The Role of Mitochondrial DNA Alterations in Cancer

线粒体 DNA 改变在癌症中的作用

• 批准号: 7465449
• 负责人: Lee-Jun C Wong
• 金额: $ 29.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465449
• 关键词: Affect; Aging; Apoptosis; Apoptotic; Binding; Biogenesis; Biological; Biological Assay; Bladder; Breast; Breast Cancer Cell; Breast Carcinoma; Cancer cell line; Capillary Electrophoresis; Cell Death; Cell Line; Cell Survival; Cells; Code; Colon; Complex; Cultured Tumor Cells; DNA Fragmentation; DNA Repair; DNA copy number; Development; Disease; Energy Metabolism; Functional RNA; Gel; Gene Expression; Gene Mutation; Generations; Genes; Genus Cola; Glycolysis; Growth; Histones; Knowledge; Lead; Leber' s Hereditary Optic Neuropathy; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Manuals; Measures; Methods; Mitochondria; Mitochondrial DNA; Multienzyme Complexes; Mutation; Mutation Analysis; Mutation Detection; Normal tissue morphology; Numbers; Organelles; Ovarian; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Phenotype; Play; Ploidies; Point Mutation; Polymerase Chain Reaction; Predisposition; Production; Proteins; Rate; Reactive Oxygen Species; Replication Origin; Reporting; Research Personnel; Research Project Grants; Resistance; Respiration; Ribosomal RNA; Role; Site; Solid Neoplasm; Somatic Mutation; System; Temperature; Testing; Therapeutic; Time; Transfer RNA; Tumor Tissue; base; cancer cell; cell growth regulation; cytochrome c; day; design; drug discovery; gel electrophoresis; genome sequencing; mitochondrial DNA mutation; mitochondrial genome; mutant; neoplastic cell; novel; polypeptide; programs; research study; respiratory enzyme; response; transcription factor; tumor; tumorigenesis; uncontrolled cell growth

DESCRIPTION (provided by applicant): The importance of mitochondria in energy metabolism, generation of reactive oxygen species (ROS), aging, and the initiation of apoptosis, have suggested that mitochondria are indispensable integrators in the pathways of tumorigenesis. The close proximity of mitochondria to the ROS producing sites, the limited DNA repair capabilities, and the lack of protective histone proteins render high susceptibility of mtDNA to mutations. Somatic mitochondrial DNA (mtDNA) mutation has been reported in solid tumors including breast, lung, bladder, ovarian, and colon; and has been regarded as a general phenomenon of cancer. However, the functional significance of these mutations has never been investigated. Marked reduction in the cellular content of mitochondria associated with elevated glycolytic activity is an abnormal bio-energetic phenotype of cancer. Both down-regulated and elevated mitochondrial gene expression have been observed in neoplastic cells. Defective mitochondria in tumor cells are constantly under oxidative stress that would generate higher levels of ROS and cause more mutations in genes involved in the regulation of cell growth and ATP production. To this day, the role that mitochondria play in the development of cancer and in maintaining uncontrolled cell growth remains unknown. Recent reports on transmitochondrial cybrid studies demonstrated that mitochondria bearing mutations causing Leber's hereditary optic neuropathy (LHON) are more sensitive to apoptosis. Our hypothesis is that if there are mutant mitochondria that are more sensitive to cell death in neuro-degeneration disease, there will be mitochondrial DNA mutants in cancer cells that are more resistant to apoptosis. To support the hypothesis, we plan to (1) identify somatic mtDNA mutations by the analysis of the entire mitochondrial genome in normal/tumor pairs of breast carcinomas and cell lines, (2) evaluate the mtDNA content that reflects the biogenesis of mitochondria in tumor, (3) determine the potential functional significance of the mtDNA mutations, and (4) assess the effect of mutant mitochondria on cellular response to apoptotic treatment by using the transmitochondrial cybrid cell system. Results from this research project will help us understand the functional role of mitochondrial DNA alterations in cancer and identify potential novel targets for more effective therapeutic development.

描述（由申请人提供）：线粒体在能量代谢、活性氧（ROS）生成、衰老和细胞凋亡启动中的重要性表明线粒体是肿瘤发生途径中不可或缺的整合者。线粒体与 ROS 产生位点非常接近，DNA 修复能力有限，并且缺乏保护性组蛋白，使得 mtDNA 对突变具有很高的敏感性。据报道，实体瘤中存在体细胞线粒体 DNA (mtDNA) 突变，包括乳腺癌、肺癌、膀胱癌、卵巢癌和结肠癌；并已被视为癌症的普遍现象。然而，这些突变的功能意义从未被研究过。与糖酵解活性升高相关的线粒体细胞含量显着减少是癌症的异常生物能量表型。在肿瘤细胞中观察到线粒体基因表达下调和升高。肿瘤细胞中存在缺陷的线粒体不断受到氧化应激，从而产生更高水平的 ROS，并导致参与细胞生长和 ATP 生成调节的基因发生更多突变。迄今为止，线粒体在癌症发展和维持不受控制的细胞生长中所起的作用仍然未知。最近关于传输线粒体细胞杂种研究的报告表明，导致莱伯遗传性视神经病（LHON）的线粒体突变对细胞凋亡更敏感。我们的假设是，如果神经退行性疾病中存在对细胞死亡更敏感的突变线粒体，那么癌细胞中也会存在对细胞凋亡更具抵抗力的线粒体 DNA 突变体。为了支持这一假设，我们计划（1）通过分析正常/肿瘤对乳腺癌和细胞系中的整个线粒体基因组来识别体细胞 mtDNA 突变，（2）评估反映肿瘤中线粒体生物发生的 mtDNA 含量，（3）确定 mtDNA 突变的潜在功能意义，以及（4）评估突变线粒体对 使用传输软骨细胞系统对细胞凋亡治疗的细胞反应。该研究项目的结果将帮助我们了解线粒体 DNA 改变在癌症中的功能作用，并确定潜在的新靶标，以实现更有效的治疗开发。

项目成果

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

• DOI: 10.1002/humu.20824
• 发表时间: 2008-09
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Wong, Lee-Jun C.;Naviaux, Robert K.;Brunetti-Pierri, Nicola;Zhang, Qing;Schmitt, Eric S.;Truong, Cavatina;Milone, Margherita;Cohen, Bruce H.;Wical, Beverly;Ganesh, Jaya;Basinger, Alice A.;Burton, Barbara K.;Swoboda, Kathryn;Gilbert, Donald L.;Vanderver, Adeline;Saneto, Russell P.;Maranda, Bruno;Arnold, Georgianne;Abdenur, Jose E.;Waters, Paula J.;Copeland, William C.
• 通讯作者: Copeland, William C.

Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways.

• DOI: 10.1371/journal.pone.0061747
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kaipparettu BA;Ma Y;Park JH;Lee TL;Zhang Y;Yotnda P;Creighton CJ;Chan WY;Wong LJ
• 通讯作者: Wong LJ