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: 2009118
• 负责人: JAMES V TRICOLI
• 金额: $ 12.84万
• 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 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2009118
• 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：（改编自研究者摘要）Y染色体缺失 染色体异常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 目前尚不清楚。 性区Y（SRY）是定位于Yp11.3的基因， 已被证明是人类男性发育的触发基因， 小鼠 SRY蛋白含有一个高度保守的AT氨基酸区 与许多转录激活因子中发现的HMG盒同源。 博士 Tricoli和同事已经证明，这种基因是可选的， 在前列腺癌中表达，在60%的肿瘤中检测到转录本 考察 在40%的SRY转录本缺失的肿瘤中， 这是由于肿瘤细胞中SRY基因含量的任何减少。 的目标 Tricoli博士的建议之一是了解Y染色体的重要性 与SRY表达相关的前列腺癌中的缺失，并鉴定 前列腺癌细胞中SRY基因的调节因子。 这些研究将使用新鲜的前列腺肿瘤组织进行， 前列腺癌细胞系PC-3、DU 145、LNCaP和TSU-PR 1。 这些研究 将包括对取自以下部位的触摸准备进行间期FISH分析： 以确定Y染色体丢失的频率和程度。 这些 研究将补充分子分析区域Y损失使用 区域定位的Y染色体探针和从邻近组织纯化的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损失是否与 与更晚期的临床疾病以及患者年龄和种族相关。 博士 Tricoli和他的同事们将研究可能影响 可能调节这些细胞中SRY的表达。 其中包括 激素睾酮，双氢睾酮和雌二醇和生长 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缺陷型细胞系PC-3中表达该基因， 将细胞注射到C.B17scid小鼠中。 该实验的目的 将使用SRY表达PC-3细胞来鉴定表达的基因 可能对前列腺肿瘤的病因学起重要作用 发展和SRY基因途径的正常功能。 数据 从这些研究中产生的将：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基因调控的机制， 3)确定SRY表达对致瘤生长的生物学效应，和 鉴定在SRY下游表达的新基因。