An Integrated Study of Mitochondrial Pathways in Colorectal Cancer

描述(由申请人提供)：线粒体功能障碍和活性氧簇(ROS)的产生增加可能在包括结直肠癌在内的几种癌症的发病机制中起关键作用。广泛的研究表明，线粒体是细胞内ROS的主要内源性来源。增加ROS暴露会导致线粒体和核DNA的氧化损伤，并激活细胞凋亡和炎症途径。通过这些活动，ROS暴露可导致细胞恶性转化。氧化损伤和恶变的程度受ROS解毒系统活性的影响。ROS的产生和解毒过程中的细微变化受到环境因素和个体间遗传变异的影响。虽然这些活动在细胞和动物研究中得到了很好的证实，但很少有人类研究评估线粒体功能障碍与结直肠癌风险之间的关系。我们将在一项频率匹配的嵌套病例对照研究中，前瞻性地评估线粒体功能障碍、遗传变异、氧化损伤和ROS解毒系统与结直肠癌之间的几个方面之间的关联，该研究包括640例结直肠癌病例和1280名对照，这是一个已建立的前瞻性队列中的新加坡华人健康研究。线粒体功能障碍的指标包括线粒体DNA拷贝数、实时定量聚合酶链式反应检测的线粒体DNA损伤以及通过尿F2-异前列腺素和血浆荧光氧化产物检测的氧化损伤。线粒体基因组和与线粒体生物发生相关的核基因将通过多态和单倍群的测量来评估其对氧化应激的遗传易感性。其他将被测量的氧化应激的主要决定因素包括ROS解毒系统的抗氧化酶、水果和蔬菜的饮食摄入量，更具体地说是通过血浆胡萝卜素。总而言之，这些措施提供了一种多管齐下的综合方法，解决了可以在人类身上分析的线粒体功能障碍和氧化应激的主要方面。这将为线粒体功能障碍和线粒体相关基因变异在结直肠癌发病风险中的作用提供有价值的信息，有助于识别高危个体，并可能为结直肠癌的预防提供新的机会。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction and increased production of reactive oxygen species (ROS) may have a key role in the pathogenesis of several cancers, including colorectal cancer. Extensive studies have shown mitochondria to be the predominant endogenous source of ROS in cells. Increased ROS exposure induces oxidative DNA damage in mitochondrial and nuclear DNA as well as the activation of apoptotic and inflammation pathways. Through these activities, ROS exposure can lead to malignant transformation of cells. The extent of oxidative damage and malignant transformation is influenced by the activity of the ROS detoxification system. Subtle changes in ROS production and detoxification are influenced by environmental factors and genetic variation between individuals. While these activities are well established in cellular and animal studies, few human studies have evaluated the relationship between mitochondrial dysfunction and colorectal cancer risk. We will prospectively evaluate the association between several aspects of mitochondrial dysfunction, genetic variation, oxidative damage and the ROS detoxification system and colorectal cancer in a frequency matched nested case-control study of 640 colorectal cancer cases and 1280 controls within a well-established prospective cohort, the Singapore Chinese Health Study. Indicators of mitochondrial dysfunction include mitochondrial DNA copy number, mitochondria DNA damage as measured by quantitative real time polymerase chain reaction and oxidative damage as measured by urinary F2-isoprostanes and plasma fluorescent oxidation products. The mitochondrial genome and nuclear genes related to mitochondrial biogenesis will be evaluated for genetic susceptibility to oxidative stress through the measurement of polymorphisms and haplogroups. Additional major determinants of oxidative stress that will be measured include antioxidant enzymes of the ROS detoxification system, dietary intake of fruits and vegetables and more specifically by plasma carotenoids. Together, these measures provide a multi-pronged and integrated approach that addresses major aspects of mitochondrial dysfunction and oxidative stress that can be analyzed in humans. It will provide valuable information on the role of mitochondrial dysfunction and the mitochondrial related genetic variation in the risk of colorectal cancer, which will aid in the identification of high risk indivduals and may provide novel opportunities for prevention of colorectal cancer.