Constitutive NFKB and Carcinogenesis in Barrett's Esophagus

Barrett 食管的组成性 NFKB 与癌变

• 批准号: 7151419
• 负责人: NAVTEJ S BUTTAR
• 金额: $ 7.4万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151419
• 关键词: adenocarcinoma; biosynthesis; carcinogenesis; esophagus; mucosa

DESCRIPTION (provided by applicant): Chronic reflux is closely associated with the development of adenocarcinoma of the esophagus, which is highly lethal and has one of the fastest rising incidence rates in the United States. Reflux injury replaces squamous epithelium in the esophagus by a pre-malignant, metaplastic columnar epithelium known as Barrett's esophagus. The therapeutic options for adenocarcinoma in Barrett's esophagus are limited and are associated with significant morbidity. The LONGTERM GOAL of our lab is to characterize the molecular mechanisms of carcinogenesis in Barrett's mucosa in order to develop safe, mechanism-based chemopreventive strategies. The esophageal refluxate contains carcinogenic bile salts that are known to activate prostaglandin E2 (PGE2) biosynthesis in Barrett's esophagus. We and others have noted that high levels of PGE2 promote carcinogenesis in Barrett's esophagus. However, the details of the underlying molecular mechanisms remain unclear. The nuclear factor-kappaB (NF-kB) is a survival factor. It is involved in the transcriptional regulation of cyclooxygenase-2, which is the key catalytic enzyme in PGE2 biosynthesis. We made the novel observations that during carcinogenesis there is a constitutive activation of NF-kB in Barrett's mucosa. We also found that NF-kB inhibition in the animal model of esophageal adenocarcinoma markedly decrease PGE2 production in Barrett's mucosa. Using Barrett's epithelial cell cultures we noted that the loss of NF-kB activation can inhibit PGE2 biosynthesis, decrease proliferation and result in increased apoptosis of Barrett's epithelial cells. The significance of this signaling in the development of esophageal adenocarcinoma needs to be further characterized. Based on these observations, we formulated the CENTRAL HYPOTHESIS that the down-regulation of constitutive NF-kB activation, which results in inhibition of PGE2 production, will prevent the development of adenocarcinoma in Barrett's mucosa. The aim of this study is to conduct focused experiments to further understand the importance of constitutive NF-kB activation in reflux induced esophageal adenocarcinoma. We will also examine if the association of NF-kB activation and the development of esophageal adenocarcinoma is PGE2 dependent. To address this, we will use an established animal model of Barrett's esophagus and adenocarcinoma. We will treat the first group of animals with an NF-kB inhibitor (by preventing 1-KB phosphorylation), the second group with NF- inhibitor plus Dimethyl PGE2 and the third group with vehicle only. We will compare the rate of esophageal adenocarcinoma among the treatment groups and assess if the PGE2 levels in Barrett's mucosa influence the effect of NF-kB inhibition on the rate of development of esophageal adenocarcinoma. A successful outcome of this study will broaden our understanding of mechanisms of carcinogenesis in Barrett's mucosa and help define new chemopreventive targets. Moreover, the information obtained from this study may help us understand the mechanisms involved in chronic injury-related cancers elsewhere in the body.

描述（由申请人提供）：慢性反流与食道腺癌的发展密切相关，该腺癌高度致命，是美国发病率最快的上升速度之一。反流损伤用一种被称为巴雷特食管的典型的，化生的柱状上皮代替了食道中的鳞状上皮。 Barrett食管中腺癌的治疗选择有限，并且与明显的发病率有关。我们实验室的长期目标是表征Barrett粘膜中癌变的分子机制，以制定基于安全的机制化学预防策略。食管反流含有致癌胆汁盐，已知可以激活Barrett食管中的前列腺素E2（PGE2）生物合成。我们和其他人指出，高水平的PGE2促进了巴雷特食管中的致癌作用。但是，基本分子机制的细节尚不清楚。核因子-kappab（NF-KB）是生存因子。它参与了环氧酶-2的转录调节，这是PGE2生物合成中的关键催化酶。我们做出了新的观察结果，即在癌变中，在巴雷特的粘膜中，NF-KB的组成型激活。我们还发现，食管腺癌动物模型中的NF-KB抑制作用显着降低了Barrett粘膜中PGE2的产生。使用Barrett的上皮细胞培养物，我们注意到NF-KB激活的丧失可以抑制PGE2生物合成，减少增殖并导致Barrett上皮细胞的凋亡增加。该信号在食管腺癌的发展中的重要性需要进一步表征。基于这些观察结果，我们提出了一个中心假设，即构成型NF-KB激活的下调会导致PGE2产生的抑制，这将阻止Barrett粘膜中腺癌的发展。这项研究的目的是进行集中实验，以进一步了解构成性NF-KB激活在反流诱导的食管腺癌中的重要性。我们还将检查NF-KB激活的关联和食管腺癌的发展是否取决于PGE2。为了解决这个问题，我们将使用Barrett食管和腺癌的既定动物模型。我们将使用NF-KB抑制剂（通过预防1-KB磷酸化），第二组NF-抑制剂加二甲基PGE2和仅使用媒介物的第三组来治疗第一组动物。我们将在治疗组中比较食管腺癌的速率，并评估Barrett粘膜中的PGE2水平是否影响NF-KB抑制对食道腺癌的发育速率的影响。这项研究的成功结果将扩大我们对Barrett粘膜癌变机制的理解，并有助于定义新的化学预防靶标。此外，从这项研究中获得的信息可能有助于我们了解体内其他地方与慢性损伤有关的癌症所涉及的机制。