ID PROTEIN FAMILY EXPRESSION AND FUNCTION IN PROSTATE CANCER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。前列腺癌的异质性表明，导致恶性转化的途径并不统一，但某些遗传改变和途径可能在导致恶性肿瘤的起始阶段是共同的。浸润性癌的发展特点是分化过程的失调，导致细胞增殖增加，细胞凋亡相应减少。已知调节这两个过程的转录因子家族是基本的螺旋-环-螺旋bHLH家族。分化抑制剂（Id）蛋白通过与bHLH转录因子形成非活性异源二聚体，作为bHLH蛋白活性的天然负调节因子。因此，Id基因在未分化、增殖和肿瘤细胞中的表达升高。Id蛋白也在多个水平上起作用，其相互作用可能不限于bHLH蛋白。Id蛋白的过度表达导致细胞凋亡和/或细胞增殖。Id能够刺激细胞周期，激活端粒酶和使细胞类型永生化，这表明Id蛋白可能作为癌基因或协同癌基因。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癌基因，令人惊讶的是，Id4作为肿瘤抑制因子。在AR-ve前列腺癌细胞系中，Id1和Id3作用于细胞增殖途径，Id2作用于细胞凋亡途径，Id4通过诱导p53、E-cadherin和雄激素受体（雄激素受体，AR）的表达而发挥抑瘤作用。有趣的是，在DU145前列腺癌细胞系中，Id3拷贝数也有所增加。因此，Id蛋白代表了前列腺癌生物学的新范式，需要仔细研究。据报道，Id1、Id2和Id3蛋白在包括人前列腺和培养肿瘤细胞在内的原发性人类肿瘤中表达增加，而Id4在许多癌细胞系和组织中表达缺失，可能是由于启动子超甲基化。初步研究表明，Id1/ Id3和Id2的功能缺失分别阻断了前列腺癌模型细胞系的增殖和凋亡，而Id4功能的获得启动了上皮表型和AR受体表达的重新出现。因此，本研究旨在验证以下假设：“Id基因（Id1、Id2、Id3和Id4）具有非冗余功能，它们的表达水平、拷贝数变化（Id3）和启动子甲基化状态（Id4）是敏感的预后标志物，是疾病管理的强治疗靶点。”本研究提出的新观点是Id3的拷贝数变化以及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.