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

TR4孤儿受体，一种长寿保证基因，在前列腺癌发生中的作用

• 批准号: 7682233
• 负责人: YI-FEN LEE
• 金额: $ 27万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682233
• 关键词: Accounting; Acidic Amino Acids; Affect; Aftercare; Age; Age-Years; Aging; Aging-Related Process; Androgens; Basal Cell; Basic Amino Acids; Behavior; Biological; Biological Markers; Cancer Patient; Carcinoma; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Classification; Clinical; Cockayne Syndrome; Complex; Cytoplasm; DNA Damage; DNA Repair; DNA Sequence; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; Drug resistance; Dysplasia; Elderly; Embryo; Epithelial; Excision Repair; Exons; Family; Fibroblasts; Freezing; Frequencies; Functional disorder; Gene Abnormality; Gene Mutation; Gene Targeting; Genes; Genetic; Genomic Instability; Genomics; Genotoxic Stress; Gleason Grade for Prostate Cancer; Goals; Growth; Histology; Homeostasis; Human; Immune response; In Vitro; Individual; Intervention; Intraepithelial Neoplasia; Knock-out; Lead; Lesion; Ligands; Location; Longevity; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Microarray Analysis; Molecular; Molecular Profiling; Mus; Mutate; Mutation; Neoplasm Metastasis; Nuclear; Nuclear Receptors; Nuclear Translocation; Oncogenic; Organ; Orphan; Outcome; Paraffin; Pathway interactions; Patients; Pattern; Phenotype; Predisposition; Premature aging syndrome; Prognostic Marker; Prostate; Prostatic; Prostatic Neoplasms; Prostatic hypertrophy; Proteins; Radiation; Radical Prostatectomy; Reactive Oxygen Species; Role; Sampling; Sequence Analysis; Signal Transduction; Specimen; Staging; Structure; Tissue Banking; Tissue Banks; Tissue Microarray; Tissues; Tumor Promotion; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor stage; aged; aging population; bone; cancer cell; cell behavior; cell growth; clinically significant; deprivation; early onset; genotoxicity; high risk; human tissue; knock-down; migration; mutant; novel; novel diagnostics; outcome forecast; prevent; programs; prostate carcinogenesis; protein B; protein expression; public health relevance; receptor; reproductive; response; therapy resistant; tumor; tumor progression; tumorigenesis; urologic

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.

描述（由申请人提供）：衰老和癌症的发展之间存在很强的关联;然而，精确的机制在很大程度上仍然未知。睾丸孤儿受体4（Testicular Orphan Receptor 4，TR 4）属于核受体超家族，敲除TR 4（TR 4-/-）可导致小鼠早衰和小鼠胚胎成纤维细胞早期G2/M期生长停滞，TR 4-/-细胞获得基因组不稳定性。进一步的机制研究表明，TR 4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”TR 4-/-小鼠在17月龄时出现前列腺增生和/或发育不良的异常增生性病变，而野生型同窝仔保留完整的前列腺结构。组织芯片分析人前列腺组织中TR 4的表达谱发现，随着疾病的进展，TR 4的表达逐渐增加，并从细胞核转移到细胞质，然后下降，仅出现在骨转移瘤的细胞质中。来自其中TR 4蛋白位于细胞质中的高级别前列腺癌标本的TR 4基因的基因组序列分析显示，TR 4基因在外显子5中的核易位信号（TR 4 m/nsl）处突变，并且该TR 4 m/nsl丧失核易位和反式激活能力。我们假设TR 4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。由突变引起的TR 4功能障碍，破坏其核转位，有助于肿瘤进展;因此TR 4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：筛选前列腺癌组织中TR 4基因突变，并与TR 4蛋白异常进行相关性研究。目的2：TR 4 m/nls行为的表征及其在前列腺癌发生和发展中的作用。目标3：阐明TR 4如何抑制前列腺癌发展和进展的潜在机制，并确定负责的分子。目的4：将TR 4表达水平/模式与前列腺癌患者的临床结局相关联。我们的目标是了解TR 4在维持前列腺稳态和预防恶性转化中的肿瘤抑制作用，并将TR 4鉴定为前列腺癌的新生物标志物，这将通过利用TR 4导致更准确的诊断和更好的预后。 公共卫生相关性：我们的提案将研究一个新发现的前列腺肿瘤抑制基因，TR 4孤儿受体的功能，并确定TR 4是否是一个新的前列腺癌生物标志物。我们的研究将导致前列腺癌更准确的诊断和更好的预后，并通过利用TR 4促进遗传或药物干预来减缓这种疾病。