃癌年龄分布的差异，提示除环境因素外，性激素与胃癌存在某种内在联系；(2)胃癌具有雄性激素依赖性肿瘤的特性，雄激素通过其受体对胃癌的病因、生长和控制过程起某种作用；(3)AR，Rb在胃癌的形成和发展起协同促进作用；cyclinD1可能是重要的胃癌促发因素；(4)cyclinD1的表达调控着AR，Rb对胃癌的作用；AR和Rb的过度表达协同影响胃癌生长、分化，参与胃癌进展和转移；(5)淋巴结转移、浸润深度显著影响胃癌预后；AR，Rb在一定程度上影响胃癌的预后，cyclinD1与预后无关；(6)AR阳性的胃癌为抗雄激素内分泌治疗提供参考；对于Rb阳性胃癌，术中须加强清扫淋巴结，以期彻底切除病灶；cyclinD1的异常表达可能作为潜在的早期诊断分子指标。
Objective To investigate the expression of androgen receptor, retinoblastoma and cyclinDl for the purpose to evaluate their prognostic function in gastric cancer relationship. Methods Samples from 73 patients with early and advanced gastric cancer, who underwent surgical resection at First Affiliated Hospital, Anhui Medical University from 1990 to 1999, were used for this study. limmunohistochemical technique was used to detect the expression of AR, Rb and cyclinDl with SP method. The software of SPSS 10.0 was used to analyze the relationship between the expression of AR, Rb and cyclinDl with clinical parameters. Results (1) The range of the patients with gastric cancer was 40-59 years old. The incidence in female was higher than that in male with the age under 40 years, but the reverse condition presented when the age was over 40 years (P<0.05); (2) The expression of AR could be found in gastric cancer with 39.73% positive ratio; (3) The positive correlation between the expression of AR and Rb was significa
nt, but there was no different with the expression of cyclinDl; (4) The expression of AR was negatively related to the tumor size and the grade of differentiation (P<0.05); Rb was positively related to lymph node metastasis, depth of tumor invasion and disease course (P<0.05); but there was no difference between the expression of cyclinDl and their clinical parameters; (5) Single-variate analysis indicated that all the factors including the expression of AR and Rb, lymph node metastasis, depth of tumor invasion, disease course, type of histology, size of carcinoma and far metastasis were related to the prognosis of gastric cancer; moreover, multivariate analysis indicated that lymph node metastasis and depth of tumor invasion could be use as independent prognostic
factors. Conclusion (1) The incidence of gastric cancer will go up along with the factors of age and sex, which hints that the sex hormone may related to the cause of gastric cancer besides entironment factor; (2) Gastric cancer have a character of male hormone dependence, which can accelerate the formation and progression of gastric cancer by its receptor; (3) The positive relationship between the expression of AR and Rb suggests that they might accelerate the formation and progression of gastric cancer synergistically. Their overexpression relate to the advance of gastric carcinoma. cyclinD1 may be a important factor to form gastric cancer; (4) The overexpression of cyclinDl can decrease the exression of AR and Rb; The overexpression of AR and Rb can accelerate the formation and differentiation of gastric cancer synergistically, and concern with the development and metastasis of gastric carncer. (5) Lymph node metastasis and depth of tumor invasion obviously affect the prognosis of gastric cancer, the expr
ession of AR and Rb may become the prognosis factor of gastric cancer on a certain degree; the expression of cyclinDl can not be used as a prognosis factor on gastric cancer. (6) The expression of AR could be use as a reference for incretion therapy to resist the sex hormone; for the patient with positive expression of Rb, the clearance of lymph node should be pay attention during the operation; The overexpression of cyclinDl may be a early event in gastric
cancer.
引文
1. Jiannming LU, Mark Danielson. Differential regulation of androgen and glucocorticoid receptors by retinoblastoma protein. J Bio Chem. 1998; 273(47):31528-31533
2. Karen E Knudsen, Karen C Arden, Webster K. Cavenee. Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells.J Bio Chem. 1998;273(32):20213-20222
3．张冠军，张学斌．P53蛋白和雄激素受体在胃癌中表达的意义．中国肿瘤临床与康复，1999；6(1)：33-34
4．刘弋，胡家骅，王震宗等．胃癌生物学行为与性激素及受体相关关系的研究．中华医学杂志，1992；12(3)：169-169
5．钱结胜．胃癌中AR，Rb，cyclinD1的表达及其相关性研究．安徽医科大学硕士研究生毕业论文集，2000；p9．
6．吴强，郑国豪，王保太等．乳腺癌类固醇激素受体的临床病理研究．中华病理学杂志，1989：18(4)：247-248
7．袁媛，吴烨秋，张佩范，等．157例早期胃癌临床病理及其30年变化趋势分析．中国医科大学学报，1987；22(5)：340-343
8. Meyers WC, Damiano RJ, Postlethwait RW, et al. Adenocarcinoma of the stomach-changing patterns over the last 4 decades. Ann Surg; 1987;205(1): 1-8
9. Tokunaga A, Kojima N, Andoth J, et al. Hormone receptors in gastric cancer.Eur J Cancer Clin Oncol. 1983; 19:687-689
10. Sica V, Nola E, Contieri E, et al. Estradiol and progesterone receptors in malignant gastrointestinal tumors.Cancer Res. 1984;44:4670-4674
11. Wu CW, Chi CW, Chang TJ, et al. Sex hormone receptors in gastric cancer. 1990;65(6):1396-1400
12. Furukawa H. Effect of sex hormones on the experimental induction of cancer in rat stomach.Digestion. 1982;23:151-155
13. Furukawa H,Lwanaga T, Koyama H,et al. Effect of sex hormones on carcinogenesis in the stomach of rats.Cancer Res, 1982;42:5181-5182
14. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily:the second decade. Cell,1995;83:835-839
15. Gao J, Isaacs JT, Isaacs. Development of an androgen receptor-null model for identifying the initiation site for androgen stimulation of proliferation and suppression of programmed death of PC-82 human prostate cancer cells. Cancer Research. 1998;58:3299-3306
16. Kuiper GGJM, Faber PW, Van Rooit HCJ, et al. Structure organization of the human androgen receptor gene. J Mol Endrocrinol. 1998;2:R1-4
17. Fronsdal K, Engedal N, Slagscold T, et al. CREB Binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1.J Bio Chem. 1998;273(48):31853-31859
18. Fang C, Cooney AJ, Omalley BW. Coling of novel orphan receptor (GCNF) expressed during germ cell development.Mol Endocrinol. 1994;8(10): 1434-1444
19．殷拥军，葛宝林，邹伟．雌雄激素受体与胃癌发生发展的相关性研究．中华病理生理杂志．1996：12(2)：209-211
20．马去非，王金钟，王汉卿等．胃癌性激素依赖性的研究．铁道医学．1996；24(6)：334-335
21．宋跃，赵青，贾明库，等．Rb1基因mRNA在人胃癌中表达的研究．实用肿瘤学杂志，1997：11(3)：170-171
22. Mittnacht S, Weinberg RA. G1/S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartement.[J]. Cell,1991,65:381-393
23. Xu HJ, Cairns P, Hu SX, Knowles MA, et al. Loss of Rb protein expression in
primary bladder cancer correlates with loss of heterozygosity at the Rb locus and tumor progression. Int J Cancer. 1993;53:781-784
24．邹建湘，王立东，陈玉龙等．p16，cyclinD1在胃癌发生过程中的表达．中国肿瘤临床，1999; 26(2)：98-100
25. Yeh S, Miyamoto H, Nishimura K, et al. Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells. Biochem-Biophys-res commun. 1998; 248(2):361-367
26．陈学良，宋丽，张茂宏．p16和p15基因缺失与造血系统恶性疾病．国外医学生理、病理科学与临床分则．1997；17(1)：4-6
27. Chen Y, Robles AI, Martinez LA, et al. Expression of Glcyclins,cyclin-dependent kinases and cyclin-depedent kinases inhibitors in androgen-induce prostate proliferation in castrated rats. Cell-Growth-Differ. 1996;7(11): 1571-1578
28. Gope R, Christensen MA, Thorson A, et al. Increased expression of the retinoblastoma gene in human colorectal carcinomas relative to normal colonic mucosa. J Nati Cancer Inst, 1990;82(4):310-314
29. Robbins PD, Horowitz JM, Mulligan RC. Negative regulation of human c-fos expression by the retinoblastoma gene product. Nature, 1990;346(16):668-671
30. Schurring E, Bristol G, Rosner E, et al. Expression of cyclinD1 is associated with advanced tumor stage and distant metastasis in human colorectal. Cancer Res, 1992;529(10):5229
31. Okabayashi T, Gotoda T, Kondo H, et al.Early carcinoma of the gastric cardia in Japan. Cancer,2000;89(12):2555-2559
2. Karen E Knudsen, Karen C Arden, Webster K. Cavenee. Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells.J Bio Chem. 1998;273(32):20213-20222
3．张冠军，张学斌．P53蛋白和雄激素受体在胃癌中表达的意义．中国肿瘤临床与康复，1999；6(1)：33-34
4．刘弋，胡家骅，王震宗等．胃癌生物学行为与性激素及受体相关关系的研究．中华医学杂志，1992；12(3)：169-169
5．钱结胜．胃癌中AR，Rb，cyclinD1的表达及其相关性研究．安徽医科大学硕士研究生毕业论文集，2000；p9．
6．吴强，郑国豪，王保太等．乳腺癌类固醇激素受体的临床病理研究．中华病理学杂志，1989：18(4)：247-248
7．袁媛，吴烨秋，张佩范，等．157例早期胃癌临床病理及其30年变化趋势分析．中国医科大学学报，1987；22(5)：340-343
8. Meyers WC, Damiano RJ, Postlethwait RW, et al. Adenocarcinoma of the stomach-changing patterns over the last 4 decades. Ann Surg; 1987;205(1): 1-8
9. Tokunaga A, Kojima N, Andoth J, et al. Hormone receptors in gastric cancer.Eur J Cancer Clin Oncol. 1983; 19:687-689
10. Sica V, Nola E, Contieri E, et al. Estradiol and progesterone receptors in malignant gastrointestinal tumors.Cancer Res. 1984;44:4670-4674
11. Wu CW, Chi CW, Chang TJ, et al. Sex hormone receptors in gastric cancer. 1990;65(6):1396-1400
12. Furukawa H. Effect of sex hormones on the experimental induction of cancer in rat stomach.Digestion. 1982;23:151-155
13. Furukawa H,Lwanaga T, Koyama H,et al. Effect of sex hormones on carcinogenesis in the stomach of rats.Cancer Res, 1982;42:5181-5182
14. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily:the second decade. Cell,1995;83:835-839
15. Gao J, Isaacs JT, Isaacs. Development of an androgen receptor-null model for identifying the initiation site for androgen stimulation of proliferation and suppression of programmed death of PC-82 human prostate cancer cells. Cancer Research. 1998;58:3299-3306
16. Kuiper GGJM, Faber PW, Van Rooit HCJ, et al. Structure organization of the human androgen receptor gene. J Mol Endrocrinol. 1998;2:R1-4
17. Fronsdal K, Engedal N, Slagscold T, et al. CREB Binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1.J Bio Chem. 1998;273(48):31853-31859
18. Fang C, Cooney AJ, Omalley BW. Coling of novel orphan receptor (GCNF) expressed during germ cell development.Mol Endocrinol. 1994;8(10): 1434-1444
19．殷拥军，葛宝林，邹伟．雌雄激素受体与胃癌发生发展的相关性研究．中华病理生理杂志．1996：12(2)：209-211
20．马去非，王金钟，王汉卿等．胃癌性激素依赖性的研究．铁道医学．1996；24(6)：334-335
21．宋跃，赵青，贾明库，等．Rb1基因mRNA在人胃癌中表达的研究．实用肿瘤学杂志，1997：11(3)：170-171
22. Mittnacht S, Weinberg RA. G1/S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartement.[J]. Cell,1991,65:381-393
23. Xu HJ, Cairns P, Hu SX, Knowles MA, et al. Loss of Rb protein expression in
primary bladder cancer correlates with loss of heterozygosity at the Rb locus and tumor progression. Int J Cancer. 1993;53:781-784
24．邹建湘，王立东，陈玉龙等．p16，cyclinD1在胃癌发生过程中的表达．中国肿瘤临床，1999; 26(2)：98-100
25. Yeh S, Miyamoto H, Nishimura K, et al. Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells. Biochem-Biophys-res commun. 1998; 248(2):361-367
26．陈学良，宋丽，张茂宏．p16和p15基因缺失与造血系统恶性疾病．国外医学生理、病理科学与临床分则．1997；17(1)：4-6
27. Chen Y, Robles AI, Martinez LA, et al. Expression of Glcyclins,cyclin-dependent kinases and cyclin-depedent kinases inhibitors in androgen-induce prostate proliferation in castrated rats. Cell-Growth-Differ. 1996;7(11): 1571-1578
28. Gope R, Christensen MA, Thorson A, et al. Increased expression of the retinoblastoma gene in human colorectal carcinomas relative to normal colonic mucosa. J Nati Cancer Inst, 1990;82(4):310-314
29. Robbins PD, Horowitz JM, Mulligan RC. Negative regulation of human c-fos expression by the retinoblastoma gene product. Nature, 1990;346(16):668-671
30. Schurring E, Bristol G, Rosner E, et al. Expression of cyclinD1 is associated with advanced tumor stage and distant metastasis in human colorectal. Cancer Res, 1992;529(10):5229
31. Okabayashi T, Gotoda T, Kondo H, et al.Early carcinoma of the gastric cardia in Japan. Cancer,2000;89(12):2555-2559