Ets-1转录调节因子与基质金属蛋白酶7在肝细胞肝癌组织中的表达及其临床意义
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摘要
肝细胞肝癌(HCC)是最常见的恶性肿瘤之一，我国HCC占全球发病的40％以上，且近年来发病率有增高趋势，严重威胁着人类的健康和生命。
肿瘤细胞的侵袭转移是肿瘤的重要生物行为，与患者的预后密切相关。它的发生发展是多阶段性、多基因参与、多种转录因子调控的过程，涉及一系列病理生理反应，包括细胞异常的增殖、粘附、运动、细胞外基质[ECM]降解、血管生成等多步骤完成的分子生物学变化的过程。Ets-1转录调节因子和基质金属蛋白酶7(MMP-7)的表达在HCC的发生、增长、和肿瘤血管生成及侵袭转移等生物学行为中起重要作用；二者在HCC中的联合表达以及他们与血管生成关系的研究目前报道很少。
目的 通过检测Ets-1转录调节因子、MMP-7在HCC组织中的表达，对其生物学意义与预后的关系及其相互之间关系进行探讨研究，试图阐明HCC的微转移机制并了解其预后。
方法 本试验以南昌大学第一附属医院2002年1月～2004年12月手术切除63例肝细胞肝癌患者的病理标本及临床资料为研究对象。应用Elivision~(TM) plus二步法(AB法)免疫组化检测CD_(34)、Ets-1和MMP-7单克隆抗体在63例HCC标本的表达情况。阴性对照用PBS代替一抗CD_(34)、Ets-1和MMP-7抗体，阳性对照以美国NEOMARKERS公司的标准阳性片作为对照。Ets-1表达以细胞核出现棕黄色至深棕色颗粒作为阳性判断标准，无阳性着色或阳性细胞数≤5％为阴性(-)；阳性细胞数在5～50％之间为阳性(+)；阳性细胞数＞50％为强阳性(++)，阳性与强阳性合计为阳性表达。MMP-7表达以细胞浆出现棕黄色至深棕色颗粒作为阳性判断标准，即阳性细胞数≤10％为阴性(-)，＞10％为阳性(+)，＞35％为强阳性(++)；阳性与强阳性合计为阳性表达。肿瘤微血管计数(MVD)：按照N Weidner的判评标准进行判断。统计学分析采用SPSS10.0统计软件进行，计量资料用T检验，计数资料用X~2检验，相关
Background HCC is one of the most common primary malignant tumors , and the patients of HCC are more than 40% of the world in china. Recently ,the morbility is shown the increasing tendency ,and threatens the health and life of mankind seriously.
The invasion and transfer of tumor cells is important biological behavior of tumor and is related with prognosis closely. Its occurrence and development are the procedure of several phases ,multiple gene participation and several transcription factors regulating ,and refer to a series of patho-physiologic reactions, including cell abnormal reduplication, adhereing ,motion ,ECM degradation, angiogenesis and so on. It is very important of the expression of Ets -1 and MMP-7 during HCC occurs, grows, invases and transfers and angiogenesis .In HCC ,it is seldom reported that Ets-1 and MMP-7 were expressed together,and were related with MVD in HCC .
Objective To investigate the expression and biological significance of Ets-1 and MMP-7 ,and to research their correlation in HCC ,which provides theoretical foundation for explaining the mechanism of micro-metastasis and comprehending the prognosis of HCC.
Method From Jan 2002 to Dec 2004, 63 patients of HCC ,which were treated in the first affiliated hospital of nanchang university, were selected in this experiment with complete clinical datas . 63 Specimens of HCC were studied by immemohistochemical Elivision~(TM) plus (AB) method .The standard positive contract was from Ameican neomarkers biological company ; and the negative contract was PBS instead of ETS-1 ,MMP-7 and CD34 as the first antibody in this experiment .It is named positive that cytoblast and cytoplasm were dyed
肿瘤细胞的侵袭转移是肿瘤的重要生物行为，与患者的预后密切相关。它的发生发展是多阶段性、多基因参与、多种转录因子调控的过程，涉及一系列病理生理反应，包括细胞异常的增殖、粘附、运动、细胞外基质[ECM]降解、血管生成等多步骤完成的分子生物学变化的过程。Ets-1转录调节因子和基质金属蛋白酶7(MMP-7)的表达在HCC的发生、增长、和肿瘤血管生成及侵袭转移等生物学行为中起重要作用；二者在HCC中的联合表达以及他们与血管生成关系的研究目前报道很少。
目的 通过检测Ets-1转录调节因子、MMP-7在HCC组织中的表达，对其生物学意义与预后的关系及其相互之间关系进行探讨研究，试图阐明HCC的微转移机制并了解其预后。
方法 本试验以南昌大学第一附属医院2002年1月～2004年12月手术切除63例肝细胞肝癌患者的病理标本及临床资料为研究对象。应用Elivision~(TM) plus二步法(AB法)免疫组化检测CD_(34)、Ets-1和MMP-7单克隆抗体在63例HCC标本的表达情况。阴性对照用PBS代替一抗CD_(34)、Ets-1和MMP-7抗体，阳性对照以美国NEOMARKERS公司的标准阳性片作为对照。Ets-1表达以细胞核出现棕黄色至深棕色颗粒作为阳性判断标准，无阳性着色或阳性细胞数≤5％为阴性(-)；阳性细胞数在5～50％之间为阳性(+)；阳性细胞数＞50％为强阳性(++)，阳性与强阳性合计为阳性表达。MMP-7表达以细胞浆出现棕黄色至深棕色颗粒作为阳性判断标准，即阳性细胞数≤10％为阴性(-)，＞10％为阳性(+)，＞35％为强阳性(++)；阳性与强阳性合计为阳性表达。肿瘤微血管计数(MVD)：按照N Weidner的判评标准进行判断。统计学分析采用SPSS10.0统计软件进行，计量资料用T检验，计数资料用X~2检验，相关
Background HCC is one of the most common primary malignant tumors , and the patients of HCC are more than 40% of the world in china. Recently ,the morbility is shown the increasing tendency ,and threatens the health and life of mankind seriously.
The invasion and transfer of tumor cells is important biological behavior of tumor and is related with prognosis closely. Its occurrence and development are the procedure of several phases ,multiple gene participation and several transcription factors regulating ,and refer to a series of patho-physiologic reactions, including cell abnormal reduplication, adhereing ,motion ,ECM degradation, angiogenesis and so on. It is very important of the expression of Ets -1 and MMP-7 during HCC occurs, grows, invases and transfers and angiogenesis .In HCC ,it is seldom reported that Ets-1 and MMP-7 were expressed together,and were related with MVD in HCC .
Objective To investigate the expression and biological significance of Ets-1 and MMP-7 ,and to research their correlation in HCC ,which provides theoretical foundation for explaining the mechanism of micro-metastasis and comprehending the prognosis of HCC.
Method From Jan 2002 to Dec 2004, 63 patients of HCC ,which were treated in the first affiliated hospital of nanchang university, were selected in this experiment with complete clinical datas . 63 Specimens of HCC were studied by immemohistochemical Elivision~(TM) plus (AB) method .The standard positive contract was from Ameican neomarkers biological company ; and the negative contract was PBS instead of ETS-1 ,MMP-7 and CD34 as the first antibody in this experiment .It is named positive that cytoblast and cytoplasm were dyed
引文
1 严律南，肝脏外科，第一版，人民卫生出版社
2 Liotta LA, Steeg PA, Stetler Stevenson WG. Cancer metastasis and angiogenesis:an imbalance of postive regulation. Cell, 1991,144: 327-331.
3 Maroulakou IG, Papas TS, Green JE. Differential expression of Ets-1 and Ets-2 protooncogenes during murine embryogenesis. Oncogene, 1994, 9(6), 1551.
4 李玉林，吴后男，失桂林等．转录调节因子Ets-1和基质金属蛋白酶1在乳腺癌中的表达及意义[J]．Clinmed J，2001，114(10)：61-75
5 Ho IC, Bhat NK, Gottschalk LR, et al. Sequence-specific binding of human Ets-1 to the T cell receptor alpha gene enhancer. Science. 1990 Nov 9;250(4982):814-8.
6 Prosser HM, Wotton D, Gegonne A, et al. A phorbol ester response element within the human T-cell receptor beta-chain enhancer. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9934-8.
7 Thompson CB, Wang CY, Ho IC, et al. cis-acting sequences required for inducible interleukin-2 enhancer function bind a novel Ets-related protein, Elf-1. Mol Cell Biol. 1992 Mar;12(3):1043-53.
8 Knox JD, BrehamDR, Walker JA, et al, Mapping of the metalloproteinase gene matrilysin(MMP-7) to human chronmo-some 11q21→q22, Cytogenet Cell Genet 1996,72:179-182.
9 Kitange G, Kishikawa M, Nakayama T, etal. Expression of the Ets-1 proto oncoge correlates with malignant potential in human astrocytic tumors. ModPathol, 1999, 12(6),618-626.
10 李晓梅，张友忠．卵巢癌血管生成的临床研究进展．实用妇产科杂志，2001，17(2)：78．
11 Ito Y, Miyoshi E,Takeda T,et al. ets-lexpression inextrahepatic bile duct carcinoma and cholangiocellular carcinoma. Oncology, 2000, 58 (3) :248.
12 Sasaki H, Yukiue H, Moiriyama S, Clinical significance of matrix metalloproteinase-7 and Ets-1 gene expression in patients with lung cancer. J Surg Res. 2001 Dec; 101 (2) :242-7.
13 He T, Mo L, Liang N. Effects of 5F from Pteri semipinnata on the expression of ETS-1 mRNA and VEGF protein of highly metastatic ovarian carcinoma HO-8910PM cells. Zhong Yao Cai. 2005 Apr;28(4): 307-9.
14 Katayama S, Nakayama T, Ito M, et al. Expression of the ets-1 proto-oncogene in human breast carcinoma: differential expression with histological grading and growth pattern. Histol Histopathol. 2005 Jan;20(1) :119-26.
15 Miwa S, Miyagawa S, Soeda J, Kawasaki S. Matrix metalloprotei-nase-7 expression and biologic aggressiveness ofcholangio-cellular carcinoma. Cancer. 2002 Jan 15;94(2) :428-34
16 Mylona E, Kapranou A, Mavrommatis J, et al. The multifunctional role of the immunohistochemical expression of MMP-7 in invasive breast cancer. APMIS. 2005 Apr; 113 (4) :246-55.
17 Wang FQ, So J, Reierstad S, Fishman DA. Matrilysin (MMP-7) promotes invasion of ovarian cancer cells by activation of progelatinase. Int J Cancer. 2005 Mar 10;114(1) :19-31.
18 方开锋 冯贤松 吴河水，转录调节因子Ets-1在结直肠癌组织中的表达及其临床意义，消化外科，2004，3(5)：343-346
19 高宝辉 谢丽辉 祁旦己等，MMP-7、MVO在子宫膜样腺癌中的表达．实用肿瘤学杂志．2004，18(5)：343—6
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38 Fingleton B, Vargo-Gogola T, Crawford HC, et al. Matrilysin [MMP-7] Expression Selects for Cells with Reduced Sensitivity to Apoptosis. Neoplasia . 2001,3(6): 459 - 468
39 Crawford HC, Scoggins CR, Washington MK, et al. Matrix metal- oproteinase-7 is expressed by pancreatic cancer precursors and regulate sacinar-to-ductal metaplasia in exocrine pancreas. J. Clin. Invest. 2002, 109:1437-1444.
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41 Borchers AH, Sanders LA, Powell MB,et al. Melanocyte mediated paracrine induction of extracellular matrix degrading proteases in squamous cell carcinoma cells. Exp. Cell Res. 231/61-65, 1997.
42 Borchers AH, Powell MB, Fusenig NE, et al. Paracrine factor and cell-cell contact-mediated induction of protease and c-ets gene expression in malignant keratinocyte/dermal fibroblast cocultures. Exp. Cell Res , 1994,213/ 143-147.
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1 Knox JD, Breham DR, Walker J-A, et al, Mapping of the metalloprot—einase gene matrilysin(MMP-7) to human chronmosome 11q21→q22, Cytogenet Cell Genet, 1996,72:179-182.
2 Vargo-Gogola T, Fingleton B, Crawford HC, Matrilysin(Matrix Metalloproteinase-7) Selects for Apoptosis-resistant Mammary Cells in Vivo Cancer Research. 2002 October 1, 62:5559- 5563
3 Fingleton B, Vargo-Gogola T, Crawford HE, et al. Matrilysin [MMP-7] Expression Selects for Cells with Reduced Sensitivity to Apoptosis. Neoplasia . 2001,3(6): 459 - 468
4 Crawford HC, Scoggins CR, Washington MK, et al. Matrix metalloprotei- nase-7 is expressed by pancreatic cancer precursors and regulate sacinar-to-ductal metaplasia in exocrine pancreas. J. Clin. Invest. 2002, 109:1437-1444.
5 OkudaK. Early recognition of hepatocellular carcinoma. Hepatology , 1986, 6: 729-738.
6 The Liver Cancer Study Group in Japan. Primary liver cancer in Japan: clinicopathologic features and results of surgical treatment. Ann. Surg. , 1990,211: 277-292.
7 noe V, Fingleton B, Jacobs KC, et al , Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1.J Cell Sci, 2001, 114 :111-118.
8 Yamashita K, Masaki Mori, Takeshi Shiraishi, et al. Clinical Significance of Matrix Metalloproteinase-7 Expression in Esophageal Carcinoma. Clinical Cancer Research, Vol. 6, 1169-1174, March 2000.
9 Borchers AH, Sanders LA, Powell MB, et al. Melanocyte mediated paracrine induction of extracellular matrix degrading proteases in squamous cell carcinoma cells. Exp. Cell Res. 231:61-65, 1997.
10 Borchers AH, Powell MB, Fusenig NE, et al. Paracrine factor and cell-cell contact-mediated induction of protease and c-ets gene expression in malignant keratinocyte/dermal fibroblast cocultures. Exp. Cell Res. 1994,213: 143-147.
11 Klein RD, Borchers AH, Sundareshan P, et al. Interleukin-1β secreted from monocytic cells induces the expression of matrilysin in the prostate cell line LNCaP. J. Biol. Chem. 1997, 272: 14188 -14192.
12 Gaire M, Magbanua Z,McDonnell S, McNeil L, et al. Structure and expression of the human gene for the matrix metalloproteinase matrilysin. J. Biol. Chem. 1994, 269:2032 -2040.
13 Bruner KL, Rodgers WH, Gold LI, et al. Transforming growth factor β mediates the progesterone suppression of an epithelial metallo-proteinase by adjacent stroma in the human endometrium. Proc. Natl. Acad. Sci. USA, 1995,92:7362 - 7366.
14 Yamamoto H, Adachi Y, Itoh F, ET AL. Association of Matrilysin Expression with Recurrence and Poor Prognosis in Human Esophageal Squamous Cell Carcinoma, CANCER RESEARCH. 1999 July 15,59, 3313-3316.
15 杜月光，陈慰浙，陈智，孔梅，万海同．人胃癌组织中基质金属蛋白酶7的基因表达及意义．中国癌症杂志，2003年第13卷第3期．
16 Liu XP, Kawauchi S, Oga A, Tsushimi K, et al. Prognostic Significance of Matrix Metalloproteinase-7 (MMP-7) Expression at the Invasive Front in Gastric Carcinoma Jpn. J. Cancer Res. 2002 March, 93,291 -295.
17 张翠萍，江月萍，武军，梁永信．MMP-2、MMP-7与胃癌的侵袭转移关系探讨．山东医药，2003年第43卷第34期．
18 Adachi T, Yamamoto H, Itoh F, et al .Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers .Gut 1999;45;252-258.
19 Matsushima T, mori M, KidoA, et al, Preoperative estimation of neural invasion in rectal carcinoma. Oncol Rep, 1998,5:73-76.
20 Ito F, Yamamoto H, hinoda Y, et al, Enhanced secretion and activation of its relationship with invasive potential of colon cancer cells, Cancer. 1996,77(Ssuppl):1712-1721.
21 Momiyama N, Koshikawa N, Ishikawa T,, et al, Inhibitory effect of matrilysin antisense oligonucleotides on human colon cancer invasion in vitro. Mol Carcinog, 1998,22:57-63.
22 Jones LE, Humphreys MJ, Campbell F, et al. Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer: Increased Expression of Matrix Metalloproteinase-7 Predicts Poor Survival. Clinical Cancer Research, 2004 April 15, 2832(10) :2832 - 2845,.
23 Fukushima H, Yamamoto H, Itoh F, et al. Association of matrilysin mRNA expression with K-ras mutations and progression in pancreatic ductal adenocarcinomas. Carcinogenesis. 2001, 22(7):1049-1052.
24 Ozaki I, Mizuta T, Zhao G, et al . Involvement of the Ets-1 Gene in Overexpression of Matrilysin in Human Hepatocellular Carcinoma CANCER RESEARCH. 2000 November 15,60:6519-6525.
25 Miwa S, Miyagawa S, Soeda J, et al. Matrix metalloproteinase-7 expression and biologic aggressiveness of cholangiocellular carcinoma. Cancer. 2002 Jan 15, 94(2):428-34.
2 Liotta LA, Steeg PA, Stetler Stevenson WG. Cancer metastasis and angiogenesis:an imbalance of postive regulation. Cell, 1991,144: 327-331.
3 Maroulakou IG, Papas TS, Green JE. Differential expression of Ets-1 and Ets-2 protooncogenes during murine embryogenesis. Oncogene, 1994, 9(6), 1551.
4 李玉林，吴后男，失桂林等．转录调节因子Ets-1和基质金属蛋白酶1在乳腺癌中的表达及意义[J]．Clinmed J，2001，114(10)：61-75
5 Ho IC, Bhat NK, Gottschalk LR, et al. Sequence-specific binding of human Ets-1 to the T cell receptor alpha gene enhancer. Science. 1990 Nov 9;250(4982):814-8.
6 Prosser HM, Wotton D, Gegonne A, et al. A phorbol ester response element within the human T-cell receptor beta-chain enhancer. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9934-8.
7 Thompson CB, Wang CY, Ho IC, et al. cis-acting sequences required for inducible interleukin-2 enhancer function bind a novel Ets-related protein, Elf-1. Mol Cell Biol. 1992 Mar;12(3):1043-53.
8 Knox JD, BrehamDR, Walker JA, et al, Mapping of the metalloproteinase gene matrilysin(MMP-7) to human chronmo-some 11q21→q22, Cytogenet Cell Genet 1996,72:179-182.
9 Kitange G, Kishikawa M, Nakayama T, etal. Expression of the Ets-1 proto oncoge correlates with malignant potential in human astrocytic tumors. ModPathol, 1999, 12(6),618-626.
10 李晓梅，张友忠．卵巢癌血管生成的临床研究进展．实用妇产科杂志，2001，17(2)：78．
11 Ito Y, Miyoshi E,Takeda T,et al. ets-lexpression inextrahepatic bile duct carcinoma and cholangiocellular carcinoma. Oncology, 2000, 58 (3) :248.
12 Sasaki H, Yukiue H, Moiriyama S, Clinical significance of matrix metalloproteinase-7 and Ets-1 gene expression in patients with lung cancer. J Surg Res. 2001 Dec; 101 (2) :242-7.
13 He T, Mo L, Liang N. Effects of 5F from Pteri semipinnata on the expression of ETS-1 mRNA and VEGF protein of highly metastatic ovarian carcinoma HO-8910PM cells. Zhong Yao Cai. 2005 Apr;28(4): 307-9.
14 Katayama S, Nakayama T, Ito M, et al. Expression of the ets-1 proto-oncogene in human breast carcinoma: differential expression with histological grading and growth pattern. Histol Histopathol. 2005 Jan;20(1) :119-26.
15 Miwa S, Miyagawa S, Soeda J, Kawasaki S. Matrix metalloprotei-nase-7 expression and biologic aggressiveness ofcholangio-cellular carcinoma. Cancer. 2002 Jan 15;94(2) :428-34
16 Mylona E, Kapranou A, Mavrommatis J, et al. The multifunctional role of the immunohistochemical expression of MMP-7 in invasive breast cancer. APMIS. 2005 Apr; 113 (4) :246-55.
17 Wang FQ, So J, Reierstad S, Fishman DA. Matrilysin (MMP-7) promotes invasion of ovarian cancer cells by activation of progelatinase. Int J Cancer. 2005 Mar 10;114(1) :19-31.
18 方开锋 冯贤松 吴河水，转录调节因子Ets-1在结直肠癌组织中的表达及其临床意义，消化外科，2004，3(5)：343-346
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