Molecular Changes During Prostate Carcinoma Progression

前列腺癌进展过程中的分子变化

• 批准号: 6990122
• 负责人: RAYMOND B NAGLE
• 金额: $ 13.03万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-19 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990122
• 关键词: biological signal transduction; carcinogenesis; carcinoma; cell adhesion; cell growth regulation; cell line; cell migration; cell proliferation; collagenase; complementary DNA; extracellular matrix; gene expression; genetic translation; human tissue; immunoelectron microscopy; immunoprecipitation; integrins; laminin; laser capture microdissection; male; membrane proteins; metalloendopeptidases; molecular oncology; neoplasm /cancer invasiveness; neoplastic process; nucleic acid sequence; prostate neoplasms; protein degradation; protein localization; protein purification; protein structure function; tissue /cell culture; western blottings

The overall hypothesis to be tested in Project 1 is that modification of the extracellular matrix (ECM) plays an important functional role in the progression of prostate carcinoma. Our group has discovered two specific alterations of the ECM. First, the loss of laminin 5 in the transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate carcinoma results in the failure of A6 B4 integrin heterodimer formation. The subsequent failure of hemidesmosome assembly results in a less stable adherence and the loss of A6 B4 transduction signaling through the MAP-kinase pathway, leading to altered gene expression. Without its ligand, B4 degrades, leaving A6 to form heterodimers with B1 and forming novel adhesion complexes attaching to the de novo -synthesized basal lamina (BL). Second, this new basal lamina expresses laminin 10 as one of its main components and interacts with the carcinoma cells through its receptors, alpha3 beta1 and A6 B1. We have more recently shown that laminin 10 is cleaved by the metalloproteinase, MT1-MMP, which is upregulated in PIN and prostate carcinoma. In Aim 1 we wish to extend our investigations into the mechanism of the failure of laminin 5 expression in carcinoma. In Aim 2 we intend to characterize the components of the new adhesion complexes, which form in prostate cancer in the absence of the A6 B4 complex. In Aim 3 we will investigate the effect of cleavage of laminin 10 by MT1-MMP on cell proliferation, migration and invasion. Finally, in Aim 4 we will investigate the effect of laminin 5 and laminin 10 and cleaved laminin 5 and 10 on gene expression. In summary, we will investigate further the discovery that there is a conversion from laminin 5/A6 B4 integrin to a laminin 10/A6 B1, A3 B1 adhesion system in prostate carcinoma progression.

项目1要验证的总体假设是，细胞外基质（ECM）的修饰在前列腺癌的进展中起着重要的功能作用。我们的研究小组发现了ECM的两种特殊变化。首先，在前列腺上皮内瘤变（PIN）向浸润性前列腺癌转变的过程中，层粘连蛋白5的缺失导致A6 B4整合素异源二聚体形成失败。随后半脂小体组装失败导致粘附不稳定和通过map -激酶途径的A6 B4转导信号丧失，导致基因表达改变。在没有配体的情况下，B4降解，使A6与B1形成异二聚体，并形成附着在新合成的基底膜（BL）上的新型粘附复合物。其次，这个新的基板表达层粘连蛋白10