基质金属蛋白酶及其组织抑制剂在滋养细胞疾病中的表达及其临床意义
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摘要
目的：通过研究基质金属蛋白酶(MMP-2、MMP-9)及其组织抑制剂(TIMP-1、TIMP-2)在不同类型滋养细胞疾病中的表达，探讨基质金属蛋白酶系统与滋养细胞疾病临床病理参数的相关性，寻求可以预测滋养细胞疾病恶变和滋养细胞肿瘤转移潜能的指标，为临床早期预测滋养细胞疾病的恶变及预防性化疗提供可靠依据。
方法：应用链霉菌抗生物素蛋白—过氧化物酶免疫组织化学方法对20例正常早孕((12周)绒毛组织、15例部分性葡萄胎、55例完全性葡萄胎、15例侵蚀性葡萄胎、8例绒毛膜癌组织中MMP-2、MMP-9、TIMP-1、TIMP-2进行检测。
结果：
(1) MMP-2在不同类型滋养细胞中的表达无显著性差异(X~2=0.926，P=0.921)；
(2) MMP-9在正常早孕绒毛组织、部分性葡萄胎、完全性葡萄胎、侵蚀性葡萄胎、绒毛膜癌中均100％表达，但随着滋养细胞恶性程度的增加其表达显著升高，差异具极显著性(X~2=26.421，P=0.0001)；
(3) TIMP-1在正常早孕绒毛组织均有表达，而在部分性葡萄胎、完全性葡萄胎、侵蚀性葡萄胎、绒毛膜癌中分别有表达6.67％、5.45％、6.67％、12.50％不表达，且随着肿瘤恶性程度的升高，其染色程度和染色细胞百分率减少，差异具极显著性(X~Z=9.575，P=0.048)：
(4) TIMP-2在各组织中的表达无显著性差异(X~2=1.462，P=0.833)。
(5) 葡萄胎患者MMP-9的表达与年龄和刮宫次数有相关性，(分别为
安徽医科大学硕士学位论文
rs==0·262，P=0，028;rs=0.390，P=0.001)。TIMP一l的表达在卵巢黄素化囊肿
有无、刮宫前血B一HCG值、血B一HCG转阴时间、妊娠呕吐、有无合并妊娠
高血压综合征等病理参数中显示有差别，与刮宫次数有相关性;
(6) MMP一9在发生恶变的葡萄胎组织中和未发生恶变的葡萄胎组织中
的表达无显著性差异(Mann一WhitneyU=1 1 6.0，p=0.320)。而TIMp一1在发生
恶变的葡萄胎组中的表达明显低于未发生恶变组，(Mann一whitneyu=77.00，
P=0 .015)。
(7)在侵蚀性葡萄胎中MMP一9、TIMP一1的表达与病理分型无相关性
(rs=0.196，p=0.485;rs=一0.495，p=0.061)，但在发生转移和未发生转移的
病例比较中MMp一9、TIMp一l表达均有显著性差异(Mann一WhitenyU=4，
P=0 .021;Mann一WhitenyU=5.5，p=0.01)。
(8) MMP一9在绒癌中的表达多为(++)一(+++)级，尤其是在有转移
瘤的病例及转移瘤个数多的病例表达增强，而TIMP一1表达多集中在(+)级。
结论:MMP一2、MMP一9参与了正常早孕滋养细胞的侵袭的过程，而
TIMP-1、TIMP一2使滋养层细胞以一种可控制的形式侵袭。MMP一9和TIMP一1
可能参与了滋养细胞疾病的浸润和血管生成，随着滋养细胞肿瘤恶性程度的
增加MMP一9表达上调而TIMP一1表达下调。MMP一9/TIMP一1比值的改变可引
起滋养细胞疾病的恶变和转移，MMP一9/TIMP一1可望成为临床早期预测滋养
细胞疾病的恶变及预防性化疗的指标。MMPs厅IMPs比例的改变也可能是滋
养细胞疾病发生妊娠高血压综合征的原因之一。MMP一2、TIMP一2可能与滋
养细胞浸润无密切关系。HCG可能影响葡萄胎TIMP一1的表达，MMP一9与葡
萄胎患者的年龄和刮宫次数有关。
Objective: To study the expression of matrix metallopreteinases (MMP-2,9) and tissue inhibitors of metallopreteinases (TIMP-1,2) in human gestational trophoblastic disease and their correlation with clinic pathological parameters in predicting the malignant transformation and metastasis.
Methods: Immunohistochemical streptavidin-peroxidase (S-P) method was used to detect the expression of MMP-2, MMP-9, TIMP-1, TIMP-2 in 20 cases of normal human cytotrophoblast cells, 15 cases of partial hydatidiform moles, 55 cases of complete hydatidiform moles, 15 cases of invasive moles and 8 cases of choriocarcinoma.
Results:
(1) No significant difference with MMP-2 expression in all cases. (X2=0.926, P=0.921)
(2) MMP-9 expression was detected in all types of trophoblastic cells, with the development of the malignant transformation the staining was markedly increased.
(X2=26.421, P=0.0001)
(3) Each cases of normal human cytotrophoblast cells expression TIMP-1, but 6.67% of partial hydatidiform moles, 5.45% of complete hydatidiform moles, 6.67% of invasive moles and 12.50% of choriocarcinoma were negative. With the
development of the malignant transformation the staining was decreased. (X2=9.575, P=0.048)
(4) The expression of TIMP-2 in all cases has no significant difference. (X2=1.462, P=0.833)
(5) In hydatidiform moles, the expression of MMP-9 correlated with age and times of curettage (rs=0.262 , P=0.028; rs=0.390, P=0.001) . The expression of TIMP-1 was decreased in women with the hydatidiform moles complicated theca lutein ovarian cyst, hyperemesis gravidarum, pregnancy-induced hypertension syndrome, higher -HCG serum values,and the longer time for negative-transition of HCG. TIMP-1 also assosciate with times of curettage in the hydatidiform moles.
(6) No significant difference of MMP-9 expression in hydatidiform mole between malignant transformation and without malignant transformation. (Mann-Whitney U=116.0 , P=0.320) But much lower TIMP-1 expression in malignant transformation cases. (Mann-Whitney U=77.00, P=0.015)
(7) In invasive moles no correlation was found among the MMP-9, TIMP-1 and the pathological types. (rs=0.196, P=0.485; rs=-0.495, P=0.061) But the expression of MMP-9 and TIMP-1 was significant difference between the malignant cases and without malignant cases. (Mann-WhitenyU=4> P=0.021 ; Mann-WhitenyU=5.5, P=0.01)
(8) The expression of MMP-9 in choriocarcinoma was increased especially in matastasis cases,while the TIMP-1 was decreased in the same cases.
Conclusion: MMP-2 and MMP-9 be involved in the invasion of the normal human cytotrophoblast cells, while TIMP-1 and TIMP-2 make this invasion controllable. MMP-9 and TIMP-1 probably be involved in invasion of the human gestational trophoblastic disease and angiogenesis. Upregulation of the MMP-9 and downregulation of the TIMP-1 with the malignancy degree in the
trophoblastic disease . The invasion and metastasis may caused by the change of MMP-9/TIMP-1 .The ratio of MMP-9/ TIMP-1 can be used as indicators to reference the stage of gestational trophoblastic disease development, provide the evidence to assess the prognosis and clinical thearpy. The change of MMPs/TIMPs might be one reason of pregnancy-induced hypertension syndrome in the human gestational trophoblastic disease. MMP-2 and TIMP-2 might have no closely related to the invision of trophoblast. Human thorionic gonadotropin may play an important role in the expression of TIMP-1. The expression of MMP-9 correlated with age and times of curettage in hydatidiform moles.
方法：应用链霉菌抗生物素蛋白—过氧化物酶免疫组织化学方法对20例正常早孕((12周)绒毛组织、15例部分性葡萄胎、55例完全性葡萄胎、15例侵蚀性葡萄胎、8例绒毛膜癌组织中MMP-2、MMP-9、TIMP-1、TIMP-2进行检测。
结果：
(1) MMP-2在不同类型滋养细胞中的表达无显著性差异(X~2=0.926，P=0.921)；
(2) MMP-9在正常早孕绒毛组织、部分性葡萄胎、完全性葡萄胎、侵蚀性葡萄胎、绒毛膜癌中均100％表达，但随着滋养细胞恶性程度的增加其表达显著升高，差异具极显著性(X~2=26.421，P=0.0001)；
(3) TIMP-1在正常早孕绒毛组织均有表达，而在部分性葡萄胎、完全性葡萄胎、侵蚀性葡萄胎、绒毛膜癌中分别有表达6.67％、5.45％、6.67％、12.50％不表达，且随着肿瘤恶性程度的升高，其染色程度和染色细胞百分率减少，差异具极显著性(X~Z=9.575，P=0.048)：
(4) TIMP-2在各组织中的表达无显著性差异(X~2=1.462，P=0.833)。
(5) 葡萄胎患者MMP-9的表达与年龄和刮宫次数有相关性，(分别为
安徽医科大学硕士学位论文
rs==0·262，P=0，028;rs=0.390，P=0.001)。TIMP一l的表达在卵巢黄素化囊肿
有无、刮宫前血B一HCG值、血B一HCG转阴时间、妊娠呕吐、有无合并妊娠
高血压综合征等病理参数中显示有差别，与刮宫次数有相关性;
(6) MMP一9在发生恶变的葡萄胎组织中和未发生恶变的葡萄胎组织中
的表达无显著性差异(Mann一WhitneyU=1 1 6.0，p=0.320)。而TIMp一1在发生
恶变的葡萄胎组中的表达明显低于未发生恶变组，(Mann一whitneyu=77.00，
P=0 .015)。
(7)在侵蚀性葡萄胎中MMP一9、TIMP一1的表达与病理分型无相关性
(rs=0.196，p=0.485;rs=一0.495，p=0.061)，但在发生转移和未发生转移的
病例比较中MMp一9、TIMp一l表达均有显著性差异(Mann一WhitenyU=4，
P=0 .021;Mann一WhitenyU=5.5，p=0.01)。
(8) MMP一9在绒癌中的表达多为(++)一(+++)级，尤其是在有转移
瘤的病例及转移瘤个数多的病例表达增强，而TIMP一1表达多集中在(+)级。
结论:MMP一2、MMP一9参与了正常早孕滋养细胞的侵袭的过程，而
TIMP-1、TIMP一2使滋养层细胞以一种可控制的形式侵袭。MMP一9和TIMP一1
可能参与了滋养细胞疾病的浸润和血管生成，随着滋养细胞肿瘤恶性程度的
增加MMP一9表达上调而TIMP一1表达下调。MMP一9/TIMP一1比值的改变可引
起滋养细胞疾病的恶变和转移，MMP一9/TIMP一1可望成为临床早期预测滋养
细胞疾病的恶变及预防性化疗的指标。MMPs厅IMPs比例的改变也可能是滋
养细胞疾病发生妊娠高血压综合征的原因之一。MMP一2、TIMP一2可能与滋
养细胞浸润无密切关系。HCG可能影响葡萄胎TIMP一1的表达，MMP一9与葡
萄胎患者的年龄和刮宫次数有关。
Objective: To study the expression of matrix metallopreteinases (MMP-2,9) and tissue inhibitors of metallopreteinases (TIMP-1,2) in human gestational trophoblastic disease and their correlation with clinic pathological parameters in predicting the malignant transformation and metastasis.
Methods: Immunohistochemical streptavidin-peroxidase (S-P) method was used to detect the expression of MMP-2, MMP-9, TIMP-1, TIMP-2 in 20 cases of normal human cytotrophoblast cells, 15 cases of partial hydatidiform moles, 55 cases of complete hydatidiform moles, 15 cases of invasive moles and 8 cases of choriocarcinoma.
Results:
(1) No significant difference with MMP-2 expression in all cases. (X2=0.926, P=0.921)
(2) MMP-9 expression was detected in all types of trophoblastic cells, with the development of the malignant transformation the staining was markedly increased.
(X2=26.421, P=0.0001)
(3) Each cases of normal human cytotrophoblast cells expression TIMP-1, but 6.67% of partial hydatidiform moles, 5.45% of complete hydatidiform moles, 6.67% of invasive moles and 12.50% of choriocarcinoma were negative. With the
development of the malignant transformation the staining was decreased. (X2=9.575, P=0.048)
(4) The expression of TIMP-2 in all cases has no significant difference. (X2=1.462, P=0.833)
(5) In hydatidiform moles, the expression of MMP-9 correlated with age and times of curettage (rs=0.262 , P=0.028; rs=0.390, P=0.001) . The expression of TIMP-1 was decreased in women with the hydatidiform moles complicated theca lutein ovarian cyst, hyperemesis gravidarum, pregnancy-induced hypertension syndrome, higher -HCG serum values,and the longer time for negative-transition of HCG. TIMP-1 also assosciate with times of curettage in the hydatidiform moles.
(6) No significant difference of MMP-9 expression in hydatidiform mole between malignant transformation and without malignant transformation. (Mann-Whitney U=116.0 , P=0.320) But much lower TIMP-1 expression in malignant transformation cases. (Mann-Whitney U=77.00, P=0.015)
(7) In invasive moles no correlation was found among the MMP-9, TIMP-1 and the pathological types. (rs=0.196, P=0.485; rs=-0.495, P=0.061) But the expression of MMP-9 and TIMP-1 was significant difference between the malignant cases and without malignant cases. (Mann-WhitenyU=4> P=0.021 ; Mann-WhitenyU=5.5, P=0.01)
(8) The expression of MMP-9 in choriocarcinoma was increased especially in matastasis cases,while the TIMP-1 was decreased in the same cases.
Conclusion: MMP-2 and MMP-9 be involved in the invasion of the normal human cytotrophoblast cells, while TIMP-1 and TIMP-2 make this invasion controllable. MMP-9 and TIMP-1 probably be involved in invasion of the human gestational trophoblastic disease and angiogenesis. Upregulation of the MMP-9 and downregulation of the TIMP-1 with the malignancy degree in the
trophoblastic disease . The invasion and metastasis may caused by the change of MMP-9/TIMP-1 .The ratio of MMP-9/ TIMP-1 can be used as indicators to reference the stage of gestational trophoblastic disease development, provide the evidence to assess the prognosis and clinical thearpy. The change of MMPs/TIMPs might be one reason of pregnancy-induced hypertension syndrome in the human gestational trophoblastic disease. MMP-2 and TIMP-2 might have no closely related to the invision of trophoblast. Human thorionic gonadotropin may play an important role in the expression of TIMP-1. The expression of MMP-9 correlated with age and times of curettage in hydatidiform moles.
引文
1. Denis L J, Verweij J. Matrix metalloproteinase inhibitors: present achievements and future prospects. Invest New Drugs, 1997,15(3): 175-185.
2. Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med, 1991,324(1):1-8.
3. Sang QX, Birkedal-Hansen H, Van Wart HE. Proteolytic and non-proteolytic activation of human neutrophil progelatinase B. Biochim Biophys Acta, 1995,1251(2):99-108.
4. Jeziorska M, Nagase H, Salamonsen LA, et al. Immunolocalization of the matrix metralloproteinases gelatinase B and stromelysin 1 in human endometrium throughout the menstrual cycle. J Reprod Fertil, 1996,107(1):43-51.
5. Xu P, Wang YL, Zhu S J, et al. Expression of matrix metralloproteinase-2,-9, and -14, tissue inhibitors of metralloproteinase- 1, and matrix proteins in human placenta during the first trimester. Biol Reprod, 2000,62(4):988-994.
6. Shimonovitz S, Hurwitz A, Dushnik M, et al. Developmental regulation of the expression of 72 and 92 kd type Ⅳ collagenases in human trophoblasts: a possible mechanism for control of trophoblast invasion. Am J Obstet Gynecol, 1994,171(3):832-838.
7. Marbaix E, Kokorine I, Henriet P, et al. The expression of interstitial collagenase in human endometrium is controlled by progesterone and by oestradiol and is related to menstruation. Biochem J, 1995, 305 (Pt 3):1027-1030.
8. Kenagy RD, Vergel S, Mattsson E, et al. The role of plasminogen, plasminogen activators, and matrix metalloproteinases in primate arterial smooth muscle cell migration. Arterioscler Thrornb Vasc Biol, 1996,16(11):1373-1382.
9. Whiteside E J, Jackson MM, Herington AC, et al. Matrix metalloproteinase-9
and tissue inhibitor of metalloproteinase-3 are key regulators of extracellular matrix degradation by mouse embryos. Biol Reprod 2001,64(5): 1331-1337
10. Hurskainen T, Seiki M, Apte SS, et al. Production of membrane-type matrix metalloproteinase-1 (MT-MMP-1) in early human placenta. A possible role in placental implantation? J Histochem Cytochem, 1998,46(2):221-229.
11. Tanaka SS, Togooka Y, Sato H, et al. Expression and localization of membrane type matrix metalloproteinase-1 (MT1-MMP) in trophoblast cells of cultured mouse blastocysts and ectoplacental cones. Placenta, 1998,19(1):41-48.
12. Oh J, Takahashi R, Kondo S, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell, 2001, 107(6): 789-800.
13. Sternlicht MD, Lochter A, Sympson CJ,et al. The stromal proteinase MMP 3/stromelysin-1 promotes mammary carcinogenesis. Cell, 1999,98(2): 137-146.
14. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, et al. Molecular aspects of tumor cell invasion and metastasis. Cancer, 1993, 71(4): 1368-1383
15. Lichtinghagen R, Helmbrecht T, Arndt B, et al. Expression pattern of matrix metalloproteinases in human liver. Eur J Clin Chem Clin Biochem, 1995, 33(2): 65-71.
16. David L, Nesland JM, Holm R, et al. Expression of laminin, collagen Ⅳ, fibronectin, and type Ⅳ collagenase in gastric carcinoma. An immunohistochemical study of 87 patients. Cancer, 1994, 73(3):518-527.
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2. Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med, 1991,324(1):1-8.
3. Sang QX, Birkedal-Hansen H, Van Wart HE. Proteolytic and non-proteolytic activation of human neutrophil progelatinase B. Biochim Biophys Acta, 1995,1251(2):99-108.
4. Jeziorska M, Nagase H, Salamonsen LA, et al. Immunolocalization of the matrix metralloproteinases gelatinase B and stromelysin 1 in human endometrium throughout the menstrual cycle. J Reprod Fertil, 1996,107(1):43-51.
5. Xu P, Wang YL, Zhu S J, et al. Expression of matrix metralloproteinase-2,-9, and -14, tissue inhibitors of metralloproteinase- 1, and matrix proteins in human placenta during the first trimester. Biol Reprod, 2000,62(4):988-994.
6. Shimonovitz S, Hurwitz A, Dushnik M, et al. Developmental regulation of the expression of 72 and 92 kd type Ⅳ collagenases in human trophoblasts: a possible mechanism for control of trophoblast invasion. Am J Obstet Gynecol, 1994,171(3):832-838.
7. Marbaix E, Kokorine I, Henriet P, et al. The expression of interstitial collagenase in human endometrium is controlled by progesterone and by oestradiol and is related to menstruation. Biochem J, 1995, 305 (Pt 3):1027-1030.
8. Kenagy RD, Vergel S, Mattsson E, et al. The role of plasminogen, plasminogen activators, and matrix metalloproteinases in primate arterial smooth muscle cell migration. Arterioscler Thrornb Vasc Biol, 1996,16(11):1373-1382.
9. Whiteside E J, Jackson MM, Herington AC, et al. Matrix metalloproteinase-9
and tissue inhibitor of metalloproteinase-3 are key regulators of extracellular matrix degradation by mouse embryos. Biol Reprod 2001,64(5): 1331-1337
10. Hurskainen T, Seiki M, Apte SS, et al. Production of membrane-type matrix metalloproteinase-1 (MT-MMP-1) in early human placenta. A possible role in placental implantation? J Histochem Cytochem, 1998,46(2):221-229.
11. Tanaka SS, Togooka Y, Sato H, et al. Expression and localization of membrane type matrix metalloproteinase-1 (MT1-MMP) in trophoblast cells of cultured mouse blastocysts and ectoplacental cones. Placenta, 1998,19(1):41-48.
12. Oh J, Takahashi R, Kondo S, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell, 2001, 107(6): 789-800.
13. Sternlicht MD, Lochter A, Sympson CJ,et al. The stromal proteinase MMP 3/stromelysin-1 promotes mammary carcinogenesis. Cell, 1999,98(2): 137-146.
14. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, et al. Molecular aspects of tumor cell invasion and metastasis. Cancer, 1993, 71(4): 1368-1383
15. Lichtinghagen R, Helmbrecht T, Arndt B, et al. Expression pattern of matrix metalloproteinases in human liver. Eur J Clin Chem Clin Biochem, 1995, 33(2): 65-71.
16. David L, Nesland JM, Holm R, et al. Expression of laminin, collagen Ⅳ, fibronectin, and type Ⅳ collagenase in gastric carcinoma. An immunohistochemical study of 87 patients. Cancer, 1994, 73(3):518-527.
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