ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 前列腺癌的异质性表明，导致恶性转化的途径并不是统一的，但某些基因改变和途径可能在导致恶性转化的起始阶段是常见的。向浸润性癌发展的特点是分化过程失控，导致增殖增加，相应的细胞凋亡减少。转录因子家族是基本的螺旋-环-螺旋bHLH家族，它调节这两个过程。分化抑制因子(ID)通过与bHLH转录因子形成非活性异源二聚体，发挥bHLH蛋白活性的天然负调节作用。因此，ID基因在未分化、增殖和肿瘤细胞中的表达增加。ID蛋白也在多个水平上发挥作用，其相互作用可能不限于bHLH蛋白。ID蛋白的过度表达会导致细胞凋亡和/或细胞增殖。ID蛋白具有刺激细胞周期、激活端粒酶和使细胞类型永生化的能力，提示ID蛋白可能作为癌基因或协同癌基因发挥作用。我们最近的研究结果表明，ID蛋白在前列腺癌细胞系中的功能是非冗余的。Id1、Id2和Id3是潜在的癌基因或协同的癌基因，令人惊讶的是，Id4具有肿瘤抑制作用。Id1和Id3靶向细胞增殖途径，Id2靶向凋亡，Id4通过诱导AR-VE细胞中P53、E-cadherin和雄激素受体(AR)的表达而发挥肿瘤抑制作用。有趣的是，在DU145前列腺癌细胞系中，ID3拷贝数也增加。因此，ID蛋白代表了前列腺癌生物学中一个需要仔细研究的新范例。Id1、Id2和Id3蛋白在包括前列腺癌和培养的肿瘤细胞在内的人类原发肿瘤中的表达增加，而Id4在许多肿瘤细胞系和组织中的表达缺失，可能是由于启动子的高甲基化所致。 初步研究表明，Id1/Id3和Id2功能的丧失分别抑制了前列腺癌细胞的增殖和凋亡，而Id4功能的增强则启动了前列腺癌细胞的上皮表型和AR受体表达的重新出现。因此，本研究旨在验证“ID基因(Id1、Id2、Id3和Id4)具有非冗余功能及其表达水平、拷贝数变化(Id3)和启动子甲基化状态(Id4)是灵敏的预后标志物和疾病治疗的有力靶点”的假说。在这项提案中正在寻求的新想法是ID3的拷贝数变化和ID4在前列腺癌中作为肿瘤抑制因子的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The heterogeneity of prostate cancer suggests that the pathways that lead to malignant transformation are not uniform but certain genetic alterations and pathways may be common in the initiation leading to malignancy. The progression to invasive carcinoma is characterized by de-regulation of differentiation process, leading to an increase in the proliferation and a corresponding decrease in apoptosis. The transcription factor family, which is known to regulate both these processes, is the basic helix-loop-helix bHLH family. The Id (Inhibitor of differentiation) proteins function as natural negative regulators of bHLH protein activity through the formation of inactive heterodimers with bHLH transcription factors. Consequently, Id gene expression is elevated in undifferentiated, proliferating and tumor cells. The Id proteins also function at multiple levels and its interactions may not be limited to bHLH proteins. Over-expression of Id proteins results in apoptosis and/or cell proliferation. The ability of Id to stimulate the cell cycle, activate telomerase and immortalize cell types suggests that Id proteins may act as oncogenes or cooperating oncogenes. Our recent results suggest that the functions of Id proteins in prostate cancer cell lines are non-redundant. Id1, Id2 and Id3 are potential oncogenes or cooperating oncogenes and surprisingly, Id4 acts as a tumor suppressor. Id1 and Id3 target cell proliferation pathways, Id2 targets apoptosis and Id4 acts as a tumor suppressor by inducing the expression of p53, E-cadherin and androgen receptor (AR) in AR-ve prostate cancer cell line. Interestingly, Id3 copy number is also increased in DU145 prostate cancer cell line. Hence Id proteins represent a new paradigm in prostate cancer biology that needs to be carefully examined. Increased expression of Id1, Id2 and Id3 proteins has been reported in primary human tumors including human prostate and cultured tumor cells, whereas Id4 expression is lost in many cancer cell lines and tissues possibly due to promoter hypermethylation. Preliminary studies have demonstrated that loss of function of Id1/ Id3 and Id2 blocks proliferation and apoptosis respectively, whereas gain of Id4 functions initiates an epithelial phenotype and re-emergence of AR receptor expression in model prostate cancer cell lines. The present study is therefore designed to test the hypothesis that "Id genes (Id1, Id2, Id3 and Id4) have non-redundant functions and their expression levels, copy number changes (Id3) and promoter methylation status (id4) are sensitive prognostic markers strong therapeutic targets for the management of the disease". The novel ideas that are being pursued in this proposal are the copy number changes in Id3 and the role of Id4 as a tumor suppressor in prostate cancer.