Mechanisms of arsenic-induced chromosomal instability and carcinogenesis

砷引起的染色体不稳定和致癌机制

• 批准号: 8413001
• 负责人: WEI DAI
• 金额: $ 39.29万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-16 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413001
• 关键词: Adenocarcinoma; Affect; Aneuploidy; Arsenic; Arsenic Trioxide; Arsenicals; Attenuated; Biological; Bladder; Bowen' s Disease; Cancer Intervention; Carcinogens; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Line; Cell division; Cells; Chromatids; Chromosomal Instability; Chromosomal Stability; Chromosome Breakage; Chromosome Segregation; Chromosome abnormality; Chromosomes; Chronic; Colon; Colon Carcinoma; Complement; Cyclin B; Cytogenetics; DNA; DNA Damage; DNA Repair; DNA biosynthesis; Development; Dicentric chromosome; Double Minutes; Embryo; Environmental Carcinogens; Epidemiologic Studies; Epidemiology; Epigenetic Process; Exposure to; Fibroblasts; Geminin; Genes; Genetic; Genomic Instability; Goals; Growth; HCT116 Cells; Hela Cells; Human; Hyperplasia; In Vitro; Knockout Mice; Laboratory Research; Laboratory Study; Lead; Licensing Factor; Lung; MXI1 gene; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Melanoma Cell; Microcephaly; Microtubules; Mitosis; Mitotic; Molecular; Molecular Target; Mus; Mutation; Neoplastic Cell Transformation; Nuclear; Oncogenic; Organ; Paclitaxel; Play; Population Study; Process; Property; Protein Deregulation; Proteins; Reactive Oxygen Species; Regulation; Replication Licensing; Research; Role; Side; Sister; Sister Chromatid; Sister Chromatid Exchange; Skin; Skin Cancer; Solid Neoplasm; Stomach; System; Testing; Tissues; Tubulin; anaphase-promoting complex; base; carcinogenesis; carcinogenicity; daughter cell; driving force; human PTTG1 protein; in vivo; micronucleus; polymerization; premature; segregation; skin lesion; tumor; tumor progression; tumorigenesis; ultraviolet irradiation

DESCRIPTION (provided by applicant): Chronic exposure to arsenic is highly associated with the occurrence of several types of malignancies, including skin, lung and bladder cancer. Despite extensive studies in the past, the mechanism by which arsenic compounds promote carcinogenesis remains largely unclear. Epidemiological studies reveal that arsenic exposure induces the formation of micronuclei, chromosomal aberrations, and aneuploidy, which may be a culprit in the genesis of cancer since most solid tumors are aneuploid. High fidelity DNA replication and faithful distribution of the chromosomal complement to daughter cells during cell division are of paramount importance to the maintenance of chromosomal stability. We previously demonstrated that arsenic trioxide [As(III)] compromises paclitaxel-induced mitotic arrest in both p53-deficient and proficient cells. We have recently shown that As(III) induces chromosomal instability by suppressing the activation of BubR1, a cell cycle checkpoint protein, leading to unscheduled activation of anaphase promoting complex/cyclosome (APC/C) in melanoma and HeLa cells. Activated APC/C apparently causes premature separation of sister chromatids, aberrant sister chromatid exchanges, and diplochromosome formation in cells with wild-type p53. Moreover, mice with haploinsufficiency of BubR1 are prone to the development of skin lesions (hyperplasia) after exposure to UV irradiation. Given the documented effect of As(III) on the induction of nuclear abnormalities, we hypothesize that As(III) compromises the BubR1-dependent spindle checkpoint, resulting in unscheduled activation of APC/C, chromosomal instability, and neoplastic transformation owing to dysregulation of DNA replication and chromosome segregation processes. To test this hypothesis, we will (1) elucidate the molecular basis by which As(III) induces chromosomal instability with an emphasis on studying the Emi1->APC/C->geminin->Cdt1 regulatory axis, (2) determine if As(III) synergizes with spindle checkpoint deficiency in promoting chromosomal instability and oncogenic transformation in vitro, (3) determine if As(III) enhances spontaneous tumor development in BubR1 haploinsufficient mice and investigate if As(III) functions as a co-carcinogen in promoting skin tumorigenesis induced by UV irradiation in these mice. The long term goal of the project is to understand whether the biological properties associated with As(III) are at least partly due to its action on the perturbation of APC/C activities, causing deregulation of proteins crucial for the control of DNA replication and chromosomal segregation during cell division. We anticipate that this line of research will lead to the identification of key molecular targets for cancer intervention, as well as for ameliorating the detrimental effects of arsenic compounds.

描述（由申请方提供）：长期暴露于砷与几种恶性肿瘤的发生高度相关，包括皮肤癌、肺癌和膀胱癌。尽管过去进行了广泛的研究，但砷化合物促进致癌作用的机制仍不清楚。流行病学研究表明，砷暴露可诱导微核、染色体畸变和非整倍体的形成，这可能是癌症发生的罪魁祸首，因为大多数实体瘤都是非整倍体。在细胞分裂过程中，高保真DNA复制和染色体互补物向子细胞的忠实分布对于维持染色体稳定性至关重要。我们以前证明，三氧化二砷[As（III）]妥协紫杉醇诱导的有丝分裂阻滞在p53缺陷和熟练的细胞。我们最近发现，As（III）诱导染色体不稳定性，通过抑制激活BubR 1，细胞周期检查点蛋白，导致不定期激活后期促进复合物/细胞周期小体（APC/C）在黑色素瘤和HeLa细胞。激活的APC/C明显导致姐妹染色单体的过早分离，异常的姐妹染色单体交换，以及野生型p53细胞中的二倍体染色体形成。此外，BubR 1单倍不足的小鼠在暴露于紫外线照射后容易发生皮肤病变（增生）。鉴于As（III）对诱导核异常的记录效果，我们假设As（III）损害BubR 1依赖的纺锤体检查点，导致APC/C的非计划性激活，染色体不稳定性和肿瘤转化，由于DNA复制和染色体分离过程的失调。为了验证这一假设，我们将（1）阐明As（III）诱导染色体不稳定性的分子基础，重点研究β 1->APC/C->geminin-> Cdt 1调节轴，（2）确定As（III）是否与纺锤体检查点缺陷协同促进体外染色体不稳定性和致癌转化，（3）确定As（III）是否增强BubR 1单倍不足小鼠的自发肿瘤发展，并研究As（III）是否在这些小鼠中作为共致癌物促进由UV照射诱导的皮肤肿瘤发生。该项目的长期目标是了解与As（III）相关的生物学特性是否至少部分是由于其对APC/C活动的扰动，导致对细胞分裂期间DNA复制和染色体分离控制至关重要的蛋白质的失调。我们预计，这一系列的研究将导致确定癌症干预的关键分子靶点，以及改善砷化合物的有害影响。