基质金属蛋白酶-7及组织抑制剂-1在宫颈癌中的表达及意义
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摘要
研究目的:宫颈癌是在全球妇女恶性肿瘤中发病率仅次于乳腺癌的最常见的恶性肿瘤,每年约有20多万妇女死于宫颈癌。而宫颈间质内富含Ⅳ型胶原,层粘连蛋白,纤维结合素及氨基葡聚糖等,多为MMP-7的降解底物,TIMP-1则对MMP-7有抑制作用,二者及其之间的平衡在宫颈癌的发生发展中作用重要。故本试验拟通过检测宫颈癌中MMP-7,TIMP-1及二者之间平衡关系的表达情况,来探寻其与宫颈癌的侵袭转移及预后的关系,以寻求新的预后判定指标及新的治疗途径。
研究方法:本研究采用免疫组化SP法对53例宫颈浸润癌组织,9例CIN,10例因子宫肌瘤而行子宫切除的正常宫颈组织标本进行MMP-7及TIMP-1蛋白表达的检测。按显色的强弱及阳性细胞所占的比例分级。
研究结果:1.MMP-7,TIMP-1在宫颈癌中的表达均高于CIN及正常宫颈组织(p<0.01),其蛋白主要表达于癌细胞的胞浆中。
2.MMP-7与TIMP-1呈弱的正相关关系(r=0.281,p<0.05),其中MMP-7在宫颈癌中多为强阳性表达,而TIMP-1则多为弱阳性表达。
3.MMP-7在宫颈鳞癌中的表达高于腺癌,低分化癌中的表达高于中-高分化者,伴淋巴结转移者中的表达高于无淋巴结转移者(p<0.05),而与患者的年龄,临床分期则无明显相关关系(p>0.05)。TIMP-1与宫颈癌
Objective: cervical cancinoma is the second most familiar malignancy following mammary carcinoma among women all over the world, and about 200,000 women die of it annually. As is known to all, cervix is consisted of IV collagen, laminin, fibrin combine element and glycosaminoglycans, which are mostly the substrate of matrix metalloproteinase-7, and tissue inhibitor of matrix metalloproteinase-1 is its' inhibitor. Both MMP-7, TIMP-1 and the balance between them play an important role in the arising and expanding of cervical carcinoma. The aim of this research is to investigate the expression of MMP-7 and TIMP-1 in the cervical carcinoma and to evaluate the relationship between the expression of both MMP-7, TIMP-1 and clinicpathologic features of cervical carcinoma in order to seek new prognosis index, and new therapy approach.Methods: The expression and distribution of MMP-7 and TIMP-1 proteins are detected by immunohistochemical technique in 53 cases of cervical carcinoma tissue, 9 cases of CIN and 10 cases of normal cervices tissue coming from operation specimen excised because of myoma of uterus.
Classification is done according to the depth of the color and the proportion of the masculine cell.Results: l.The level of MMP-7 and TIMP-1 are significantly higher in cervical carcinoma than in CIN and normal cervices (p<0.01). The protein mainly expresses in the cytoplasm of cervical carcinoma cells. 2. There is a weak relationship between MMP-7 and TIMP-1 (r=0.281, p<0.05). And the expression of MMP-7 is strong in most cases while that of TIMP-1 is weak in most ones.3.The expression of MMP-7 is related to pathological classification, differentiation and lymph node metastasis (p<0.05), and has nothing to do with age, clinical stages (p>0.05). However there is no sign showing the expression of TIMP-1 has something to do with the biological behavior of cervical carcinoma in carcinoma cell (p>0.05).Conclusion: MMP-7 owns its importance in the invasion, metastasis and prognosis of cervical carcinoma, which can act as the new therapy target and be inhibited by TIMP-1.
研究方法:本研究采用免疫组化SP法对53例宫颈浸润癌组织,9例CIN,10例因子宫肌瘤而行子宫切除的正常宫颈组织标本进行MMP-7及TIMP-1蛋白表达的检测。按显色的强弱及阳性细胞所占的比例分级。
研究结果:1.MMP-7,TIMP-1在宫颈癌中的表达均高于CIN及正常宫颈组织(p<0.01),其蛋白主要表达于癌细胞的胞浆中。
2.MMP-7与TIMP-1呈弱的正相关关系(r=0.281,p<0.05),其中MMP-7在宫颈癌中多为强阳性表达,而TIMP-1则多为弱阳性表达。
3.MMP-7在宫颈鳞癌中的表达高于腺癌,低分化癌中的表达高于中-高分化者,伴淋巴结转移者中的表达高于无淋巴结转移者(p<0.05),而与患者的年龄,临床分期则无明显相关关系(p>0.05)。TIMP-1与宫颈癌
Objective: cervical cancinoma is the second most familiar malignancy following mammary carcinoma among women all over the world, and about 200,000 women die of it annually. As is known to all, cervix is consisted of IV collagen, laminin, fibrin combine element and glycosaminoglycans, which are mostly the substrate of matrix metalloproteinase-7, and tissue inhibitor of matrix metalloproteinase-1 is its' inhibitor. Both MMP-7, TIMP-1 and the balance between them play an important role in the arising and expanding of cervical carcinoma. The aim of this research is to investigate the expression of MMP-7 and TIMP-1 in the cervical carcinoma and to evaluate the relationship between the expression of both MMP-7, TIMP-1 and clinicpathologic features of cervical carcinoma in order to seek new prognosis index, and new therapy approach.Methods: The expression and distribution of MMP-7 and TIMP-1 proteins are detected by immunohistochemical technique in 53 cases of cervical carcinoma tissue, 9 cases of CIN and 10 cases of normal cervices tissue coming from operation specimen excised because of myoma of uterus.
Classification is done according to the depth of the color and the proportion of the masculine cell.Results: l.The level of MMP-7 and TIMP-1 are significantly higher in cervical carcinoma than in CIN and normal cervices (p<0.01). The protein mainly expresses in the cytoplasm of cervical carcinoma cells. 2. There is a weak relationship between MMP-7 and TIMP-1 (r=0.281, p<0.05). And the expression of MMP-7 is strong in most cases while that of TIMP-1 is weak in most ones.3.The expression of MMP-7 is related to pathological classification, differentiation and lymph node metastasis (p<0.05), and has nothing to do with age, clinical stages (p>0.05). However there is no sign showing the expression of TIMP-1 has something to do with the biological behavior of cervical carcinoma in carcinoma cell (p>0.05).Conclusion: MMP-7 owns its importance in the invasion, metastasis and prognosis of cervical carcinoma, which can act as the new therapy target and be inhibited by TIMP-1.
引文
1. Cox G, O byrne KJ. Matrix metalloproteinase and cancer [J]. Anticancer Res, 2001, 21(613):4207-4219
2. Okada A. Roles of matrix metalloproteinase and tissue inhibitor of metalloproteinase (TIMPs) in cancer invasion and metastasis. Gan to Kagakd Ryoho, 1999,26(14):2247-2252
3. Brinckerhoff G, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince [J]. Nat Rev Mol Cell Biol, 2002,3(3):207-214
4. Connor CMO, Fitz gerald. Matrix metalloproteinases and lung diease [J]. Thorax, 1994,49(6):602
5. Nagase H, Woessner JFJ. Matrix metalloproteinases [J]. J Isiol Cham, 1999,272:21491-21494
6. Massova I, Kotra LP, Fridman R, et al. Matrix metalloproteinases: Structures, evolution, and diversification [J]. FASEB J, 1998, 12:1075-1095
7. Murphy G, Cockett MI, Ward TV, et al. Matrix metalloproteinase degredation of elastin, type IV collagen and proteoglycan-a quantitative comparision of the activities of 95 kDa and 72X103 gelatinase, stromelysin-1 and -2 and punctuates metalloproteinase (pump). Bioche mJ, 1991,277-279
8. Ymashita Y, Azumano I, Mai M, et al. Expression and tissue location of matrix metalloproteinases-7 (matrilysin) in human gastric carcinomas [J]. Int J Cancer. 1998,79:187-194
9. Mcoonnell S, Navre M, Coffey RJ, et al. Expression and location of the
matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. [J]. Mol carcino, 1991,4:527-533
10. Yoshimoto M, Intoh F, Yamamoto H, et al. Expression of MMP-7 mRNA in human colorectal cancers [J]. Int J Cancer, 1993,54:614-618
11. Zhao WQ, Li H, Yamashita K, et al. Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts [J]. J Cell sci, 1998,111:1147-1153
12. Hashimoto K, Kihira Y, Matuo Y, et al. Expression of matrix metalloproteinase-7 and tissue inhibitor of metalloproteinase-1 in human prostate [J]. Urology, 1998,160(5): 1872
13. Bramhall SR, Neoptolems JP, Stamp GNH, et al. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma [J].J Pathol, 1997,182:347
14. 曹泽毅.中华妇产科学,人民卫生出版社,1999:1746-174.
15. Goldberg I, Davidson B, Lerner-Geva L, et al. Expression of extracellular matrix proteins in cervical squamous cell carcinoma a clinicopathological study. J Clin Pathol, 1998, 51(10): 78-85
16. Moser PL, Kieback DG, Hefler I, et al. Immnohistochemcal detection of matrix metalloproteinases (MMP) 1 and 2, and tissue inhibitor of metalloproteinase 2 (TIMP-2) in stage IB cervical cancer. Anticancer Res, 1999,19(51): 4391-4393
17. Knox JD, Boxeham DR, Walker JA, et al. Mapping of the metalloproteinase gene matrilysin (MMP-7) to human chromosome: Hq21-q22.Cytogenet cell Gene, 1996,72:179-182
18. Parons SL, Swatson SA, Brown pd , et al. Matrix metalloproteinases. Brit j surg. 1997,84(2): 160
19. Mori M, Barnard GF, Mimori K, et al. Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinomas. Cancer, 1995,75:1516-1519
20. Lamik Yokohama y, Nakanishil, et al. Matrix metalloproteinase-7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalioproteinases and enzymic properities. J, Boil, Chen, 1995,270:6691-6697
21. Tamakoshi K, Kikkawa F, Nawa A et al. Characterization of extracellula, matrix metalloproteinase and inhibitor in gynecologic cancer tissues with clinically different metastatic form. Cancer, 1995,76:2565-2571
22. Mitsiades N, Yu WH, Poulakiv V, et al. Matrix metalloproteinase-7 mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res, 2001, 61:577
23. Powell WC, Fingleton B, Wilson CL, et al. The metalloproteinase matrilysin proteoltically generates activer soluble Fas ligand and potentiantes epithelial cell apoptosis. Curr Biol, 1999,9:1441-1447
24. Mitsiades N, Yu WH, Poulaki V, et al. Matrix metalloproteinase-7 mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res, 2001,61:577-581
25. Yu WH, Woessner JF Jr, Mc Neish JD, et al. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodely. Genes Dev, 2002, 16:307-323
26. Tamakoshi K, Kikkawa F, Nawa A et al. Characterization of extracellula, matrix metalloproteinase and inhibitor in gynecologic cancer tissues with clinically different metastatic form. Cancer, 1995,76:2565-2571
27. Salmela MT, Karjalainen-lindsberg ML, Puolakkainen P, Saarillho-kere U.uPregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma. Br J Cancer, 2001,Aug3: 85(3):383-392
28. Price JT, Thompson EW. Mechanism of tumor in invasion and metastasis: emerging targets for therapy. Expertopin ther target, 2002,6(2): 217-233
29. Davidson B, Goldberg I, Kopolovic J, et al. Expressiong of matrix metalloproteinase-9 in squamous cell carcinoma of the uterine cerviex clinicopathologic study using immunohistochemistry and mRNA in situ hybridization. Gynecol Oncol, 1999, 73(3):372-382
30. Hurskainen T. Expression and localization of matrix metalloproteinases (MMPs)-2, -9, -14(MT-MMP-1) and the tissue inhibitors of metallopro-teinases (TIMPs) in human placent and some malignant tumors implications for trophoblasts and tumor cell invasion. Acta Universitatis Ouluensis Medica, 1996, D382 (4): 17-36
31. Reponen P. The primary structure and development expression of mouse type IV collagenases. Acta Universitatis Ouluensis, A Scirntiae Rerum Naturalium, 1994, A262 (1): 1-33
32. Hulboy D L, Rudolph L A, Matrisian L M. Matrix metalloproteinases as mediators of reproductive function. Molecular Human Reproduction,1997,3(1): 27-45
33. Shigemasa K, Tanimoto H, Sakata, et al. Induction of matrix metalloproteinase-7 is common in mucinous ovarian tumors including early stage disease [J]. Med Oncol, 2000, 17: 52-58
34.郭颖,刘军,吴静等.基质金属蛋白酶在卵巢浆液性肿瘤中的表达.细胞与免疫学分子杂志,2002,18(5):471-473
35. Samlal RK, Velden JVD, Kate FWL, et al. Surgical pathologic factor that predict recurrence in stage Ib and Iib cervical carcinoma patients with negative pelvic lymph modes [J]. Cancer, 1997, 80(7): 1234-1240
36. Brewster W, Disan Y, Monk B, et al. Yangage as a progonostic factor in cervical cancer: Results of a population-based study [J]. Am J Obstet Gynecol, 1999, 180: 1464-1467
37. Serur E, Fruchter R, Maiman M, et al. Age, substance abuse, and survival of patients with cervical carcinoma. [J]. Cancer, 1995, 75(10): 2530-2538
38. Schiffm MH, Baner HM, Hoover RN, et al. Epidemiological evidence showing that human palilom avirus infection cause most cervical intraepithelial neoplasia [J]. J Natl Cancer Inst, 1993, 85: 958-964
39. Sun Y, Wengerl, et al. P53 down regulaters human matrix metallo-proteinase-1 (collagenase-1) gene expression [j]. J boil Chem, 1999, 274 (17): 11535-11540
40. Sun Y, Cheung JM, Martel-pelletier J, et al. Wild type and mutant P53 differentially regulate the gene expression of human collagease-3 (Hmmp-13). J Biol Chem, 2000, 275(15): 11327-11332
41. Sedlis A, Bundy B, Rotman M, et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage Ib carcinoma of the cervix after radical hysterectoing and pelvic lymphadenectomy: a Gynecologic Oncology Group study [J]. Gynecol Oncol, 1999,73: 177-183
42. Girardi F, Haas J.The impotance of the histologic processing of pelvic lympic noder in the treatment on cervical cancer. Int J Gynecol cancer,1993,3(4): 219
43. Ueno H, Yamashita K, Azumano I, et al. Enhanced production and activation of matrix metalloproteinase-7 (matrlysin) in human endometrial carcinomas [j]. Int J Cancer, 1999, 84: 470-477
44. Itoh F, Yamamoto H, Himoda Y, et al. Enhanced secretionand activation of matrilysin during malignant conversion of human colorectal epithelium and its relationship with invasive potential of colon cancer cells. Cancer, 1996,77:17
45. Yoshida H, Sumi Thyun Y, et al. Expression of surviving and matrix metalloproteinases in adenocarcinoma and squamous cell carcinoma of the uterine cervix. Oncol Rep, 2003, 10(1): 45-49
46. Kjorstad KE, Bond B. Stage Ib adenocarcinoma of the cervix: metastatic potential and patterns of dissemination. Am J Obstet Gynecol, 1984, 150:297-299
47. Tabata M, Ichinoc K, Sakurag N, et al. Incidence of ovarian metastasis in patients with cancer of the uterine cervix. Gynecol Oncol, 1987, 28:255
48. Toki N, Tsukamuto N, Kakn T, et al. Microscopic ovarian metastasis of the uterine cervical cancer. Gynecol oncol, 1991, 41:46
49. Chung CK, Stryker JA, Ward SP, et al. Histologic grade and prognosis of carcinoma of the cervix. Obstet Gynecol, 1981,57:636
2. Okada A. Roles of matrix metalloproteinase and tissue inhibitor of metalloproteinase (TIMPs) in cancer invasion and metastasis. Gan to Kagakd Ryoho, 1999,26(14):2247-2252
3. Brinckerhoff G, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince [J]. Nat Rev Mol Cell Biol, 2002,3(3):207-214
4. Connor CMO, Fitz gerald. Matrix metalloproteinases and lung diease [J]. Thorax, 1994,49(6):602
5. Nagase H, Woessner JFJ. Matrix metalloproteinases [J]. J Isiol Cham, 1999,272:21491-21494
6. Massova I, Kotra LP, Fridman R, et al. Matrix metalloproteinases: Structures, evolution, and diversification [J]. FASEB J, 1998, 12:1075-1095
7. Murphy G, Cockett MI, Ward TV, et al. Matrix metalloproteinase degredation of elastin, type IV collagen and proteoglycan-a quantitative comparision of the activities of 95 kDa and 72X103 gelatinase, stromelysin-1 and -2 and punctuates metalloproteinase (pump). Bioche mJ, 1991,277-279
8. Ymashita Y, Azumano I, Mai M, et al. Expression and tissue location of matrix metalloproteinases-7 (matrilysin) in human gastric carcinomas [J]. Int J Cancer. 1998,79:187-194
9. Mcoonnell S, Navre M, Coffey RJ, et al. Expression and location of the
matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. [J]. Mol carcino, 1991,4:527-533
10. Yoshimoto M, Intoh F, Yamamoto H, et al. Expression of MMP-7 mRNA in human colorectal cancers [J]. Int J Cancer, 1993,54:614-618
11. Zhao WQ, Li H, Yamashita K, et al. Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts [J]. J Cell sci, 1998,111:1147-1153
12. Hashimoto K, Kihira Y, Matuo Y, et al. Expression of matrix metalloproteinase-7 and tissue inhibitor of metalloproteinase-1 in human prostate [J]. Urology, 1998,160(5): 1872
13. Bramhall SR, Neoptolems JP, Stamp GNH, et al. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma [J].J Pathol, 1997,182:347
14. 曹泽毅.中华妇产科学,人民卫生出版社,1999:1746-174.
15. Goldberg I, Davidson B, Lerner-Geva L, et al. Expression of extracellular matrix proteins in cervical squamous cell carcinoma a clinicopathological study. J Clin Pathol, 1998, 51(10): 78-85
16. Moser PL, Kieback DG, Hefler I, et al. Immnohistochemcal detection of matrix metalloproteinases (MMP) 1 and 2, and tissue inhibitor of metalloproteinase 2 (TIMP-2) in stage IB cervical cancer. Anticancer Res, 1999,19(51): 4391-4393
17. Knox JD, Boxeham DR, Walker JA, et al. Mapping of the metalloproteinase gene matrilysin (MMP-7) to human chromosome: Hq21-q22.Cytogenet cell Gene, 1996,72:179-182
18. Parons SL, Swatson SA, Brown pd , et al. Matrix metalloproteinases. Brit j surg. 1997,84(2): 160
19. Mori M, Barnard GF, Mimori K, et al. Overexpression of matrix metalloproteinase-7 mRNA in human colon carcinomas. Cancer, 1995,75:1516-1519
20. Lamik Yokohama y, Nakanishil, et al. Matrix metalloproteinase-7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalioproteinases and enzymic properities. J, Boil, Chen, 1995,270:6691-6697
21. Tamakoshi K, Kikkawa F, Nawa A et al. Characterization of extracellula, matrix metalloproteinase and inhibitor in gynecologic cancer tissues with clinically different metastatic form. Cancer, 1995,76:2565-2571
22. Mitsiades N, Yu WH, Poulakiv V, et al. Matrix metalloproteinase-7 mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res, 2001, 61:577
23. Powell WC, Fingleton B, Wilson CL, et al. The metalloproteinase matrilysin proteoltically generates activer soluble Fas ligand and potentiantes epithelial cell apoptosis. Curr Biol, 1999,9:1441-1447
24. Mitsiades N, Yu WH, Poulaki V, et al. Matrix metalloproteinase-7 mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res, 2001,61:577-581
25. Yu WH, Woessner JF Jr, Mc Neish JD, et al. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodely. Genes Dev, 2002, 16:307-323
26. Tamakoshi K, Kikkawa F, Nawa A et al. Characterization of extracellula, matrix metalloproteinase and inhibitor in gynecologic cancer tissues with clinically different metastatic form. Cancer, 1995,76:2565-2571
27. Salmela MT, Karjalainen-lindsberg ML, Puolakkainen P, Saarillho-kere U.uPregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma. Br J Cancer, 2001,Aug3: 85(3):383-392
28. Price JT, Thompson EW. Mechanism of tumor in invasion and metastasis: emerging targets for therapy. Expertopin ther target, 2002,6(2): 217-233
29. Davidson B, Goldberg I, Kopolovic J, et al. Expressiong of matrix metalloproteinase-9 in squamous cell carcinoma of the uterine cerviex clinicopathologic study using immunohistochemistry and mRNA in situ hybridization. Gynecol Oncol, 1999, 73(3):372-382
30. Hurskainen T. Expression and localization of matrix metalloproteinases (MMPs)-2, -9, -14(MT-MMP-1) and the tissue inhibitors of metallopro-teinases (TIMPs) in human placent and some malignant tumors implications for trophoblasts and tumor cell invasion. Acta Universitatis Ouluensis Medica, 1996, D382 (4): 17-36
31. Reponen P. The primary structure and development expression of mouse type IV collagenases. Acta Universitatis Ouluensis, A Scirntiae Rerum Naturalium, 1994, A262 (1): 1-33
32. Hulboy D L, Rudolph L A, Matrisian L M. Matrix metalloproteinases as mediators of reproductive function. Molecular Human Reproduction,1997,3(1): 27-45
33. Shigemasa K, Tanimoto H, Sakata, et al. Induction of matrix metalloproteinase-7 is common in mucinous ovarian tumors including early stage disease [J]. Med Oncol, 2000, 17: 52-58
34.郭颖,刘军,吴静等.基质金属蛋白酶在卵巢浆液性肿瘤中的表达.细胞与免疫学分子杂志,2002,18(5):471-473
35. Samlal RK, Velden JVD, Kate FWL, et al. Surgical pathologic factor that predict recurrence in stage Ib and Iib cervical carcinoma patients with negative pelvic lymph modes [J]. Cancer, 1997, 80(7): 1234-1240
36. Brewster W, Disan Y, Monk B, et al. Yangage as a progonostic factor in cervical cancer: Results of a population-based study [J]. Am J Obstet Gynecol, 1999, 180: 1464-1467
37. Serur E, Fruchter R, Maiman M, et al. Age, substance abuse, and survival of patients with cervical carcinoma. [J]. Cancer, 1995, 75(10): 2530-2538
38. Schiffm MH, Baner HM, Hoover RN, et al. Epidemiological evidence showing that human palilom avirus infection cause most cervical intraepithelial neoplasia [J]. J Natl Cancer Inst, 1993, 85: 958-964
39. Sun Y, Wengerl, et al. P53 down regulaters human matrix metallo-proteinase-1 (collagenase-1) gene expression [j]. J boil Chem, 1999, 274 (17): 11535-11540
40. Sun Y, Cheung JM, Martel-pelletier J, et al. Wild type and mutant P53 differentially regulate the gene expression of human collagease-3 (Hmmp-13). J Biol Chem, 2000, 275(15): 11327-11332
41. Sedlis A, Bundy B, Rotman M, et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage Ib carcinoma of the cervix after radical hysterectoing and pelvic lymphadenectomy: a Gynecologic Oncology Group study [J]. Gynecol Oncol, 1999,73: 177-183
42. Girardi F, Haas J.The impotance of the histologic processing of pelvic lympic noder in the treatment on cervical cancer. Int J Gynecol cancer,1993,3(4): 219
43. Ueno H, Yamashita K, Azumano I, et al. Enhanced production and activation of matrix metalloproteinase-7 (matrlysin) in human endometrial carcinomas [j]. Int J Cancer, 1999, 84: 470-477
44. Itoh F, Yamamoto H, Himoda Y, et al. Enhanced secretionand activation of matrilysin during malignant conversion of human colorectal epithelium and its relationship with invasive potential of colon cancer cells. Cancer, 1996,77:17
45. Yoshida H, Sumi Thyun Y, et al. Expression of surviving and matrix metalloproteinases in adenocarcinoma and squamous cell carcinoma of the uterine cervix. Oncol Rep, 2003, 10(1): 45-49
46. Kjorstad KE, Bond B. Stage Ib adenocarcinoma of the cervix: metastatic potential and patterns of dissemination. Am J Obstet Gynecol, 1984, 150:297-299
47. Tabata M, Ichinoc K, Sakurag N, et al. Incidence of ovarian metastasis in patients with cancer of the uterine cervix. Gynecol Oncol, 1987, 28:255
48. Toki N, Tsukamuto N, Kakn T, et al. Microscopic ovarian metastasis of the uterine cervical cancer. Gynecol oncol, 1991, 41:46
49. Chung CK, Stryker JA, Ward SP, et al. Histologic grade and prognosis of carcinoma of the cervix. Obstet Gynecol, 1981,57:636