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

描述(由申请人提供)：衰老和癌症的发展之间有很强的联系；然而，确切的机制在很大程度上仍然不清楚。睾丸孤儿受体4(TR4)属于核受体超家族，TR4-/-基因敲除会导致小鼠过早衰老，使小鼠胚胎成纤维细胞提前发生G2/M期生长停滞，从而导致TR4-/-细胞基因组不稳定。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，这两者都抵消了肿瘤的促进作用。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/或异常增生的异常增殖性病变，而野生型小鼠保留了完整的前列腺结构。组织芯片分析发现，随着疾病的发展，TR4的表达增加，并从细胞核向胞浆转移，然后下降，仅出现在骨转移瘤标本的胞浆中。对TR4蛋白位于细胞质中的高级别前列腺癌标本的基因组序列分析表明，TR4基因在第5外显子的核易位信号(TR4m/NSL)处发生突变，该外显子失去了核易位和反式激活能力。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，以防止遗传不稳定性。由突变引起的TR4功能障碍，破坏了其核转位，促进了肿瘤的进展；因此，TR4的表达谱是预测疾病行为结果的新的预后标志物。提出了四个目标。目的1：筛查前列腺癌标本中TR4基因突变及其与TR4蛋白异常的关系。目的2：TR4m/NLS的行为特征及其在前列腺癌发生发展中的作用。目的3：阐明TR4抑制前列腺癌发生和发展的潜在机制，并确定起作用的分子。目的4：探讨前列腺癌患者TR4表达水平/模式与临床预后的关系。我们的目标是了解TR4在维持前列腺内环境稳定和防止恶性转化中的抑癌作用，并确定TR4是前列腺癌的一个新的生物标志物，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癌抑制基因TR4孤儿受体的功能，并确定TR4是否为前列腺癌的新生物标记物。我们的研究将有助于前列腺癌更准确的诊断和更好的预后，并通过利用TR4进行遗传或药物干预来减缓前列腺癌的发生。

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.