Molecular Changes During Prostate Carcinoma Progression

在项目1中待检验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重要的功能作用。我们的团队已经发现了ECM的两个特定改变。首先，层粘连蛋白5在前列腺上皮内瘤变（PIN）到浸润性前列腺癌的转变中的丢失导致A6 B4整合素异二聚体形成的失败。随后的半桥粒组装失败导致较不稳定的粘附和通过MAP-激酶途径的A6 B4转导信号的丧失，从而导致改变的基因表达。在没有其配体的情况下，B4降解，留下A6与B1形成异二聚体，并形成附着到从头合成的基底层（BL）的新型粘附复合物。第二，这个新的基底层表达层粘连蛋白10， 作为其主要成分之一，并通过其受体α 3 β 1和A6 B1与癌细胞相互作用。我们最近发现层粘连蛋白10被金属蛋白酶MT 1-MMP切割，而金属蛋白酶MT 1-MMP在PIN和前列腺癌中上调。在目标1中，我们希望扩大我们的调查层粘连蛋白5在癌中表达失败的机制。在目标2中，我们打算表征新的粘附复合物的组分，其在没有A6 B4复合物的情况下在前列腺癌中形成。在目的3中，我们将研究MT 1-MMP切割层粘连蛋白10对细胞增殖、迁移和侵袭的影响。最后，在目标4中，我们将研究层粘连蛋白5和层粘连蛋白10以及切割的层粘连蛋白5和10对基因表达的影响。总之，我们将进一步调查发现， 在前列腺癌进展中存在从层粘连蛋白5/A6 B4整联蛋白到层粘连蛋白10/A6 B1，A3 B1粘附系统的转化。

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.