Impact of heme iron from red meat on colorectal carcinogenesis and relevance of DNA repair

红肉中血红素铁对结直肠癌发生的影响以及 DNA 修复的相关性

• 批准号: 258652740
• 负责人: Professor Dr. Jörg Fahrer
• 金额: --
• 依托单位: Fachrichtung Lebensmittelchemie / Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258652740?language=en
• 关键词: Impact; heme; iron; red; meat

Dietary factors are well known to increase the risk to develop colorectal cancer (CRC), which is the third most common tumor entity in Germany. Various studies suggest that the intake of heme iron, as relevant constituent of red meat, plays an important role in colorectal carcinogenesis. However, the underlying mechanisms are only partially understood and may involve a) an increased proliferation of the colon crypts linked to microbial dysbiosis, b) the generation of genotoxic N-nitroso compounds (NOC) in the colorectum and c) the induction of lipid peroxidation. NOC are alkylating agents, which cause premutagenic DNA adducts such as O6-methylguanine (O6-MeG) and O6-carboxymethylguanine (O6-CMG). In turn, lipid peroxidation products such as malondialdehyde and hydroxynonenal (HNE) give rise to premutagenic DNA lesions such as pyrimidopurinone (M1G) and HNE-G adducts. This raises the issue whether heme iron from red meat exhibits tumor initiating and/or tumor promoting potential in the colorectum and which DNA repair pathway is involved in the protection against heme iron-associated CRC formation. O6-MeG and O6-CMG are substrates for direct damage reversal by O6-methylguanine-DNA methyltransferase (MGMT). M1G and HNE-G adducts undergo nucleotide excision repair, which essentially involves xeroderma pigmentosum complementation group A (XPA) protein. Transgenic mouse models with deficiencies in MGMT and XPA are available in our group, which will allow studying the causal role of these DNA adducts in heme iron-triggered colorectal carcinogenesis. First, the tumor initiating and tumor promoting properties of dietary heme iron will be analyzed in wildtype animals in comparison to an iron balanced control diet. To this end, a non-invasive mini-endoscopy unit will be used, by which tumor formation and progression is monitored over time in a quantitative manner, which is complemented by histopathological analysis of the whole colorectum. Furthermore, the dose-response relationship in heme iron-triggered CRC formation and the impact of DNA repair deficiencies will be assessed. Next, we will analyze critical heme iron-induced DNA damage in colorectal tissue as well as other endpoints such as cell death induction, cell proliferation and MGMT promoter methylation. Finally, the contribution of intestinal inflammation in heme-associated colorectal carcinogenesis will be analyzed.

众所周知，饮食因素会增加患结直肠癌（CRC）的风险，结直肠癌是德国第三大常见肿瘤。大量研究表明，作为红肉相关成分的血红素铁在大肠癌的发生中起重要作用。然而，其潜在机制仅部分了解，可能涉及a）与微生物生态失调相关的结肠隐窝增殖增加，B）结肠直肠中遗传毒性N-亚硝基化合物（NOC）的产生和c）脂质过氧化的诱导。NOC是一种烷化剂，可导致DNA预诱变加合物，如O 6-甲基鸟嘌呤（O 6-MeG）和O 6-羧甲基鸟嘌呤（O 6-CMG）。反过来，脂质过氧化产物，如丙二醛和羟基壬烯醛（HNE）引起的预致突变DNA损伤，如嘧啶嘌呤酮（M1 G）和HNE-G加合物。这就提出了一个问题，即来自红肉的血红素铁是否在结肠直肠中表现出肿瘤引发和/或肿瘤促进潜力，以及哪种DNA修复途径参与了对血红素铁相关CRC形成的保护。O 6-MeG和O 6-CMG是O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）直接逆转损伤的底物。M1 G和HNE-G加合物经历核苷酸切除修复，其基本上涉及着色性干皮病互补组A（XPA）蛋白。在我们的小组中有MGMT和XPA缺陷的转基因小鼠模型，这将允许研究这些DNA加合物在血红素铁触发的结直肠癌发生中的因果作用。首先，将在野生型动物中分析膳食血红素铁的肿瘤引发和肿瘤促进特性，并与铁平衡的对照膳食进行比较。为此，将使用非侵入性微型内窥镜装置，通过该装置以定量方式随时间监测肿瘤形成和进展，并通过整个结肠直肠的组织病理学分析进行补充。此外，将评估血红素铁触发的CRC形成的剂量-反应关系和DNA修复缺陷的影响。接下来，我们将分析结直肠组织中血红素铁诱导的关键DNA损伤以及其他终点，如细胞死亡诱导，细胞增殖和MGMT启动子甲基化。最后，将分析肠道炎症在血红素相关结直肠癌发生中的作用。