Inflammation and Cancer

慢性产生的反应性氮物种(RNS)可导致DNA损伤，也可能直接修改DNA修复蛋白。RNS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糖基酶(AAG)。AAG活性部位含有几个酪氨酸和半胱氨酸，是RNS的潜在修饰部位。在体外，我们证明RNS根据修饰的部位和类型不同地改变AAG的活性。酪氨酸162的硝化削弱了1，N(6)-乙烯腺嘌呤(EpsilonA)的切割活性，而半胱氨酸167的亚硝化则增加了epsilonA的切割活性。为了了解RNS对体内BER的影响，我们检查了肠腺瘤中诱导型一氧化氮合酶(INOS)和AAG的水平。AAG与诱导型一氧化氮合酶表达呈正相关(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在人类腺瘤中是硝化的，这表明这种RNS修饰与人类疾病有关。同时检测BER的关键下游成分--脱嘌呤/脱嘧啶核酸内切酶1(APE1)和DNA聚合酶β(POLbeta)的表达。与癌旁组织相比，POLbeta蛋白在几乎所有腺瘤组织中均升高，而APE1仅在大约一半的腺瘤组织中表达增强，并且在腺瘤组织中也重新定位于细胞质。总而言之，这些结果表明BER在结肠腺瘤中调节失调。RNS诱导的AAG翻译后修饰是BER失调的机制之一，这种修饰类型可能决定了AAG在肿瘤发生中的作用。越来越多的证据表明，炎症在癌症的发生和发展中发挥了作用。我们小组最近在肺组织中发现了一个与肺癌预后相关的细胞因子基因信号。因此，我们假设血清中循环细胞因子的浓度可能与肺癌的存活率有关。对马里兰州大巴尔的摩地区353例非小细胞肺癌患者血清中的IL-1β、IL-4、IL-5、IL-6、IL-8、IL-10、IL-12、粒-巨噬细胞集落刺激因子、干扰素-γ、肿瘤坏死因子-α等10种细胞因子进行了检测。用超灵敏的电化学发光免疫分析法检测细胞因子。在非裔美国人[危险比(HR)2.71；95%可信区间(CI)1.26-5.80]和高加索人(HR，1.71；95%CI，1.22-2.40)中，IL-6血清浓度(大于或=4.0pg/mL)与显著较差的生存相关。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相关。在高加索人中观察到一些证据表明肿瘤坏死因子-α水平与存活率有关，尽管这些结果并不显著。这些假说产生的发现表明，选定的血清细胞因子浓度与肺癌存活率相关，并表明有必要进行进一步研究，以更好地了解这些关联的机制基础。

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.