Inflammation and Cancer

活性氮物质（RNS）的慢性产生可导致DNA损伤，也可直接修饰DNA修复蛋白。RNA修饰的DNA主要通过碱基切除修复（BER）途径修复，其中包括烷基腺嘌呤DNA糖基化酶（AAG）。AAG活性位点含有几个酪氨酸和半胱氨酸，它们是RNS修饰的潜在位点。在体外，我们证明，RNS差异改变AAG活性取决于网站和类型的修改。酪氨酸162的硝化作用损害了1，N（6）-乙烯基腺嘌呤（ε A）-切除活性，而半胱氨酸167的亚硝化作用增加了ε A切除活性。为了了解RNS在体内对BER的影响，我们检测了肠腺瘤诱导型一氧化氮合酶（iNOS）和AAG的水平。AAG与iNOS表达呈显著相关（r = 0.76，P = 0.00002）。有趣的是，AAG水平的变化与酶活性之间没有相关性。我们发现AAG在人类腺瘤中被硝化，这表明这种RNS修饰与人类疾病有关。还检测了BER的关键下游组分脱嘌呤/脱嘧啶核酸内切酶1（APE 1）和DNA聚合酶β（POL β）的表达。与邻近的非肿瘤组织相比，POLbeta蛋白在几乎所有的腺瘤中增加，而APE 1表达仅在大约一半的腺瘤中增加，并且在腺瘤中也重新定位于细胞质。总的来说，结果表明BER在结肠腺瘤中失调。RNS诱导的AAG翻译后修饰是BER失调的机制之一，并且修饰的类型可以定义AAG在癌变过程中的作用。越来越多的证据表明，炎症在癌症的发展和进展中起着重要作用。我们的研究小组最近在肺组织中发现了一种与肺癌预后相关的细胞因子基因特征。因此，我们假设血清中循环细胞因子的浓度可能与肺癌生存有关。对来自马里兰州大巴尔的摩肺癌病例对照研究的353例非小细胞肺癌患者的10种血清细胞因子，即白细胞介素（IL）-1 β、IL-4、IL-5、IL-6、IL-8、IL-10、IL-12、粒细胞巨噬细胞集落刺激因子、干扰素（IFN）-γ和肿瘤坏死因子-α进行了评估。使用超灵敏电化学发光免疫测定法测定细胞因子。IL-6血清浓度（≥ 4.0 pg/mL）与非裔美国人[风险比（HR），2.71; 95%置信区间（CI），1.26 - 5.80]和白人（HR，1.71; 95% CI，1.22 - 2.40）的生存率显著降低相关。IL-10（HR，2.62; 95% CI，1.33 - 5.15）和IL-12（HR，1.98; 95% CI，1.14 - 3.44）仅与非裔美国人的肺癌生存率相关。在高加索人中观察到肿瘤坏死因子-α水平与生存率相关的一些证据，尽管这些结果并不显著。这些产生假设的发现表明，选定的血清细胞因子浓度与肺癌生存率相关，并表明进一步的研究是必要的，以更好地了解这些协会的机制基础。

Chronic generation of reactive nitrogen species (RNS) can cause DNA damage and may also directly modify DNA repair proteins. RNS-modified DNA is repaired predominantly by the base excision repair (BER) pathway, which includes the alkyladenine DNA glycosylase (AAG). The AAG active site contains several tyrosines and cysteines that are potential sites for modification by RNS. In vitro, we demonstrate that RNS differentially alter AAG activity depending on the site and type of modification. Nitration of tyrosine 162 impaired 1,N(6)-ethenoadenine (epsilonA)-excision activity, whereas nitrosation of cysteine 167 increased epsilonA excision. To understand the effects of RNS on BER in vivo, we examined intestinal adenomas for levels of inducible nitric oxide synthase (iNOS) and AAG. A striking correlation between AAG and iNOS expression was observed (r = 0.76, P = 0.00002). Interestingly, there was no correlation between changes in AAG levels and enzymatic activity. We found AAG to be nitrated in human adenomas, suggesting that this RNS modification is relevant in the human disease. Expression of key downstream components of BER, apurinic/apyrimidinic endonuclease 1 (APE1) and DNA polymerase beta (POLbeta), was also examined. POLbeta protein was increased in nearly all adenomas compared with adjacent non-tumor tissues, whereas APE1 expression was only increased in approximately half of the adenomas and also was relocalized to the cytoplasm in adenomas. Collectively, the results suggest that BER is dysregulated in colon adenomas. RNS-induced posttranslational modification of AAG is one mechanism of BER dysregulation, and the type of modification may define the role of AAG during carcinogenesis. Accumulating evidence suggests a role for inflammation in the development and progression of cancer. Our group recently identified a cytokine gene signature in lung tissue associated with lung cancer prognosis. Therefore, we hypothesized that concentrations of circulating cytokines in serum may be associated with lung cancer survival. Ten serum cytokines, namely interleukin (IL)-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, granulocyte macrophage colony-stimulating factor, interferon (IFN)-gamma, and tumor necrosis factor-alpha, were assessed in 353 non-small cell lung cancer cases from a case-control study of lung cancer in the greater Baltimore, Maryland area. Cytokines were measured using an ultrasensitive electrochemiluminescence immunoassay. IL-6 serum concentrations ( greater than or = 4.0 pg/mL) were associated with significantly poorer survival in both African Americans [hazard ratio (HR), 2.71; 95% confidence interval (CI), 1.26 - 5.80] and Caucasians (HR, 1.71; 95% CI, 1.22 - 2.40). IL-10 (HR, 2.62; 95% CI, 1.33 -5.15) and IL-12 (HR, 1.98; 95% CI, 1.14 - 3.44) were associated with lung cancer survival only in African Americans. Some evidence for an association of tumor necrosis factor-alpha leves with survival in Caucasians was observed, although these results were not significant. These hypothesis-generating findings indicate that selected serum cytokine concentrations are associated with lung cancer survival, and indicate that further research is warranted to better understand the mechanistic underpinnings of these associations.