DNA Repair and Tobacco Smoke in Bladder Carcinogenesis

DNA 修复和烟草烟雾在膀胱癌发生中的作用

• 批准号: 8596898
• 负责人: Eric Moon-shong M. TANG
• 金额: $ 21.82万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596898
• 关键词: Acrolein; Animal Model; Aromatic Amines; Autophagocytosis; Base Excision Repairs; Binding; Binding Sites; Bladder; Bladder Neoplasm; Bladder Urothelial Cell; Breathing; Cancer Etiology; Carcinogens; Cells; Chemicals; Cigarette; Codon Nucleotides; Complex; Consumption; DNA Adducts; DNA Binding; DNA Damage; DNA Methylation; DNA Repair; DNA Repair Gene; DNA Sequence; DNA repair protein; Data; Deoxyguanosine; Disease; Down-Regulation; FGFR3 gene; Frequencies; Gene Expression; Genes; HRAS gene; Human; Incidence; Induced Mutation; Instruction; Kinetics; Laboratories; Lead; Light; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maps; Mediating; Methylation; Modeling; Molecular Carcinogenesis; Mucous Membrane; Mutation; Normal tissue morphology; Nucleotides; Occupations; Organ; Pathogenesis; Pathway interactions; Pattern; Phenotype; Play; Point Mutation; Predisposition; Rattus; Role; Running; Sampling; Site; Smoker; Specificity; TP53 gene; TP53 gene; Testing; Tissue Sample; Tobacco; Tobacco smoke; Transgenic Mice; Tumor Tissue; United States; Urine; Urothelial Cell; Ursidae Family; adduct; cancer cell; cancer invasiveness; cancer risk; carcinogenesis; carcinogenicity; chemical carcinogen; insight; interest; mouse model; mutant; neoplastic cell; non-smoker; novel; prevent; repaired; tumorigenesis

Bladder cancer (BC) is the fifth most frequent cancer found in the United States (US). Tobacco smoke (TS) is the major cause of BC in US, and tobacco smokers have a 5-fold higher BC incidence than nonsmokers. TS contains more than 60 carcinogens; however, which carcinogens are responsible for BC is not well established. Arylamines, 4-hydroxy-aminoblphenyl (ABP) in particular, are the major cause of occupation-related BC, but the amount of arylamines in TS is minute. In fact, TS contains 100,000 fold more acrolein (Acr) than ABP, and Acr is a potent and organ-specific carcinogen capable of Inducing BC in rat models. Our laboratory has a longstanding interest in studying the role of chemical carcinogen induced DNA damage and repair in tumorigenesis. We recently made three important findings regarding Acr: (1) Acr damages DNA by forming Acr-DNA adducts that are mutagenic; (ii) Acr inhibits DNA repair by modifying and accelerating autophagy-mediated degradation of the modified DNA repair proteins; and (iii) Acr-DNA adducts are poorly repaired in human cells. We propose that Acr Is a major bladder carcinogen and its carcinogenicity Is via these three detrimental effects (Hypothesis 1). Most BC can be classified as either noninvasive (N-lnv) or invasive (Inv); while N-lnv-BC often bear mutations in codon 12 ofthe H-RAS (<20%) and codons 248, 249, 372 and 652 ofthe FGFRS gene (80%), Inv-BC mainly carry mutations in the p53 (30-60%) and RB genes. We hypothesize that these mutation hotspots in BC are Acr preferential binding sites in bladder urothelial cells (Hypothesis 2). We found that DNA damage induces much higher mutations in Inv-BC cells than in N-lnv-BC cells and that N-lnv-BC cells have a much higher DNA damage repair capacity than Inv-BC cells. We also recently found that p63 gene is highly expressed in N-lnv-BC but not in Inv-BC cells, and that introduction of p63 gene elevates DNA repair capacity in Inv-BC cells. These results lead us to hypothesize that H- RAS/FGFR3 mutation-activation enhances DNA repair capacity via activation of p63 and that p53 mutations reduce DNA repair capacity via down regulation of p63 (Hypothesis 3). We will test these hypotheses in cultured human urothelial cells, human bladder tumor tissue samples and transgenic mouse models to understand the relationship between DNA repair capacity and divergent pathways of bladder cancer.

膀胱癌（BC）是美国（US）发现的第五大常见癌症。在美国，烟草烟雾（TS）是BC的主要原因，吸烟者的BC发病率比不吸烟者高5倍。TS含有60多种致癌物;然而，哪些致癌物导致BC尚未得到很好的确定。芳香胺，特别是4-羟基-氨基联苯（ABP）是职业性接触性接触的主要原因，但TS中芳香胺的含量很少。事实上，TS含有的丙烯醛（Acr）是ABP的100，000倍，Acr是一种有效的器官特异性致癌物，能够在大鼠模型中诱导BC。本实验室长期致力于研究化学致癌物诱导的DNA损伤和修复在肿瘤发生中的作用。我们最近取得了三个重要的发现关于Acr：（1）Acr通过形成Acr-DNA加合物，是致突变的DNA损伤;（ii）Acr通过修改和加速自噬介导的降解修饰的DNA修复蛋白抑制DNA修复;和（iii）Acr-DNA加合物在人类细胞中修复不良。我们提出Acr是一种主要的膀胱癌致癌物，其致癌性是通过这三种有害作用（假设1）。大多数BC可分为非侵袭性（N-Inv）和侵袭性（Inv）两类，N-Inv-BC常在H-RAS的密码子12（<20%）和FGFRS基因的密码子248、249、372和652（80%）处发生突变，而Inv-BC主要在p53（30-60%）和RB基因处发生突变。我们假设BC中的这些突变热点是膀胱尿路上皮细胞中的Acr优先结合位点（假设2）。我们发现，DNA损伤诱导Inv-BC细胞比N-lnv-BC细胞高得多的突变，并且N-lnv-BC细胞比Inv-BC细胞具有高得多的DNA损伤修复能力。我们最近还发现，p63基因在N-lnv-BC中高度表达，但在Inv-BC细胞中不表达，并且p63基因的引入提高了Inv-BC细胞中的DNA修复能力。这些结果使我们假设H-RAS/FGFR 3突变激活通过激活p63增强DNA修复能力，并且p53突变通过下调p63降低DNA修复能力（假设3）。我们将在培养的人尿路上皮细胞，人膀胱肿瘤组织样本和转基因小鼠模型中测试这些假设，以了解DNA修复能力和膀胱癌不同途径之间的关系。