TR4 orphan receptor, a longevity assurance gene, in prostate carcinogenesis

描述（由申请人提供）：衰老与癌症的发展有很强的联系；然而，确切的机制在很大程度上仍然未知。睾丸孤儿受体4 （TR4）属于核受体超家族，敲除TR4 （TR4-/-）会导致小鼠早衰和小鼠胚胎成纤维细胞G2/M生长停滞的早期发作，其中TR4-/-细胞获得基因组不稳定。进一步的机制研究表明，TR4能够通过阻断活性氧和促进DNA修复能力来介导细胞对DNA损伤信号的反应，这两者都可以抵消肿瘤的促进作用。少数存活的“老年”TR4-/-小鼠在17个月大时出现了前列腺增生和/或不典型增生的异常增生性病变，而野生型幼崽则保留了完整的前列腺结构。组织微阵列分析人类前列腺样本的TR4谱发现，随着疾病的进展，TR4的表达呈比例增加，从细胞核向细胞质转移，然后下降，只出现在骨转移标本的细胞质中。对位于细胞质中TR4蛋白的高级别前列腺癌标本的TR4基因基因组序列分析显示，TR4基因在5外显子的核易位信号（TR4m/nsl）上发生突变，该TR4m/nsl同时失去核易位和反激活能力。我们假设TR4是一种抗癌屏障，在肿瘤发生的早期阶段被激活，以防止遗传不稳定。突变导致TR4功能障碍，破坏其核易位，促进肿瘤进展；因此，TR4表达谱是预测疾病行为结果的新预后标志物。提出了四个目标。目的1：筛选人前列腺癌标本中TR4基因突变及其与TR4蛋白畸变的相关性。目的2:TR4m/nls行为特征及其在前列腺癌发生和进展中的作用。目的3：阐明TR4如何抑制前列腺癌发生和进展的潜在机制，并确定负责的分子。目的4：研究前列腺癌患者TR4表达水平/模式与临床预后的相关性。我们的目标是了解TR4在维持前列腺稳态和预防恶性转化中的抑瘤作用，并确定TR4作为前列腺癌的一种新的生物标志物，从而利用TR4进行更准确的诊断和更好的预后。公共卫生相关性：我们的提案将研究新发现的前列腺肿瘤抑制基因TR4孤儿受体的功能，并确定TR4是否为前列腺癌的新生物标志物。我们的研究将使前列腺癌更准确的诊断和更好的预后，并促进利用TR4进行遗传或药物干预以延缓前列腺癌的发展。

DESCRIPTION (provided by applicant): There is a strong association between aging and the development of cancer; however, precise mechanisms remain largely unknown. Testicular Orphan Receptor 4 (TR4) belongs to the nuclear receptor superfamily, and knockout of TR4 (TR4-/-) results in premature aging in mice and early onset of G2/M growth arrest in the mouse embryonic fibroblasts, where TR4-/- cells acquire genome instability. Further mechanistic studies suggest that TR4 is able to mediate cellular response to DNA-damage signals by blocking reactive oxygen species and promoting DNA repair capacity, both of which counteract tumor promotion. A few surviving "aged" TR4-/- mice developed abnormal proliferative lesions of prostatic hyperplasia and/or dysplasia at the age of 17 months while wild type littermates retained an intact prostatic structure. Tissue Microarray Analysis of TR4 profiles from human prostate samples found TR4 expressions were increased and shifted from the nucleus to cytoplasm proportionally with the progression of disease, then declined and appeared only in the cytoplasm of specimens of metastases in bone. Genomic sequence analyses of TR4 gene from high-grade prostate cancer specimens where TR4 protein is located in the cytoplasm showed TR4 gene is mutated at the nuclear translocation signal (TR4m/nsl), in the exon 5, and this TR4m/nsl loses both nuclear translocation and transactivating ability. We hypothesize that TR4 is an anti-cancer barrier that is activated in the early stage of tumorigenesis to guard against genetic instability. Dysfunction of TR4 caused by a mutation, which disrupts its nuclear translocation, contributes to tumor progression; thereby the TR4 expression profile is a new prognostic marker for predicting disease behavior outcomes. Four aims are proposed. AIM 1: To screen TR4 gene mutation in human prostate cancer specimens and correlate with TR4 protein aberrations. AIM 2: Characterization of TR4m/nls behavior and its contribution to prostate cancer development and progression. AIM 3: To elucidate the underlying mechanisms of how TR4 suppresses prostate cancer development and progression, and to identify the molecules which are responsible. AIM 4: To correlate TR4 expression levels/patterns with clinical outcomes in prostate cancer patients. Our goals are to understand the tumor suppressive roles of TR4 in maintaining prostate homeostasis and preventing malignant transformation as well as to identify TR4 as a novel biomarker for prostate cancer, which will lead to more accurate diagnoses and better prognosis by utilizing TR4. PUBLIC HEALTH RELEVANCE: Our proposal will study the functions of a newly identified prostate tumor suppressor gene, TR4 orphan receptor, and determine whether TR4 is a novel biomarker for prostate cancer. Our study will lead to more accurate diagnosis and better prognosis for prostate cancer, and facilitate genetic or pharmacological intervention to slow this disease by utilizing TR4.