Human RNA Binding Protein as a Cancer Marker

人类 RNA 结合蛋白作为癌症标志物

• 批准号: 6620662
• 负责人: JEFFREY ROSS
• 金额: $ 14.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620662
• 关键词: RNA binding protein; biomarker; breast neoplasms; colon neoplasms; gene expression; human tissue; lung neoplasms; natural gene amplification; neoplasm /cancer genetics; polymerase chain reaction; prostate neoplasms; western blottings

DESCRIPTION (provided by applicant): The goal of this proposal is to determine if a recently discovered RNA-binding protein is expressed specifically in human cancer tissue. The protein binds to a segment of the c-myc mRNA coding region that causes the mRNA to be unstable. This segment is called the Coding Region instability Determinant or CRD. The protein that binds to the CRD is the CRD-Binding Protein or CRD-BP. We discovered the CRD-BP using a cell-free mRNA decay system. We observed that polysome-associated c-myc mRNA was specifically and rapidly degraded by an endonuclease when competitor RNA corresponding to the c-myc CRD was added to the reactions. Cleavage occurred within the CRD of the mRNA. We reasoned that a protein might be shielding the CRD from endonuclease attack and that competitor CRD RNA was titrating the protein off of the mRNA. This protein, the CRD-BP, was later purified, sequenced, and cloned in our laboratory. Four subsequent observations from our lab revealed strong links between the CRD-BP and human cancer. Two findings suggest that the CRD-BP is an oncofetal protein: (i) The CRD-BP is expressed abundantly in fetuses but not in adults. (ii) The CRD-BP is expressed in most transformed human tissue culture cells. Two other findings suggest that the CRD-BP is a potential human tumor marker: (iii) The CRD-BP gene is amplified in approximately one-third of human breast cancer cases. (iv) The CRD-BP is expressed in some cases of human colon cancer but not in normal colon. Our working hypotheses are that (i) the CRD-BP is overexpressed in some or many human carcinomas and (ii) the CRD-BP might therefore be a new cancer marker. The following aims/questions explore these hypotheses: Aim I. The CRD-BP is overexpressed in colon cancer. Is it also overexpressed in lung, breast, and prostate cancers? The CRD-BP gene is amplified in breast cancer. Is it also amplified in colon, lung, and prostate cancers? If so, does CRD-BP gene amplification correlate with CRD-BP overexpression? Aim II. Do patients with colon, lung, breast, and prostate cancer make antibodies to the CRD-BP? Aim III. Is the CRD-BP itself detectable in serum from patients with colon, lung, breast, and prostate cancer? Aim IV. Does CRD-BP expression in these cancers correlate with cancer grade or with a poorer prognosis? These studies could provide clinicians with a novel tumor marker. They might also stimulate future studies to evaluate the CRD-BP as a therapeutic target.

描述(由申请人提供)：本提案的目标是确定 如果最近发现的RNA结合蛋白在人类体内特异表达 癌症组织。该蛋白与c-myc mrna编码区的一段结合。 这会导致信使核糖核酸不稳定。这个片段被称为编码区 不稳定行列式或CRD。与CRD结合的蛋白质是 CRD结合蛋白或CRD-BP。我们使用一种无细胞的mRNA发现了CRD-BP 腐烂系统。我们观察到多聚体相关的c-myc mRNA是特异的 当竞争对手RNA对应于 反应中加入了c-myc CRD。卵裂发生在CRD内 信使核糖核酸我们推测，一种蛋白质可能正在保护CRD免受 核酸内切酶攻击和竞争对手CRD RNA滴定蛋白质 信使核糖核酸。这种名为CRD-BP的蛋白质后来被提纯、测序和 在我们实验室克隆的。我们实验室随后的四次观察揭示了 CRD-BP与人类癌症之间的密切联系。两项研究结果表明， CRD-BP是一种癌胎儿蛋白：(1)CRD-BP在 胎儿，但不是成人。(Ii)CRD-BP在大多数转化中表达 人体组织培养细胞。另外两个发现表明CRD-BP是一种 潜在的人类肿瘤标志物：(Iii)CRD-BP基因在 大约三分之一的人类乳腺癌病例。(Iv)CRD-BP是 在某些人结肠癌组织中表达，但在正常结肠组织中不表达。我们的 工作假说是：(I)CRD-BP在某些或许多情况下过度表达 因此，CRD-BP可能是一种新的癌症标志物。 以下目标/问题探讨了这些假设：目标I。CRD-BP是 在结肠癌中过度表达。它是否也在肺、乳房和 前列腺癌？CRD-BP基因在乳腺癌中被扩增。它是不是也 在结肠癌、肺癌和前列腺癌中扩增？如果是这样，CRD-BP基因 扩增与CRD-BP过度表达相关吗？AIM II.患者是否患有 结肠癌、肺癌、乳腺癌和前列腺癌会产生CRD-BP抗体吗？目标 CRD-BP本身是否可在结肠、肺、 乳腺癌和前列腺癌？目的IV.CRD-BP在这些肿瘤中的表达 与癌症分级有关还是与预后较差有关？这些研究可能 为临床医生提供一种新的肿瘤标志物。它们还可能刺激未来 评价CRD-BP作为治疗靶点的研究。