肿瘤特异性抗原MAGE、BAGE、GAGE在子宫内膜癌组织及细胞株中表达的研究
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摘要
【目的】 研究MAGE、BAGE、GAGE基因在子宫内膜癌组织、正常子宫内膜组织及子宫内膜癌细胞株KLE中的表达情况，探讨这些肿瘤特异性抗原作为子宫内膜癌免疫治疗特异性靶位的可能性。同时研究5—杂氮脱氧胞嘧啶(DAC)对子宫内膜癌细胞株KLE增殖和肿瘤特异性抗原MAGE、BAGE、GAGE表达的影响。
【方法】 采用逆转录—聚合酶联反应(RT-PCR)技术，检测35例子宫内膜癌组织、15例正常子宫内膜组织及子宫内膜癌细胞株KLE中MAGE-1、MAGE-3、BAGE、GAGE1-2基因mRNA水平的表达情况；同时将处于对数生长期的子宫内膜癌细胞株与5—杂氮脱氧胞嘧啶(DAC)共同培养，应用RT-PCR法检测子宫内膜癌细胞株KLE在DAC作用前后肿瘤特异性抗原基因MAGE、BAGE、GAGE mRNA水平表达情况的变化。以β—actin作为内参照。
【结果】 35例子宫内膜癌组织中，MAGE-1、MAGE-3、BAGE、GAGE1-2表达阳性率分别是46％(16／35)、49％(17／35)、20％(7／35)和26％(9／35)，有77％的标本至少表达其中一种基因。15例正常子宫内膜组织中MAGE-1、MAGE-3、BAGE、GAGE1-2基因表达均为阴性。子宫内膜癌细胞株KLE中BAGE基因表达阳性，而MAGE-1、MAGE-3、和GAGE1-2基因阴性，DAC诱导后肿瘤特异性抗原基因表达增加，MAGE-1出现阳性表达。
【结论】 MAGE、BAGE、GAGE基因表达产物是一种肿瘤特异性抗原，
Objective: The aim of this study was to observe the expression of MAGE, BAGE , GAGE genes in endometrial carcinoma , normal endometrium and endometrial carcinoma cell line (KLE), and to evaluate the possibility of using these genes as molecular markers and as the targets of specific immunotherapy for endometrial carcinoma. The other aim of this study was to investigate the effect of 5-aza-2'-deoxycytidine(DAC)in proliferation of endometrial carcinoma cell line and expression of tumor specific antigen MAGE, BAGE, GAGE .
Materials and Methods: Samaples of 35 endometrial carcinoma, 15 normal endometrial tissues and endometrial carcinoma cell line were examined with reverse-transcription polymerase chain reaction (RT-PCR) for the expression of MAGE-1, MAGE-3, BAGE and GAGE1-2. Endometrial carcinoma cell were treated with 5-aza-2'-deoxycytidine (DAC) in co-culture, the growth curves were observed; the genes expression pattern before and after drug treatment was measured by RT-PCR.
Results: In 35 endometrial carcinoma of samples, MAGE-1, MAGE-3, BAGE and GAGE1 -2 mRNAs were expressed in 46% (16/35), 49% (17/35), 20% (7/35) and 26% (9/35) , respectively. At least one transcript was detected in 77%. While no expression was observed in 15 normal endometrial tissues. There was no significant
【方法】 采用逆转录—聚合酶联反应(RT-PCR)技术，检测35例子宫内膜癌组织、15例正常子宫内膜组织及子宫内膜癌细胞株KLE中MAGE-1、MAGE-3、BAGE、GAGE1-2基因mRNA水平的表达情况；同时将处于对数生长期的子宫内膜癌细胞株与5—杂氮脱氧胞嘧啶(DAC)共同培养，应用RT-PCR法检测子宫内膜癌细胞株KLE在DAC作用前后肿瘤特异性抗原基因MAGE、BAGE、GAGE mRNA水平表达情况的变化。以β—actin作为内参照。
【结果】 35例子宫内膜癌组织中，MAGE-1、MAGE-3、BAGE、GAGE1-2表达阳性率分别是46％(16／35)、49％(17／35)、20％(7／35)和26％(9／35)，有77％的标本至少表达其中一种基因。15例正常子宫内膜组织中MAGE-1、MAGE-3、BAGE、GAGE1-2基因表达均为阴性。子宫内膜癌细胞株KLE中BAGE基因表达阳性，而MAGE-1、MAGE-3、和GAGE1-2基因阴性，DAC诱导后肿瘤特异性抗原基因表达增加，MAGE-1出现阳性表达。
【结论】 MAGE、BAGE、GAGE基因表达产物是一种肿瘤特异性抗原，
Objective: The aim of this study was to observe the expression of MAGE, BAGE , GAGE genes in endometrial carcinoma , normal endometrium and endometrial carcinoma cell line (KLE), and to evaluate the possibility of using these genes as molecular markers and as the targets of specific immunotherapy for endometrial carcinoma. The other aim of this study was to investigate the effect of 5-aza-2'-deoxycytidine(DAC)in proliferation of endometrial carcinoma cell line and expression of tumor specific antigen MAGE, BAGE, GAGE .
Materials and Methods: Samaples of 35 endometrial carcinoma, 15 normal endometrial tissues and endometrial carcinoma cell line were examined with reverse-transcription polymerase chain reaction (RT-PCR) for the expression of MAGE-1, MAGE-3, BAGE and GAGE1-2. Endometrial carcinoma cell were treated with 5-aza-2'-deoxycytidine (DAC) in co-culture, the growth curves were observed; the genes expression pattern before and after drug treatment was measured by RT-PCR.
Results: In 35 endometrial carcinoma of samples, MAGE-1, MAGE-3, BAGE and GAGE1 -2 mRNAs were expressed in 46% (16/35), 49% (17/35), 20% (7/35) and 26% (9/35) , respectively. At least one transcript was detected in 77%. While no expression was observed in 15 normal endometrial tissues. There was no significant
引文
1．曹泽毅主编．中华妇产科学．第二版．北京：人民卫生出版社，2004，2120．
2．孔北华主编．妇产科学．北京：高等教育出版社，2005，307-311．
3. Peterson F. Annual report of the results of the treatment in Gynecological Cancer. Int Gynecol Obstet, 1991, 36(supple): 132-137.
4. Peterson F. Annual report of the results of the treatment in Gynecological Cancer: Twenty-first volume. Statement of results obtained in patients, 1982 to 1986, inclusive 3 and 5 Year survival up to 1990. Int Gynecol Obstet, 1991, 36: 1315-1320.
5．郝素珍 王桂琴主编．实用医学免疫学．北京：高等教育出版社，2005，221．
6. De Smet C, Lurquin C, vander Bruggen P, et al. Sequence and expression pattern of the human MAGE2 gene. Immunogenetics, 1994, 39: 121-129.
7. Weber J, Salgaller M, Samid D, et al. Expression of the MAGE-1 tumor antigen is upregulated by the demethylating agent 5-aza-2' -deoxytidine. Cancer Res, 1994, 54(7): 1766-1771.
8．卢学春，楼方定，许周敏等．去甲基化和组蛋白去乙酰化转移酶抑制剂对K562细胞增殖和肿瘤相关基因表达的影响．中国实验血液学杂志，2004，12(1)：44-47．
9．马鸣，俞莉章，那彦群等．肾及膀胱肿瘤组织中MAGE基因及其产物的表达．北京大学学报(医学版)，2004，36：159-163．
10. Li J, Yang Y, Fujie T, Baba K, et al. Expression of BAGE, GAGE and MAGE Genes in Human Gastic Carcinoma. Clin Cancer Res, 1996, 2: 1619-1625.
11．郝素珍 王桂琴主编．实用医学免疫学．北京：高等教育出版社，2005，219．
12. van der B, ruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science, 1991, 254: 1643-1647.
13. Vanden E, ynde B, Peeters O, et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. Exp Med,1995,182:689-698.
14. Boel P, Wildmann C , Sensi ML, et al. BAGE:a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity, 1995, 2 :1 67-175.
15. Desmet C, Lurquin C, vander B I, et al. Sequence and expression pattern of the human MAGE2 gene. Immunogenetics, 1994, 39: 121 -129.
16. Chomez P, DeBacker O, Bertrand M, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Research, 2001,61:5544-5551.
17. Dabovic B , Zanaria E , Bardoni B , et al. A family of rapidly evolving genes from the sex reversal cr iticalre -gionin X p21. Mamm. G enome, 1995, 6(9):571-580.
18. Muscatelli F , Walker AP, Deplaen E , et al. Isolation and characterization of a new MAGE gene family in the Xp21.3 region.Proc Natl Acad Sci USA, 1995, 92 (11):4987-4992.
19. Lucas S , Deplaen E , Boon T . M AGE-B5, MAGE-B6, MAGE-C2 and MAGE-C3: four new members of the MAGE family w ith tumor-specific expression, Int J Cancer, 2000, 8 7:55-60.
20. Lucas S, Brasseur F , Boon T . A new MACE gene with ubiquitous expression doesnot code for known MAGE antigens recognized by T cells.Cancer Res, 1999, 59 :4100-4103.
21. Ruault M, van der B, Brun ME, et al. New BAGE (B melanoma antigen) genes mapping to the juxtacentromeric regions of human chromosomes 13 and 21 have a cancer/testis expression profile. Eu J Human Genetics, 2002, 10:838-840.
22. Chitale DA, Jungbluth AA, Marshall DS, et al. Expression of cancer-testis antigens in endometrial carcinomas using a tissue microarray. Mod Pathol, 2005 Jan, 18:119-126.
23. Mori M, Inoue H, Mimori K, et al. Expression of MAGE genes in human eolorectal carcinoma. Ann Surg,1996,224:183-188.
24. Desmet C, Lurquin C, Lethe B, et al. DNA methylation is the primary siliencing mechanism for a set of germ line and tumor specific genes with a CpG— rich promoter. Mol Cell Bi ol, 1999, 19:7327-7335.
25. Kobayashi Y, Higashi T, Nouso K, et al. Expression of MAGE, GAGE and BAGE genes in human liver diseases: utility as molecular markers for henatocellular carcinoma. Heoatol, 2000, 32: 612-617. "
26. Inoue H, Mori M, Honda M, et al. The expression of tumor-rejection antigen "MAGE" genes in human gastric carcinoma. Gastoenterology, 1995, 109: 1522-1525.
27. Weynants P, Lethe B, Brasseur F, et al. Expressionof MAGE genes by non-small-cell lung carcinomas. Int J Cancer, 1994, 56: 8269.
28. Yamashita N, Ishibashi H, Hayashida K, et al. High frequency of the MAGE-1 gene expression in hepatocellular carcinoma. Hepatology, 1996,24: 143740.
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1. van der Bruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science, 1991, 254: 1643-1647.
2. Vanden EyndeB, Peeters O, DeBacker O, et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. Exp Med, 1995, 182: 689-98.
3. Boel P, Wildmann C, Sensi M L, et al. BAGE:a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity, 1995, 2:167-175.
4. DeSmet C, Lurquin C, van der Bruggen I', et al. Sequence and expression pattern of the human MAGE2 gene. Immunogenetics, 1994, 39: 121-129.
5. Chomez P, DeBacker O, Bertrand M, etal.An overview of the MAGE gene family with the identification of all human members of the family. Cancer Research, 2001, 61, 5544-5551.
6．房金波，王丽．肿瘤特异性抗原(MAGE)在肿瘤免疫治疗中的作用．生理科学进展，2005，36：273-275．
7. Weber J, Salgaller M, Samid D, et al. Expression of the MAGE 1 tumor antigen is up-regulated by the de methylating agent 5-aza-2'-deoxycytidine. Cancer Res, 1994, 54: 1766-1771.
8．蔡胜利，冷希圣，等．肿瘤特异性抗原MAGE家族的研究进展．中华外科杂志，2001，39：645-647．
9. Li J, Yang Y, Fujie T, Baba K, et al. Expression of BAGE, GAGE, and MAGE Genes in Human Gastic Carcinoma. Clin Cancer Res, 1996, 2: 1619-1625.
10. De S met C, Lurquin C, Lethe B, et al. DNA methylation is the primary silencing mechanism for a set of germ line-and tumor specific genes with a CpG rich promoter. Mol Cell Biol, 1999, 19: 7327-7335.
11. Hofmann M, Ruschenburg L. mRNA Detection of Tumor—Rejection Genes BAGE,GAGE and MAGE in Peritoneal Fluid from Patients with Ovarian Carcinoma as a Potential Diagnostic Tool. Int J. Cancer, 2002, 96:187-193.
12. Gillespie AM, Rodgers S, Wilson AP, et al. MAGE, GAGE and BAGE:tumour antigen expression in benign and malignant ovarian tissue. Br J cancer, 1998, 78:816-821.
13. Sarcevic B, Spagnoli G, Terracciano L, et al. Expression of Cancer/Testis Tumor Associated Antigens in Cervical Squamous Cell Carcinoma. Oncology, 2003, 64:443-449.
14. Hee-Kyung C, JongW P, Woo GK, et al. The expression of MAGE and GAGE genes in uterine cervical carcinoma of Korea by RT-PCR with common primers. Gyn On, 2005, 97:342-347.
15. Chitale DA, Jungbluth AA, Marshall DS, et al. Expression of cancer-testis antigens in endometrial carcinomas using a tissue microarray. Mod Pathol, 2005 Jan, 18:119-126.
16. Kawagoe H, Yamada A, Matsumoto H, et al. Serum MAGE-4 protein in ovarian cancer patients. Gnecol Oncol, 2000 , 76 :336-339.
17. Gillespie AM, Coleman RE. The potential of melanoma antigen expression in cancer therapy. Cancer Treat Rev, 1999,25 (4):219-227.
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27. Kawagoe H, Yamada A, Matsumoto H, et al. Serum MAGE-4 protein in ovarian cancer patients. Gynecol Oncol, 2000, 76(3): 336-339.
28．张毓青，宋天强，等．原发性肝癌患者外周血AFP mRNA和MAGE-1 mRNA水平的联合检测与术后复发转移的关系．中国肿瘤临床与康复，2005，12(4)：297-300．
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2．孔北华主编．妇产科学．北京：高等教育出版社，2005，307-311．
3. Peterson F. Annual report of the results of the treatment in Gynecological Cancer. Int Gynecol Obstet, 1991, 36(supple): 132-137.
4. Peterson F. Annual report of the results of the treatment in Gynecological Cancer: Twenty-first volume. Statement of results obtained in patients, 1982 to 1986, inclusive 3 and 5 Year survival up to 1990. Int Gynecol Obstet, 1991, 36: 1315-1320.
5．郝素珍 王桂琴主编．实用医学免疫学．北京：高等教育出版社，2005，221．
6. De Smet C, Lurquin C, vander Bruggen P, et al. Sequence and expression pattern of the human MAGE2 gene. Immunogenetics, 1994, 39: 121-129.
7. Weber J, Salgaller M, Samid D, et al. Expression of the MAGE-1 tumor antigen is upregulated by the demethylating agent 5-aza-2' -deoxytidine. Cancer Res, 1994, 54(7): 1766-1771.
8．卢学春，楼方定，许周敏等．去甲基化和组蛋白去乙酰化转移酶抑制剂对K562细胞增殖和肿瘤相关基因表达的影响．中国实验血液学杂志，2004，12(1)：44-47．
9．马鸣，俞莉章，那彦群等．肾及膀胱肿瘤组织中MAGE基因及其产物的表达．北京大学学报(医学版)，2004，36：159-163．
10. Li J, Yang Y, Fujie T, Baba K, et al. Expression of BAGE, GAGE and MAGE Genes in Human Gastic Carcinoma. Clin Cancer Res, 1996, 2: 1619-1625.
11．郝素珍 王桂琴主编．实用医学免疫学．北京：高等教育出版社，2005，219．
12. van der B, ruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science, 1991, 254: 1643-1647.
13. Vanden E, ynde B, Peeters O, et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. Exp Med,1995,182:689-698.
14. Boel P, Wildmann C , Sensi ML, et al. BAGE:a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity, 1995, 2 :1 67-175.
15. Desmet C, Lurquin C, vander B I, et al. Sequence and expression pattern of the human MAGE2 gene. Immunogenetics, 1994, 39: 121 -129.
16. Chomez P, DeBacker O, Bertrand M, et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Research, 2001,61:5544-5551.
17. Dabovic B , Zanaria E , Bardoni B , et al. A family of rapidly evolving genes from the sex reversal cr iticalre -gionin X p21. Mamm. G enome, 1995, 6(9):571-580.
18. Muscatelli F , Walker AP, Deplaen E , et al. Isolation and characterization of a new MAGE gene family in the Xp21.3 region.Proc Natl Acad Sci USA, 1995, 92 (11):4987-4992.
19. Lucas S , Deplaen E , Boon T . M AGE-B5, MAGE-B6, MAGE-C2 and MAGE-C3: four new members of the MAGE family w ith tumor-specific expression, Int J Cancer, 2000, 8 7:55-60.
20. Lucas S, Brasseur F , Boon T . A new MACE gene with ubiquitous expression doesnot code for known MAGE antigens recognized by T cells.Cancer Res, 1999, 59 :4100-4103.
21. Ruault M, van der B, Brun ME, et al. New BAGE (B melanoma antigen) genes mapping to the juxtacentromeric regions of human chromosomes 13 and 21 have a cancer/testis expression profile. Eu J Human Genetics, 2002, 10:838-840.
22. Chitale DA, Jungbluth AA, Marshall DS, et al. Expression of cancer-testis antigens in endometrial carcinomas using a tissue microarray. Mod Pathol, 2005 Jan, 18:119-126.
23. Mori M, Inoue H, Mimori K, et al. Expression of MAGE genes in human eolorectal carcinoma. Ann Surg,1996,224:183-188.
24. Desmet C, Lurquin C, Lethe B, et al. DNA methylation is the primary siliencing mechanism for a set of germ line and tumor specific genes with a CpG— rich promoter. Mol Cell Bi ol, 1999, 19:7327-7335.
25. Kobayashi Y, Higashi T, Nouso K, et al. Expression of MAGE, GAGE and BAGE genes in human liver diseases: utility as molecular markers for henatocellular carcinoma. Heoatol, 2000, 32: 612-617. "
26. Inoue H, Mori M, Honda M, et al. The expression of tumor-rejection antigen "MAGE" genes in human gastric carcinoma. Gastoenterology, 1995, 109: 1522-1525.
27. Weynants P, Lethe B, Brasseur F, et al. Expressionof MAGE genes by non-small-cell lung carcinomas. Int J Cancer, 1994, 56: 8269.
28. Yamashita N, Ishibashi H, Hayashida K, et al. High frequency of the MAGE-1 gene expression in hepatocellular carcinoma. Hepatology, 1996,24: 143740.
29. Lucas S, De Smet C, Axden KC, et al. Identification of a new MAGE gene with tumor-specific expression by representational difference analysis. Cancer Res, 1998, 58 :743-752.
30. Sarcevic B, Spagnoli G, Terracciano L, et al. Expression of Cancer/Testis Tumor Associated Antigens in Cervical Squamous Cell Carcinoma. Oncology, 2003, 64:443-449.
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