ROLES OF MEMBRANE TYPE MATRIX METALLOPROTEINASE IN BREAST TUMOR METASTASIS

膜型基质金属蛋白酶在乳腺肿瘤转移中的作用

• 批准号: 07044240
• 负责人: SEIKI Motoharu
• 金额: $ 6.34万
• 依托单位: UNIVERSITY OF TOKYO (1997)Kanazawa University (1995-1996)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07044240/
• 关键词: CANCER; INVASON AND METASTASIS; BREAST CARCINOMA; MATRIX METALLOPROTEINASE; MT1-MMP; MT2-MMP; MT3-MMP; 浸潤・転移; 膜型メタロプロデアーゼ; ゼラチナーゼA; 乳癌細胞株; MT-MMP

Gelatinase A (GelA) is believed to be important for cancer cell invasion and metastasis. Gelatinase A is produced as an inactive proenzyme (proGelA) and activated by a cell surface activator on cancer cells. We identified membrane-type 1 matrix metalloproteinase as a possible cell surface activator in 1994 and have extended the study to elucidate its relevance to cancer including breast carcinomas. During the three years we obtained the following results supported by the grant.1. MT1-MMP expression was demonstrated in various types of human cancers such as breast, gastric, colon, head and neck, and nasophagial carcinomas.2. Expression of MT1-MMP in carcinomas correlated well to the activation of GelA in the tissue suggesting that MT1-MMP is surely the GelA activator in cancers.3. Immunohistochmistry localized both MT1-MMP and gelatinase A to the cancer cells and also surrounding stromal fibroblasts.4. However carcinoma cells did not express GelA but it was expressed in the surrounding fibroblasts.5. MT1-MMP was shown to bind proGelA by using TIMP-2 as a adapter. Thus Three molecular complex is thought to be formed on cancer cell surface. ProGelA in the complex is thought to be activated by the neighboring free MT1- MMP.

明胶酶A（Gelatinase A，GelA）被认为在癌细胞的侵袭和转移中起重要作用。明胶酶A作为无活性的酶原（proGelA）产生，并由癌细胞上的细胞表面活化剂活化。我们在1994年确定了膜型1基质金属蛋白酶作为一种可能的细胞表面活化剂，并扩大了研究，以阐明其与癌症，包括乳腺癌的相关性。在这三年中，我们取得了以下成果的支持赠款。MT1-MMP在乳腺癌、胃癌、结肠癌、头颈部癌、鼻咽癌等多种肿瘤中均有表达.肿瘤组织中MT1-MMP的表达与组织中GelA的激活密切相关，提示MT1-MMP确实是肿瘤组织中GelA的激活因子.免疫组化定位MT1-MMP和明胶酶A的癌细胞和周围的基质成纤维细胞。而癌细胞不表达GelA，但在癌细胞周围的成纤维细胞中表达.通过使用TIMP-2作为衔接子，MT1-MMP显示出与proGelA结合。因此，三分子复合物被认为是在癌细胞表面形成的。复合物中的ProGelA被认为是由邻近的游离MT1-MMP激活的。

项目成果

Kinoh,H.,Sato,H.,Seiki,M.et al.: "MT-MMP,the cell surface activator of proMMP-2 is expressed with its substrate in mouse tissue during embryogenesis" J.Cell Science. 109. 953-959 (1996)

Kinoh,H.、Sato,H.、Seiki,M.等人：“MT-MMP，proMMP-2 的细胞表面激活剂在胚胎发生过程中在小鼠组织中与其底物一起表达”J.Cell Science。

Yu, M. 他6名: "Tyrosin phosphorylation mediates ConA-induced membrane type-1 matirix metalloproteinase expression and matrix metalloproteinase-2 activation in MDA-MB-231 human breast carcinoma cells." Cancer Research. 57. 5028-5032 (1997)

Yu, M. 和其他 6 人：“酪氨酸磷酸化介导 MDA-MB-231 人乳腺癌细胞中 ConA 诱导的膜 1 型基质金属蛋白酶表达和基质金属蛋白酶 2 激活。” 57. 5028-5032 (1997) ）

Gum,R.,Sato,H.,Seiki,M.et al.: "Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase." J.Biological Chemistry. 271. 10672-10680 (1996)

Gum,R.,Sato,H.,Seiki,M.等人：“ras 刺激 92-kDa 明胶酶 B 启动子活性是丝裂原激活的蛋白激酶激酶。”

Sato,H.,Seiki,M.et al: "Activation of a recombinant membrane type a matrix metalloproteinase by furin and its interaction with TIMP-2." FEBS Letters. 393. (1996)

Sato,H.,Seiki,M.等人：“弗林蛋白酶激活重组膜型基质金属蛋白酶及其与 TIMP-2 的相互作用。”

曹 鑑: "The C-Terminal region of MT-MMP is a functional TM required for progelatise dctivation" J.Biol.Chem. 270. 801-805 (1995)

曹健：“MT-MMP 的 C 末端区域是原胶化激活所需的功能性 TM”，J.Biol.Chem. 270. 801-805 (1995)