O'Riordan J M, Abdel-latif M M, Ravi N, McNamara D, Byrne P J, McDonald G S A, Keeling P W N, Kelleher D, Reynolds J V
University Department of Surgery, St James's Hospital, The Dublin Molecular Medicine Centre, Trinity College, Dublin, Ireland.
Am J Gastroenterol. 2005 Jun;100(6):1257-64. doi: 10.1111/j.1572-0241.2005.41338.x.
The incidence of esophageal adenocarcinoma has increased significantly in the western world over the last 20 yr. Most cases arise in a background of chronic gastroesophageal reflux, and specialized intestinal metaplasia in Barrett's esophagus is frequently an antecedent phenotype or evident in association with adenocarcinoma. The molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood.
To examine the expression of the proinflammatory cytokines IL-8 and IL-1beta along the esophagitis, metaplasia, dysplasia, and adenocarcinoma pathway, and to correlate this with histological changes and expression of the transcription factor NF-kappaB.
Fresh biopsy specimens were collected from patients with reflux esophagitis (n=15), Barrett's esophagus (n=35), Barrett's adjacent to adenocarcinoma (n=8), and esophageal adenocarcinoma (n=35). IL-8 and IL-1beta expression were measured using enzyme-linked immunosorbent assay. NF-kappaB expression was measured by electrophoretic mobility shift assay.
Elevated expression of NF-kappaB was found in 2 (13%) out of 15 patients with reflux esophagitis, 21 (60%) out of 35 patients with Barrett's esophagus, and 28 (80%) out of 35 patients with esophageal adenocarcinoma. All 5 patients with Barrett's esophagus and high-grade dysplasia showed elevated expression of NF-kappaB. IL-8 and IL-1beta were significantly increased in esophagitis, Barrett's, and adenocarcinoma compared with squamous epithelium, and in adenocarcinoma compared with all other groups. There was a stepwise increase in the expression of IL-8, IL-1beta, and NF-kappaB from normal through Barrett's epithelium to adenocarcinoma in eight cases of esophageal adenocarcinoma. The levels of both IL-8 and IL-1beta in adenocarcinoma patients correlated with stage of disease. Patients with adenocarcinoma who were NF-kappaB positive had significantly higher levels of both IL-8 (p=0.04) and IL-1beta (p=0.03) compared to adenocarcinoma patients who were NF-kappaB negative.
The proinflammatory cytokines IL-8 and IL-1beta are elevated in esophagitis and Barrett's epithelium, and markedly elevated in adenocarcinoma. NF-kappaB activation is infrequent in esophagitis, but is increased in Barrett's epithelium and adenocarcinoma. The association of NF-kappaB activation with cytokine upregulation was only evident in patients with adenocarcinoma. These patterns may play an important role in Barrett's inflammation and tumourigenesis, and inhibition of the NF-kappaB/proinflammatory cytokine pathway may be an important target for future chemoprevention strategies.
在过去20年中，西方世界食管腺癌的发病率显著上升。大多数病例发生在慢性胃食管反流的背景下，Barrett食管中的特殊肠化生常常是一种前期表型或与腺癌相关。从炎症到化生再到发育异常和腺癌的分子事件仍知之甚少。
研究促炎细胞因子IL-8和IL-1β在食管炎、化生、发育异常和腺癌途径中的表达，并将其与组织学变化及转录因子NF-κB的表达相关联。
从反流性食管炎患者（n = 15）、Barrett食管患者（n = 35）、腺癌旁Barrett食管患者（n = 8）和食管腺癌患者（n = 35）中收集新鲜活检标本。使用酶联免疫吸附测定法测量IL-8和IL-1β的表达。通过电泳迁移率变动分析测量NF-κB的表达。
15例反流性食管炎患者中有2例（13%）NF-κB表达升高，35例Barrett食管患者中有21例（60%），35例食管腺癌患者中有28例（80%）。所有5例Barrett食管伴高级别发育异常患者均显示NF-κB表达升高。与鳞状上皮相比，食管炎、Barrett食管和腺癌中的IL-8和IL-1β显著增加，与所有其他组相比，腺癌中的IL-8和IL-1β也显著增加。在8例食管腺癌病例中从正常组织经Barrett上皮到腺癌，IL-8、IL-1β和NF-κB的表达呈逐步增加。腺癌患者中IL-8和IL-1β的水平与疾病分期相关。NF-κB阳性的腺癌患者与NF-κB阴性的腺癌患者相比，IL-8（p = 0.04）和IL-1β（p = 0.03）水平显著更高。
促炎细胞因子IL-8和IL-1β在食管炎和Barrett上皮中升高，在腺癌中显著升高。NF-κB激活在食管炎中不常见，但在Barrett上皮和腺癌中增加。NF-κB激活与细胞因子上调的关联仅在腺癌患者中明显。这些模式可能在Barrett炎症和肿瘤发生中起重要作用，抑制NF-κB/促炎细胞因子途径可能是未来化学预防策略的重要靶点。
