Deregulation of Matriptase in Breast Cancer Cells

乳腺癌细胞中基质酶的失调

基本信息

批准号：
7500468
负责人：
CHEN-YONG LIN
金额：
$ 7.51万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7500468
关键词：
Affect Applications Grants Behavior Binding Proteins Biological Models Blood Breast Cancer Cell Cell surface Cells Chemicals Complex Condition Dependence Diagnosis Disease Doctor of Philosophy Endopeptidases Enzymes Epidermal Growth Factor Epithelial Epithelial Cells Epithelium Equilibrium Excision Extracellular Matrix Gene Expression Gene Targeting Genes Hepatocyte Growth Factor Human In Vitro Intercellular Junctions Intervention Invaded Investigation Knockout Mice Lead Malignant Neoplasms Mammary gland Membrane Molecular Molecular Weight Nature Normal Cell Nude Mice Peptide Hydrolases Phenotype Physiological Plasminogen Process Protein Overexpression Protein Precursors Proteins Recruitment Activity Regulation Role ST14 gene Serine Protease Serine Proteinase Inhibitors Signal Pathway Signal Transduction Site System Tight Junctions Tissues Transactivation Urokinase Xenograft procedure atypical protein kinase C base cancer cell cell behavior cell growth cell motility claudin-1 protein crosslink extracellular genetic regulatory protein in vivo inhibitor/antagonist malignant breast neoplasm malignant phenotype matriptase neoplastic cell programs protein kinase C zeta protein protein interaction response sphingosine 1-phosphate

项目摘要

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 $1P-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.

虽然一些癌症特异性或癌症相关基因的过度表达可能会导致癌症的发生和发展。在人类癌症的进展过程中，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，导致这些蛋白质永久激活或不受限制恶性细胞与正常细胞相比。在本提案中，我们提出了一个密切相关的案例上皮间连接处的受控蛋白酶（matriptase）已被组成性激活并不适当地分布到癌细胞的入侵前沿。 Matriptase 广泛表达于几乎所有人类上皮组织，表明 matriptase 的生理作用可能与上皮的一些基本特征，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激活 matriptase，以响应其生理、血液- 携带激活剂 1-磷酸鞘氨醇 (S1P) 仅发生在细胞间连接处。此外，非典型蛋白激酶 C zeta 是一种紧密连接蛋白，可能参与 $1P 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，并且激活的基质酶不限于细胞与细胞的接触，并且已在膜褶边和细胞内。因此，在乳腺癌细胞中，matriptase可以作为膜激活剂来招募并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。在当前拨款提案中，我们将实现四个目标。首先，我们将通过以下方式阐明matriptase的生理作用：研究其功能定位并寻找其生理相关底物和靶标基因。其次，我们将研究matriptase活性密切相关的分子机制。受监管。第三，我们将表征来自matriptase复合物的matriptase结合蛋白。最后，我们将研究如何在模型系统中增强 matriptase 活性，或被抑制，影响乳腺癌细胞的表型。这些研究可能会带来新的观点乳腺癌中这种生理蛋白酶的失调，为诊断和治疗提供了新途径对疾病的干预。