SRY GENE REGULATION AND YP LOSS IN PROSTATE CARCINOMA

前列腺癌中的 SRY 基因调控和 YP 丢失

• 批准号: 2895430
• 负责人: JAMES V TRICOLI
• 金额: $ 13.62万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895430
• 关键词: SCID mouse; age difference; carcinogenesis; carcinoma; cell line; chromosome deletion; clinical research; dihydrotestosterone; disease /disorder etiology; estradiol; fluorescent in situ hybridization; gene expression; genetic regulation; growth factor; human tissue; neoplasm /cancer classification /staging; neoplastic cell; neoplastic process; nucleic acid probes; prostate neoplasms; racial /ethnic difference; sex chromosomes; testosterone; transfection

DESCRIPTION: (adapted from the investigator's abstract) Loss of the Y chromosome is one of the most frequent cytogenetic abnormalities observed in human prostate cancer. However, the biological significance of this event is presently unknown. Sex-region Y (SRY) is a gene which maps to Yp11.3 and has been shown to be the trigger gene for male development in humans and mice. The SRY protein contains a highly conserved AT amino acid region homologous to the HMG box found in many transcriptional activators. Dr. Tricoli and coworkers have demonstrated that this gene is alternatively expressed in prostate cancer with transcripts detected in 60% of the tumors examined. In the 40% of tumors in which SRY transcript is absent, it is not due to any reduction in the SRY gene content of the tumor cells. The goals of Dr. Tricoli's proposal are to understand the significance of Y chromosome loss in prostate cancer as it relates to SRY expression, and to identify factors responsible for regulation of the SRY gene in prostate cancer cells. These studies will be conducted using fresh prostate tumor tissue and the prostate carcinoma cell lines PC-3, DU145, LNCaP and TSU-PR1. These studies will include interphase FISH analysis of touch preparations taken from tumors to determine the frequency and extent of Y chromosomal loss. These studies will be complemented by molecular analysis for regional Y loss using regional mapped Y chromosomal probes and DNA purified from tissues adjacent to touch preparation sections. The result of these studies will be correlated with tumor stage and grade to determine if Y loss is associated with more advanced clinical disease and with patient age and race. Dr. Tricoli and coworkers will examine the effects of factors which could potentially regulate SRY expression in these cells. These include the hormones testosterone, dihydrotestosterone and estradiol and the growth factors of FGF-beta, PDGFa, TGF-beta and EGF. Finally, Dr. Tricoli will determine the effects of SRY gene expression on prostate tumorigenesis by expressing the gene in the SRY deficient cell line PC-3 followed by injection of the cells into C.B17scid mice. The goal of this experiment will be to use the SRY expression PC-3 cells to identify genes expressed downstream of SRY that may be important to the etiology of prostate tumor progression and the normal function of the SRY gene pathway. The data generated from these studies will: 1) define any relationship between Y chromosome loss and advancing tumor stage and grade and patient age, race and disease-free survival, 2) identify mechanisms of SRY gene regulation and 3) determine biological effects of SRY expression on tumorigenic growth, and the identification of novel genes which are expressed downstream of SRY.

描述：（改编自研究者的摘要）Y 的丢失 染色体是最常见的细胞遗传学异常之一 人类前列腺癌。 然而，这一事件的生物学意义 目前未知。 性别区 Y (SRY) 是映射到 Yp11.3 的基因， 已被证明是人类男性发育的触发基因 老鼠。 SRY蛋白含有高度保守的AT氨基酸区域 与许多转录激活剂中发现的 HMG 盒同源。 博士。 Tricoli 和他的同事已经证明该基因可以替代 在前列腺癌中表达，并在 60% 的肿瘤中检测到转录本 检查了。 在 40% 的肿瘤中，SRY 转录物缺失，但它并不存在。 由于肿瘤细胞的 SRY 基因含量减少。 目标 Tricoli 博士的建议之一是了解 Y 染色体的重要性 前列腺癌的损失，因为它与 SRY 表达有关，并确定 负责调节前列腺癌细胞中 SRY 基因的因素。 这些研究将使用新鲜的前列腺肿瘤组织和 前列腺癌细胞系 PC-3、DU145、LNCaP 和 TSU-PR1。 这些研究 将包括对接触制剂进行相间 FISH 分析 肿瘤以确定 Y 染色体丢失的频率和程度。 这些 研究将通过使用区域 Y 损失的分子分析来补充 区域绘制的 Y 染色体探针和从邻近组织中纯化的 DNA 触摸准备部分。 这些研究的结果将是 与肿瘤分期和分级相关，以确定 Y 丢失是否相关 与更晚期的临床疾病以及患者的年龄和种族有关。 博士。 特里科利和他的同事将研究各种因素的影响 潜在地调节这些细胞中的 SRY 表达。 这些包括 激素睾酮、二氢睾酮和雌二醇与生长 FGF-β、PDGFa、TGF-β和EGF因子。 最后，特里科利博士将 确定 SRY 基因表达对前列腺肿瘤发生的影响 在 SRY 缺陷细胞系 PC-3 中表达该基因，然后 将细胞注射到 C.B17scid 小鼠中。 本次实验的目的 将使用SRY表达PC-3细胞来鉴定表达的基因 SRY 下游可能对前列腺肿瘤的病因学很重要 SRY 基因途径的进展和正常功能。 数据 这些研究产生的结果将：1）定义 Y 之间的任何关系 染色体丢失和肿瘤分期和分级进展以及患者年龄、种族 和无病生存，2) 确定 SRY 基因调控机制和 3)确定SRY表达对致瘤性生长的生物学效应，以及 鉴定在 SRY 下游表达的新基因。