The Role of Tobacco-Related Chemical Carcinogens and Oxyradicals in Human Cancer

烟草相关化学致癌物和氧化自由基在人类癌症中的作用

• 批准号: 6433193
• 负责人: CURTIS HARRIS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6433193
• 关键词: cancer risk; chemical carcinogen; chemical carcinogenesis; clinical research; colon neoplasms; enzyme activity; free radical oxygen; gene mutation; human tissue; neoplasm /cancer genetics; nitric oxide synthase; polymerase chain reaction; restriction fragment length polymorphism; tobacco abuse; tumor suppressor genes; ulcerative colitis

High concentrations of nitric oxide (NO) regulation of NO synthase (NOS) activity is essential for minimizing effects of cytotoxic and genotoxic nitrogen oxide species. We have shown previously, that NO-induced p53 protein accumulation, down-regulates basal and cytokine-modulated inducible NOS (NOS2) expression in human cells in vitro, and that p53-null mice have elevated NOS2 enzymatic activity. Our investigation of primary colon tumors establishes a strong positive relationship between the presence of NOS2 in tumors and the frequency of G:C to A:T transitions at CpG dinucleotides. These mutations also are common in lymphoid, esophageal, head and neck, stomach, brain and breast cancers. Increased NOS2 expression has been demonstrated in four of these cancers. Tumor-associated NO production may modify DNA directly, or may inhibit DNA repair activities, such as the recently described human thymine-DNA glycosylase, which has been shown to repair G:T mismatches at CpG dinucleotides. Because NO production also induces the accumulation of wild-type p53, the resulting growth inhibition can provide an additional strong selection pressure for nonfunctional, mutant p53. NO may, therefore, act as both an endogenous initiator and promoter in human colon carcinogenesis, and specific inhibitors of NOS2, as demonstrated recently in an animal tumor model, may have important chemopreventive potential in human colorectal cancer. These and other findings indicate that NO has a pathophysiological role in carcinogenesis. To determine the role of NO in tumor progression, we generated human carcinoma cell lines that produced NO constitutively. Cancer cells expressing NOS2 that had wild-type p53, had reduced tumor growth in athymic nude mice, whereas those with mutated p53 had accelerated tumor growth associated with increased vascular endothelial growth factor expression and neovascularization. Our data indicate that tumor-associated NO production may promote cancer progression by providing a selective growth advantage to tumor cells with mutant p53, and that inhibitors of NOS2 may have therapeutic activity in these tumors. We are also investigating chronic inflammatory diseases, e.g., ulcerative colitis, and genetic oxyradical overload diseases, e.g., hemochromatosis and Wilson Disease, that are cancer prone. p53 mutation load is increased in these cancer-prone conditions. NOS2 and COX2 are increased in a portion of the cases. NOS2 expression can be regulated by the WNT-APC-b-catenin pathway. Nitric oxide activates p53 by its post-translation by serine kinases. Currently, we are investigating the interaction of the NOS2 and COX2 pathways.

高浓度一氧化氮（NO）对一氧化氮合成酶（NOS）活性的调节对于减少细胞毒性和基因毒性氮氧化物的影响是必不可少的。我们之前已经证明，no诱导的p53蛋白积累可以下调体外人细胞中基础和细胞因子调节的诱导型NOS （NOS2）的表达，并且p53缺失小鼠的NOS2酶活性升高。我们对原发性结肠肿瘤的研究发现，肿瘤中NOS2的存在与CpG二核苷酸上G:C向a:T转变的频率之间存在强烈的正相关关系。这些突变在淋巴癌、食管癌、头颈癌、胃癌、脑癌和乳腺癌中也很常见。其中4种癌症中NOS2表达增加。肿瘤相关NO的产生可能直接修饰DNA，也可能抑制DNA修复活性，例如最近描述的人类胸腺嘧啶-DNA糖基酶，它已被证明可以修复CpG二核苷酸上的G:T错配。由于NO的产生也会诱导野生型p53的积累，由此产生的生长抑制可以为无功能的突变型p53提供额外的强大选择压力。因此，NO可能在人类结肠癌发生过程中同时作为内源性的引发剂和启动剂，而NOS2的特异性抑制剂，正如最近在动物肿瘤模型中所证明的，可能在人类结直肠癌中具有重要的化学预防潜力。这些和其他发现表明NO在癌变中具有病理生理作用。为了确定NO在肿瘤进展中的作用，我们产生了组成性产生NO的人癌细胞系。在胸腺裸小鼠中，表达NOS2的癌细胞具有野生型p53，其肿瘤生长减慢，而p53突变的癌细胞具有加速肿瘤生长的能力，并增加了血管内皮生长因子的表达和新生血管的形成。我们的数据表明，肿瘤相关NO的产生可能通过为p53突变的肿瘤细胞提供选择性生长优势来促进癌症的进展，并且NOS2抑制剂可能在这些肿瘤中具有治疗活性。我们也在研究慢性炎症性疾病，如溃疡性结肠炎，以及遗传性氧自由基超载疾病，如血色素沉着症和威尔逊病，这些都是癌症易感性。在这些易患癌症的情况下，P53突变负荷增加。部分病例NOS2和COX2升高。NOS2的表达可通过WNT-APC-b-catenin通路调控。一氧化氮通过丝氨酸激酶的后翻译激活p53。目前，我们正在研究NOS2和COX2途径的相互作用。