摘要
目的：检测MMP-7及TIMP-1、Survivin、Ki-67在子宫腺肌病异位内膜、在位内膜和对照组内膜中的表达情况，以了解侵袭因素与细胞凋亡、增殖在子宫腺肌病发病过程中的作用及其相关性，并探讨其在临床早期诊断和治疗中的应用价值。
方法：采用免疫组化S-P法检测子宫腺肌病异位内膜、在位内膜及正常对照组内膜中MMP-7及TIMP-1，Survivin，Ki-67的表达。
结果：1．MMP-7在子宫腺肌病异位内膜、在位内膜的表达显著高于正常内膜，差异有显著意义(P＜0.05)，且这种表达的差异主要体现在分泌期子宫内膜(P＜0.05)。TIMP-1在正常子宫内膜的表达高于腺肌病异位内膜、在位内膜，差异有显著意义(P＜0.05)，且这种表达的差异主要体现在分泌期子宫内膜(P＜0.05)。在正常子宫内膜组织中MMP-7与TIMP-1的表达之间有负相关关系(P＜0.05)，在腺肌病异位内膜、在位内膜中二者不具有相关性(P＞0.05)。
2．子宫腺肌病异位内膜中Survivin的表达显著高于在位内膜及正常内膜(P＜0.05)，且这种表达的差异主要体现在增生期子宫内膜(P＜0.05)，而在位内膜与正常内膜比较，差异无显著性意义(P＞0.05)。在腺肌病异位内膜组织中Survivin与MMP-7的表达之间有正相关关系(P＜0.05)；
3．在位内膜与正常内膜中Ki-67的表达有周期性变化，增生期显著强于分泌期(P＜0.05)。而在子宫腺肌病异位内膜中，Ki-67的表达在分泌期和增生期差异无显著性(P＞0.05)。在腺肌病异位内膜组织中Ki-67与Survivin、MMP-7的表达之间有正相关关系(P＜0.05)；
4．子宫腺肌病患者的痛经程度与异位内膜中MMP-7的表达之间存在正相关性(P＜0.05)，而与Survivin、Ki-67不存在相关性(P＞0.05)。
结论：MMP-7及TIMP-1的比例失调，可能是子宫腺肌病的异位内膜、在位内
Objective: To investigate the expression of matrix metalloproteinase-7(MMP-7), tissue inhibitor of matrix metalloproteinase-1(TIMP-1), Survivin and Ki-67 in eutopic endometrium, ectopic endometrium of adenomyosis and normal human endometrium in order to study the function and relativity of invasion ,apoptosis and proliferation in the course of adenomyosis . Its early clinical diagnosis and the treatment application are discussed.
Method: Specimens of normal endometrium , eutopic endometrium of adenomyosis and ectopic endometrium of adenomyosis were obtained for immunohistochemical MMP-7 , TIMP-1, Survivin and Ki-67. Results:1. The expression of MMP-7 in eutopic endometrial tissue and ectopic endometrial tissue of adenomyosis was significantly higher than that of normal endometrium(P<0. 05). The discrepancy was mainly reflected in secretory phase. TIMP-1 in normal endometrium was expressed significantly higher than eutopic endometrial tissue and ectopic endometrial tissue of adenomyosis (P<0. 05). The correlation between the expression of MMP-7 and TIMP-1 in normal endometrium was negative (P<0.05), while no correlation had been found in eutopic endometrial tissue and ectopic endometrial tissue of adenomyosis(P>0. 05). 2. The expression of Survivin in ectopic endometrium of adenomyosis was significantly higher than that of normal endometrium and eutopic endometrium of adenomyosis, as it was seen mostly in proliferative phase(P<0.05). No significant diferences between the eutopic endometrium of adenomyosis and of normal endometrium were observed (P>0. 05). There
引文
1．白红，赵丽嫣．子宫腺肌病病因与发病机制研究进展．中国妇产科临床杂志，2003，46：460-463．
2．周少敏，林仲秋．111例子宫腺肌病的病因及诊断．广东医学，2000，21(6)：491-492．
3. Benson RC, Sneeden VD. Adenomyosis: a reappraisal of symptomatology. Am J Obstet Gynecol, 1958, 76: 1044-1061.
4．郎景和．子宫内膜异位症研究的新里程．中华妇产科杂志，2005，40：324．
5. Matsuda M, Sasabe H, Adachi Y, et al. Increased invasion activity of endometrial stromal cells and elevated expression of matrix metalloproteinase messenger RNA in the uterine tissue of mice with experimentally induced adenomyosis, Am J Obstet Gynecol, 2001, 18 5: 1374-1380.
6. Ueda M, Yamashita Y, Takehara M, et al. survivin gene expression in endometriosis. J Clin Endocrinol Metab, 2002, 87(7): 3452-3459.
7. Fonatsch C, Duchrow G, Rieder H, Assignment of the humen Ki67 gene(MKI67) to 10q25-qter. Genomics, 1991, 11: 467-477.
8．胡浴桓主编．疼痛心理学．乌鲁木齐：新疆科技卫生出版社，1999：44-45．
9. Leyendeeker G, Herbertz M, Kunz G, et al, Endometriosis results from the dislocation of basal endometrium. Human Reprod, 2002, 17(10): 2725-2736.
10. Ferenezy A. Pathophysiology of adenomyosis. Hum Reprod Update, 1998, 4: 312-322.
11. Garcia-Velasco JA, Mulayashi H, Ishihara H, et al, Ocstrogen receptor alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Human Reprod, 2001, 16(1): 51-55.
12. Propst AM, Quade BJ, Gargiulo AR, et al. Adenomyosis demonstrates increased expression of the basic fibroblast growth factor receptor/ligand System compared with autologous endometrium. Menopause, 2001, 8: 368-371.
13. Knox JD, Boreham DR, Walker JA, et al. Mapping of metalloproteinase gene matrilysin(MMP-7)to human chromosome 11q21-q22. Cytogenet Cell genet, 1996, 72: 179-182.
14. Curry TE Jr, Osteen KG. Cyclic changes in the matrix metalloproteinases system in thebovary and uterus. Biol Reprod, 2001, 64(5): 1285-1296.
15．齐璇．基质金属蛋白酶及其抑制物与子宫内膜异位症．国外医学妇幼保健分册，2002，13(1)：14-16．
16. Freitas S, Meduri G, Le Nestour E, et al. Expression of metalloproteinAses and their inhibitors in blood vessels in human endometrium. Biol Reprod, 1999, 61(4): 1070-1082.
17．王晗，董旭，葛常辉．基质金属蛋白酶在生殖中的作用与调控．国外医学计划生育分册．2002，21(3)：141-144．
18. Mori S, Fujii M, Kudo R, et al. Expression of the Small Molecular Weight MatrixMetalloproteinase in Adenomyosis of the Mouse Uterus. Ac2ta Obst Gynace Jpn, 1996, 48: 386-392.
19. Mori T, Nakahashi K, Kyokuwa M, et al. A matrix metalloproteinase inhibitor, ONO-4817, retards the development of mammary tumor and the progression of uterine adenomyosis in mice[J]. Anticancer Res, 2002, 22(6c): 3985-3988.
20. Mori T, Yamasaki S, Masui F, et al. suppression of the development of experimentally induced uterine adenomyosis by a novel matrix metalloproteinase inhibitor, ONO-4817, in mice[J]. Exp-BioMed(Maywood), 2001, 226(5): 429-433.
21. Ambrosini G, Adida G, Sirugo G, et al. Induction of apoptosis and inhibiton of cell proliferation by surviving gene targeting. J Biol Chem, 1998, 273(18): 1177-1182.
22. Conway EM, Pollefeyt S, Steiner Mosonyi M, et al. Deficiency of surviving in transgenic mice exacerbates Fas-induced apoptosis via mitochondrial pathways. Gastroenterology, 2002, 123(2): 619-631.
23. Agui T, McConkey DJ, Tanigawa N1 Comparative study of various biological parameters, including expression of survivin, betweenp rimary and metastatic human colonic adenocarcinomasl Anticancer Res, 2002, 22: 17692-17761.
24. Tarkowski R, Kotarski J, Polak G, et al, Expression of the survivin gene in the scar endometriosis and in nomal human endometrium. Ginekol Pol, 2001, 2(12A): 1539-1542.
25．陆才德，戴德坚，孟化．SurviVin—值得关注的抗癌治疗靶．世界华人消化杂志2005：13(6)：701-705．
26. Fonatsch C, Duchrow G, Rieder H, Assignment of the humeri Ki67 gene (MKI67) to 10q25-qter. Genomics, 1991, 11: 467-477.
27. Jones RK, Bulmer JN, Searle RF. Immunohistochemical characterization of proliferation, oestrogen receptor and progesterone receptor expression inendometriosis: comparison of eutopic and ectopic endometrium with normal cycling endometrium. Human Reproduction, 1995, 12: 3272-3279.
28. Matsumoto Y, Iwasaka T, Yamasaki F, et al. Apoptosis and ki67 expression in adenomyotic lesions and in the corresponding eutopic endometrium. Obstetrics and Gynecology, 1999, 94(1): 71277.
29. Harris MA, Hansen RA, Vidsudhiphan P, et al. Effects of conjugated Linoleic acids and docosahexaenoic acid on rat liver and reproductive tissue fatty acids, prostaglandins and matrix matrix metalloproteinase production. Prostaglandins Leukot Essent Fatty Acids, 2001, 65(1): 23-29.
1．周应芳，子宫腺肌病的基础研究和药物治疗的进展．继续医学教育，2006，20(16)：46-49．
2．袁发焕，细胞外基质、基质金属蛋白酶及抑制因子的研究进展，国外医学临床生物化学与检验学分册，2000，21(2)：62-65．
3. Mclennan S, Fisher E, Martell S, et al. Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells: possible role in diabetic nephropathy. Kidney Int 2000; 58(suppl 77): 581.
4．齐璇．基质金属蛋白酶及其抑制物与子宫内膜异位症．国外医学妇幼保健分册，2002，13(1)：14-16．
5. Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem, 1999, 274(31): 21491-21494.
6. Woessner J F. Matrix metalloproteinases and their inhibitors on connective tissue remodeling[J]. FASEB J, 1991, 5: 2145～2154.
7. Vaalamo M, Leivo T, Saarialho-kere U. Differential expression of tissue inhibitors of metalloproteinases(TIMP-1,2,3, and-4) in normal and aberrant wound healing[J]. Hum Pathol, 1999, 30(7): 795-802.
8. Lee E, Vaughan DE, Parikh SH, et al. Regulat ion of matrix metalloproteinases and plasm inogen activator inhibitor-1 synthesis by plasm inogen in cultured human vascular amooth muscle. Circ Res, 1996; 78 (1): 44.
9. Brenner RM, Nayak NR, Slayden OD, et al. Premenstroal and menstrual changes in the macaque and human endometrium: relevance to endometriosis. Ann N Y Acad Sci, 2002, 955: 60-74.
10. Bruner KL, Matrisian LM, Rodgers W H. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest, 1997; 99(12): 2851.
11. Starzinski A, Gaetje R, Zeitvogel A. et al. Tracing cellular and molecular mechanisms involved in endometriosis. Hum Reprod Update, 1998; 4(5): 724.
12. Freitas S, Meduri G, Le Nestour E, et al. Expression of metalloproteinase and there inhibits in blood vessels in human endometrium. Biol Reprod, 1999, 61(4): 1070-1082.
13. Curry TE Jr, Osteen KG. Cyclic changes in the matrix metalloproteinases system in the ovary and uterus. Biol Reprod, 2001, 64(5): 1285-1296.
14. Soini Y, Alarakkola E, Autio-Harmainen H, Expression of messenger RNAs for metalloproteinases 2 and 9, type Ⅳ collagen, and laminin in nonneoplastic and neoplastic endometrium. Hum Pathol, 1997, 28(2): 220-226
15. Zhang J, Hampton AL, Nie G, et al. Progesterone inhibits activation of latent matrix metalloproteinase-2(MMP-2) by membrane-type MMP: enzymes coordinately expressed in human endometrium. Biol Reprod, 2000, 62(1): 85-94.
16. Osteen K G, Brunet - Tran KL, Keller NR et al. Progesterone - mediated endometrial maturation limits matrix metalloproteinase (MMP) expression in an inflammatorg - like environment: a regulatory system altered in endometriosis. Ann N YAcad Sci, 2002, 95(5): 37-47.
17. Sillem M, Prifti S, Neher M, et al. Extracellular matrix remodeling in the endometrium and its possible relevance to the pathogenesis of endometriosis. Hum reprod, 1998, 4(5): 730-735.
18. Mizumoto H, Saito T, Ashihara K et al. Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study andenzyme immunoassay. Life Sci, 2002, 71(3): 259-273.
19. Ria R, Loverro G, Vacca A et al. Angiogenesis extent and expressionof matrix metalloproteinase-2 and-9 agree with progression of ovarian endometriomas. Eur J Clin Invest, 2002, 32(3): 199-206.
20．王凌，濮德敏，张萍，等，基质金属蛋白酶-2，-9在子宮腺肌病的表达[J]．中国组织化学与细胞化学杂志，2002，11(3)：310-313．
21. Matsuda M, Sasabe H, Adachi Y, et al. Increased invasion activity of endometrial stromal cells and elevated expression of matrix metalloproteinase messenger RNA in the uterine tissue of mice with experimentally induced adenomyosis,Am J Obstet Gynecol,2001,185:13 74-1380.
22. Lichte A, Kolkenbroch H, Tschesche H, et al.The recombinant catalytic domain of membrane-type matrix metalloproteinase-1(MT1-MMP) induce activation of progelatinase A and progelatinase complexed with TIMP-2. FEBSLett, 1996, 397:277-282.
23. Mori S, Fujii M, Kudo R, et al . Expression of the Small Molecular Weight MatrixMetalloproteinase in Adenomyosis of the Mouse Uterus. Acta Obst Gynace Jpn, 1996, 48:386-392.
24. Mori T, Nakahashi K, Kyokuwa M, et al.A matrix metalloproteinase inhibitor, ONO-4817, retards the development of mammary tumor and the progression of uterine adenomyosis in mice[J]. Anticancer Res, 2002, 22 (6c):3985-3988.
25. Mori T, Yamasaki S, Masui F, et al. suppression of the development of experimentally induced uterine adenomyosis by a novel matrix metalloproteinase inhibitor,ONO-4817,in mice[J]. Exp-BioMed(M aywood), 2001, 226(5):429-433.
26. Zhou YF, Mori T, Kudo H, et al. Effects of angiogenesis inhibitor TNP-470 on the development of uterine adenomyosis in mice. Fertil Steril,2003, 80:788-794.
27. Steward WP. Marimastat(BB2516):current status of development [J]. Cancer Chemother Pharmacol, 1999, 43(Suppl):S56-60