Oxidative DNA Damage, DNA Repair and Oral Cancer

DNA 氧化损伤、DNA 修复和口腔癌

• 批准号: 6370707
• 负责人: Chun-Yang Fan
• 金额: $ 13.29万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6370707
• 关键词: DNA damage; DNA methylation; DNA repair; clinical research; gene mutation; genetic promoter element; human subject; immunocytochemistry; loss of heterozygosity; neoplasm /cancer genetics; oral pharyngeal neoplasm; oxidative stress; polymerase chain reaction; squamous cell carcinoma

DESCRIPTION (provided by applicant): Cigarette smoking is the major known head and neck cancer risk factor and represents the single leading preventable cause of death in the United States. Tobacco enhances the production of reactive oxygen species (ROS) in cells, resulting in the generation of oxidative lesions in DNA, such as strand breaks and oxidative DNA base lesions. Among various oxidative DNA lesions, 8-hydroxyguanine (8-OH-G) is by far the most abundant. If not sufficiently repaired, 8-OH-G can cause mutation by mispairing with adenine, yielding G:C to T:A transversion upon DNA replication. The human gene responsible for the repair of this specific DNA lesion was recently cloned and named human 8-oxoguanine DNA glycosylase (hOGG1). The hOGG1 gene is implicated in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC) for several reasons. 1) The hOGG1 gene is located at 3p25, a chromosomal region with frequent allelic loss in HNSCC. 2) Yeast with mutations in this gene produce a mutator phenotype with accumulation of G:C to T:A transversions. 3) Studies of p53 mutations in HNSCC-related tumors showed a bias in favor of G:C to T:A transversions, as indeed would be expected if hOGG1 repair function was disabled. 4) The hOGG1 gene is amenable to the proposed study because of availability of its complete genomic DNA sequence, intragenic single nucleotide polymorphism (SNP) sites, and antibodies to the gene product. We hypothesize that hOGG1 inactivation promotes the development of oral SCC and this hypothesis will be tested by the following three specific aims. 1) Determine the frequency of loss of heterozygosity (LOH) in the hOGG1 gene. 2) Characterize the hOGG1 protein expression patterns in normal and neoplastic squamous mucosa. 3) Explore the genetic or epigenetic mechanisms of hOGG1 inactivation by identifying somatic mutations or promoter methylation in the oral SCC cases with evidence of LOH or lack of protein expression of hOGG1. The role of hOGG1 inactivation has never been previously examined in oral SCC. This study will help to determine whether hOGG1 can be used as a genetic marker for early detection, prognostic prediction, and a potential target for gene therapy in oral SCC. By obtaining a K award, the PI will have the opportunity to develop skills for patient- oriented research under the direction of basic and clinical science mentors.

描述（由申请人提供）： 吸烟是已知的主要 头颈癌的危险因素，代表了单一的主要可预防的 美国的死因。 烟草提高了 细胞内的活性氧（ROS），导致产生 DNA中的氧化损伤，如链断裂和氧化DNA碱基 病变 在各种氧化性DNA损伤中，8-羟基鸟嘌呤（8-OH-G）是通过 最丰富的。 如果没有充分修复，8-OH-G可能会导致 与腺嘌呤错配的突变，在DNA上产生G：C到T：A的颠换 复制的 负责修复这种特定DNA的人类基因 最近克隆了一个损伤并命名为人8-氧代鸟嘌呤DNA糖基化酶 （hOGG1）。 hOGG 1基因与头颈部癌的发生有关 鳞状细胞癌（HNSCC）的原因有很多。 1)hOGG 1基因是 位于3 p25，HNSCC中常见等位基因丢失的染色体区域。 2)在该基因中具有突变的酵母产生增变子表型， G：C到T：A颠换的积累。 3)p53基因突变的研究 HNSCC相关肿瘤显示出有利于G：C至T：A颠换的偏倚， 如果hOGG 1修复功能被禁用，则确实会预期到。 4)hogg1 基因是适合拟议的研究，因为其完整的可用性， 基因组DNA序列，基因内单核苷酸多态性（SNP）位点， 和针对该基因产物的抗体。 我们假设hOGG 1失活 促进口腔鳞状细胞癌的发展，这一假设将通过 三个具体目标。 1)确定损失的频率 hOGG 1基因的杂合性（洛）。 2)表征hOGG 1蛋白 正常和肿瘤鳞状粘膜中的表达模式。 3)探索 hOGG 1失活的遗传或表观遗传机制， 有洛缺失证据的口腔鳞状细胞癌病例中的突变或启动子甲基化 或缺乏hOGG 1的蛋白表达。 hOGG 1失活的作用 以前从未在口腔SCC中检查过。 这项研究将有助于确定 hOGG 1是否可作为早期检测、预后判断、 预测，并在口腔鳞癌的基因治疗的潜在目标。 通过获得 一个K奖，PI将有机会发展技能，为病人- 在基础和临床科学导师的指导下进行面向研究。