Matriptase: Activation and Function in Breast Cancer

Matriptase：乳腺癌中的激活和功能

• 批准号: 7098046
• 负责人: CHEN-YONG LIN
• 金额: $ 25.2万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-26 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098046
• 关键词: angiogenesis; athymic mouse; biological models; breast neoplasms; cell motility; cell proliferation; clinical research; disease /disorder onset; enzyme activity; hepatocyte growth factor; human tissue; immunocytochemistry; low density lipoprotein receptor; mammary epithelium; metastasis; monoclonal antibody; neoplastic cell; neoplastic process; protein protein interaction; protein structure function; serine proteinases; site directed mutagenesis; tissue /cell culture; transfection; western blottings; xenotransplantation

DESCRIPTION (provided by applicant): Matriptase (also termed epithin and MTSP-1) is a novel, epithelial cell-specific, type II transmembrane serine protease (TTSP), whose initial characterization was funded under an NIH R21 grant. We also characterized HAI-1 (hepatocyte growth factor activator inhibitor-1) as the physiologically relevant, cognate inhibitor of matriptase-the only cognate inhibitor yet described for a TTSP family member. We now know that expression of high levels of both matriptase and HAI-1 in early stage (non-metastatic) human breast cancer are significantly correlated with poor patient outcome. We hypothesize that, based on its constitutive activation in breast cancer, its important substrates (urokinase and hepatocyte growth factor), and its correlation with poor prognosis human breast cancer, that matriptase may be involved in malignant progression (metastasis) of the disease. In addition, we propose that this enzyme may be a target for therapy of human breast cancer. In our prior published work, we have shown that in non-malignant mammary epithelial cells, activation of matriptase depends upon exposure of the cells to serum, serum-derived lipopoproteins, or lipoprotein-derived sphingosine-1-phosphate. Activation of matriptase is associated with its extracellular shedding, and glycosylation of matriptase dramatically prolongs the half life of its protein and its enzymatic activity. Indeed, in our recent collaborative study, enforced expression of matriptase in gastric carcinoma cells enhanced their metastatic ability; studies in breast cancer are underway. Matriptase may be unique among carcinoma-expressed proteases, in that its expression is both restricted to the epithelial component and its activation is autonomous in cancer cells, compared to non-cancer cells. Because of its constitutive activation, directly on breast cancer cell surfaces, matriptase may function upstream of other malignancy-associated, pericellular events. Inhibition of matriptase may therefore provide a key target for interfering with the ability of carcinomas to degrade the extracellular matrix (ECM), to activate growth factors, and to promote cell motility, all cellular features of progression-associated, epithelial-mesenchymal transitions of poor prognosis carcinomas. In the current grant proposal, we will carry out 3 Aims. First, we will further elucidate the mechanisms of activation of matriptase in non-malignant, contrasted to malignant mammary epithelial cells. Second, we will examine functional aspects of matriptase and HAI-1 in human xenograft and transgenic models of mammary cancer. Finally, we will further examine the pathophysiologic roles of matriptase and HAI-1 in archival specimens of human breast cancer. These studies could lead to new perspectives on the mechanisms of regulation and cancer-associated role(s). They may also provide new avenues for diagnosis and therapy of human breast cancer.

描述（由申请人提供）：Matriptase（也称为表皮蛋白和 MTSP-1）是一种新型上皮细胞特异性 II 型跨膜丝氨酸蛋白酶 (TTSP)，其初步表征由 NIH R21 拨款资助。我们还将 HAI-1（肝细胞生长因子激活剂抑制剂-1）描述为生理相关的 matriptase 同源抑制剂，这是迄今为止为 TTSP 家族成员描述的唯一同源抑制剂。我们现在知道，早期（非转移性）人类乳腺癌中高水平的 matriptase 和 HAI-1 表达与患者不良预后显着相关。基于其在乳腺癌中的组成性激活、其重要底物（尿激酶和肝细胞生长因子）以及其与人类乳腺癌不良预后的相关性，我们假设matriptase可能参与该疾病的恶性进展（转移）。此外，我们建议这种酶可能成为人类乳腺癌治疗的靶点。在我们之前发表的工作中，我们已经表明，在非恶性乳腺上皮细胞中，matriptase 的激活取决于细胞暴露于血清、血清来源的脂蛋白或脂蛋白来源的 1-磷酸鞘氨醇。 matriptase 的激活与其胞外脱落有关，matriptase 的糖基化可显着延长其蛋白质的半衰期及其酶活性。事实上，在我们最近的合作研究中，胃癌细胞中基质酶的强制表达增强了它们的转移能力；乳腺癌的研究正在进行中。 Matriptase 在癌症表达的蛋白酶中可能是独特的，因为与非癌细胞相比，其表达既限于上皮成分，而且其激活在癌细胞中是自主的。由于其直接在乳腺癌细胞表面上的组成型激活，matriptase 可能在其他恶性肿瘤相关的细胞周事件的上游发挥作用。因此，matriptase 的抑制可能为干扰癌症降解细胞外基质 (ECM)、激活生长因子和促进细胞运动的能力提供一个关键靶标，这些能力是与进展相关的上皮-间质转化的所有细胞特征。预后癌。在当前的拨款提案中，我们将实现 3 个目标。首先，我们将进一步阐明与恶性乳腺上皮细胞相比，非恶性乳腺上皮细胞中基质酶的激活机制。其次，我们将检查人类异种移植和转基因乳腺癌模型中 matriptase 和 HAI-1 的功能。最后，我们将进一步研究 matriptase 和 HAI-1 在人类乳腺癌档案标本中的病理生理学作用。这些研究可能会给调控机制和癌症相关作用带来新的视角。它们还可能为人类乳腺癌的诊断和治疗提供新的途径。