The Role of CYP1B1 in the Recurrence of Head and Neck Cancer

CYP1B1在头颈癌复发中的作用

• 批准号: 7802603
• 负责人: Ekaterina G. Shatalova
• 金额: $ 5.38万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802603
• 关键词: 8-hydroxy-2' -deoxyguanosine; Accounting; Adult; Adverse effects; Age; Alcohol consumption; Alcohols; Alleles; Apoptosis; Belief; Benzo(a)pyrene; Biological; Biological Assay; Biological Markers; Biological Markers; Carcinogens; Cell Proliferation; Cells; Characteristics; Country; Cultured Cells; Cytochrome P450; DNA Damage; Data; Development; Diagnosis; Disease; Early Diagnosis; Enzymes; Epithelium; Estrogens; Ethanol; Exposure to; Female; Gender; Genes; Genetic Polymorphism; Genotype; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Hormones; Human; Human Engineering; Incidence; Individual; Intervention; Invaded; Malignant Neoplasms; Messenger RNA; Metabolism; Molecular Target; Operative Surgical Procedures; Oral Leukoplakia; Organ; Pathway interactions; Patients; Play; Premalignant; Prevention; Proteins; Recurrence; Risk; Risk Factors; Role; Smoke; Time; Tissue Sample; Tissues; Tobacco; Tobacco smoke; Tobacco smoking; Tongue Squamous Cell Carcinoma; Translating; Treatment Protocols; alternative treatment; base; cancer type; carcinogenesis; cell type; disease phenotype; drinking; high risk; lung Carcinoma; mRNA Expression; mortality; neoplastic; oral tissue; overexpression; oxidative damage; problem drinker; public health relevance; response; tumor

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common type of cancer. Its incidence increased 60% recently in adults age 40 or less. Mortality among HNSCC patients is very high, often due to recurrence of primary disease. Major risk factors for HNSCC include tobacco and alcohol use. Data from this group and others suggest that estrogens may also contribute to the development of HNSCCs. The tobacco smoke carcinogen benzo(a)pyrene (B(a)P), ethanol from alcoholic drinks and the female hormone estrogen are all metabolized by cytochrome P450 (CYP) 1B1 to potentially carcinogenic metabolites. The hypothesis of the proposed studies is that a polymorphism in CYP1B1 (CYP1B1*2) confers a more aggressive disease phenotype and a greater risk of recurrence of HNSCC. Rationale for the role of CYP1B1 in HNSCC is provided by preliminary data that suggest that 1) the CYP1B1*2 polymorphism, which results in elevated basal expression of CYP1B1, confers increased risk of recurrence for HNSCC; 2) CYP1B1 protein is elevated in human HNSCCs as compared to non-neoplastic epithelium and 3) ethanol and estrogen induce CYP1B1 mRNA levels. In Aim 1, the effect of overexpressing a high-risk CYP1B1*2 allele vs wild type on selected biomarkers (cell proliferation, anchorage independence, invasion, survival, apoptosis and oxidative damage) will be evaluated in cultured premalignant oral leukoplakia (MSK-Leuki) cells following exposure to B(a)P, ethanol and estrogen. Results from studies in MSK-Leuki cells will be translated to an analysis of oral tissue from HNSCC patients in Aim 2. Patients with HNSCC will be genotyped for CYP1B1 (using TaqMan(R) assays) and the effect of the CYP1B1*2 allele on tumor recurrence will be examined in patients stratified by smoking, alcohol use and gender. Sections from tissue blocks from patients will be evaluated immunohistochemically for the level of biomarkers (apoptosis, proliferation and oxidative damage). The association of biomarker levels with CYP1B1 genotype will be investigated. The resulting data are anticipated to significantly enhance our understanding of the function of CYP1B1 in the recurrence of HNSCC and aid in determining the contribution of exposures to tobacco, estrogen and/or alcohol to recurrence in individuals carrying the high-risk CYP1Br2 allele. PUBLIC HEALTH RELEVANCE: Our findings suggest for the first time that a common polymorphism in the CYP1B1 gene increases risk of recurrence of HNSCC. Successful confirmation of this belief will greatly help us to more accurately predict who is at highest risk for recurrence of HNSCC, and aid in the development of new treatments and markers for the early detection and prevention of this devastating disease.

描述（由申请人提供）：头颈鳞状细胞癌（HNSCC）是第六种最常见的癌症。最近，40 岁以下成年人的发病率增加了 60%。 HNSCC 患者的死亡率非常高，通常是由于原发性疾病的复发。 HNSCC 的主要危险因素包括吸烟和饮酒。该小组和其他小组的数据表明，雌激素也可能有助于 HNSCC 的发展。烟草烟雾致癌物苯并(a)芘 (B(a)P)、酒精饮料中的乙醇和女性激素雌激素均通过细胞色素 P450 (CYP) 1B1 代谢为潜在致癌代谢物。拟议研究的假设是 CYP1B1 (CYP1B1*2) 的多态性赋予 HNSCC 更具侵袭性的疾病表型和更大的复发风险。初步数据提供了 CYP1B1 在 HNSCC 中作用的基本原理，这些数据表明：1) CYP1B1*2 多态性导致 CYP1B1 基础表达升高，导致 HNSCC 复发风险增加； 2) 与非肿瘤上皮相比，人 HNSCC 中的 CYP1B1 蛋白升高，3) 乙醇和雌激素诱导 CYP1B1 mRNA 水平。在目标 1 中，将在暴露于 B(a)P、乙醇和雌激素后，在培养的癌前口腔白斑 (MSK-Leuki) 细胞中评估与野生型相比过表达高风险 CYP1B1*2 等位基因对选定生物标志物（细胞增殖、贴壁独立性、侵袭、存活、凋亡和氧化损伤）的影响。 MSK-Leuki 细胞的研究结果将转化为目标 2 中对 HNSCC 患者口腔组织的分析。将对 HNSCC 患者进行 CYP1B1 基因分型（使用 TaqMan® 检测），并在按吸烟、饮酒和性别分层的患者中检查 CYP1B1*2 等位基因对肿瘤复发的影响。来自患者的组织块切片将通过免疫组织化学方法评估生物标志物（细胞凋亡、增殖和氧化损伤）的水平。将研究生物标志物水平与 CYP1B1 基因型的关联。由此产生的数据预计将显着增强我们对 CYP1B1 在 HNSCC 复发中的功能的理解，并有助于确定暴露于烟草、雌激素和/或酒精对携带高风险 CYP1Br2 等位基因的个体复发的影响。 公共健康相关性：我们的研究结果首次表明 CYP1B1 基因的常见多态性会增加 HNSCC 复发的风险。成功证实这一信念将极大地帮助我们更准确地预测谁是头颈部鳞状细胞癌复发的最高风险，并有助于开发新的治疗方法和标记物，以早期发现和预防这种破坏性疾病。