Deregulation of Matriptase in Breast Cancer Cells

乳腺癌细胞中基质酶的失调

• 批准号: 7111016
• 负责人: CHEN-YONG LIN
• 金额: $ 24.85万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111016
• 关键词: athymic mouse; binding proteins; biological signal transduction; breast neoplasms; cellular oncology; endopeptidases; enzyme activity; enzyme complex; enzyme mechanism; enzyme substrate; gene expression; laboratory mouse; mammary epithelium; molecular oncology; molecular pathology; neoplasm /cancer genetics; neoplastic cell; phenotype; protein localization; protein protein interaction; protein purification; tight junctions; tissue /cell culture; xenotransplantation

DESCRIPTION (provided by applicant): While overexpression of some cancer-specific or cancer-associated genes could contribute to the onset and progression of human cancer, malignant tumor cells could also inappropriately express and regulate a preexisting normal cell program, leading to these proteins to be perpetually activated or unrestrained in malignant cells compared with normal counterparts. In this proposal, we present the case of a closely controlled protease (matriptase) at interepithelial junctions that has been constitutively activated and inappropriately distributed to the invading fronts of cancer cells. Matriptase is broadly expressed by almost all human epithelial tissues, suggesting that the physiological role of matriptase may be associated with some rudimentary feature of epithelium, such as interepithelial junctions. Indeed, we have observed that in nontransformed mammary epithelial cells activation of matriptase in response to its physiological, blood-borne activator sphingosine 1-phosphate (S1P) only occurs on intercellular junctions. Furthermore, atypical protein kinase C zeta, a tight junction protein, is likely to be involved in S1P-indcued matriptase activation. In contrast, breast cancer cells constitutively activate matriptase regardless of the presence of S1P, and the activated matriptase is not restricted to cell-cell contacts and has been detected on membrane ruffles and within the cells. Therefore, in breast cancer cells matriptase could serve as membrane activator to recruit and activate urokinase-type plasminogen activator (uPA) and hepatocyte growth factor (HGF), an extracellular matrix-degrading protease system and cell growth/motility factor, respectively. In the current grant proposal, we will carry out four aims. First, we will elucidate physiological role of matriptase by investigating its functional localization and searching for its physiologically relevant substrates and target genes. Second, we will investigate the molecular mechanisms whereby matriptase activity is closely regulated. Third, we will characterize binding proteins of matriptase from matriptase complexes. Finally, we will investigate how matriptase activity, in a model system which matriptase activation can be enhanced or suppressed, affects the phenotypes of breast cancer cells. These studies could lead to new perspectives on the deregulation of this physiological protease in breast cancer and provide new avenues for diagnosis and intervention of the disease.

描述（由申请人提供）：虽然一些癌症特异性或癌症相关基因的过度表达可能导致人类癌症的发生和进展，但恶性肿瘤细胞也可能不恰当地表达和调节预先存在的正常细胞程序，导致这些蛋白质与正常细胞相比，恶性细胞中的细胞永远被激活或不受限制。在本提案中，我们介绍了上皮间连接处的一种严格控制的蛋白酶（matriptase）的情况，该蛋白酶已被组成性激活并不适当地分布到癌细胞的入侵前沿。 Matriptase 在几乎所有人类上皮组织中广泛表达，这表明 Matriptase 的生理作用可能与上皮的一些基本特征有关，例如上皮间连接。事实上，我们观察到，在未转化的乳腺上皮细胞中，matriptase 响应其生理学、血源性激活剂 1-磷酸鞘氨醇 (S1P) 的激活仅发生在细胞间连接处。此外，非典型蛋白激酶 C zeta（一种紧密连接蛋白）可能参与 S1P 诱导的 matriptase 激活。相比之下，无论S1P是否存在，乳腺癌细胞都会持续激活matriptase，并且激活的matriptase并不局限于细胞与细胞的接触，并且已在膜皱褶处和细胞内检测到。因此，在乳腺癌细胞中，基质酶可以作为膜激活剂来招募和激活尿激酶型纤溶酶原激活剂（uPA）和肝细胞生长因子（HGF），分别是细胞外基质降解蛋白酶系统和细胞生长/运动因子。在当前的拨款提案中，我们将实现四个目标。首先，我们将通过研究其功能定位并寻找其生理相关底物和靶基因来阐明matriptase的生理作用。其次，我们将研究密切调节基质酶活性的分子机制。第三，我们将表征来自matriptase复合物的matriptase结合蛋白。最后，我们将研究在可以增强或抑制 Matriptase 激活的模型系统中，Matriptase 活性如何影响乳腺癌细胞的表型。这些研究可能会为乳腺癌中这种生理蛋白酶的失调带来新的视角，并为该疾病的诊断和干预提供新的途径。