Lord Reginald V N, Brabender Jan, Wickramasinghe Kumari, DeMeester Steven R, Holscher Arnulf, Schneider Paul M, Danenberg Peter V, DeMeester Tom R
Department of Surgery, University of Southern California Keck School of Medicine/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Surgery. 2005 Nov;138(5):924-31. doi: 10.1016/j.surg.2005.05.007.
The CDX2 (caudal-related homeobox gene 2) and PITX1 (pituitary homeobox 1) genes have essential roles in human development. Forced expression of Cdx2 alone in the murine stomach results in gastric intestinal metaplasia (IM). This study was undertaken to investigate the expression pattern of these critical morphogenesis genes in the Barrett's multistage carcinogenesis model.
CDX2 and PITX1 messenger RNA (mRNA) expression levels, relative to the control gene beta-actin, were measured by reverse transcription-polymerase chain reaction in specimens of Barrett's IM (n = 21), dysplasia (n = 18), adenocarcinoma (n = 20), and matching normal squamous esophagus tissues (n = 39) collected from 19 patients with Barrett's esophagus and 20 patients with esophageal adenocarcinoma. CDX2 protein expression was assessed by immunohistochemistry in specimens of normal squamous esophagus (n = 13), IM (n = 10), dysplasia (n = 8,) and adenocarcinoma (n = 5).
The median relative CDX2 mRNA expression was approximately 200 times higher in Barrett's esophagus tissues (0.83) than in matching normal squamous esophagus (0.004) in the patients with Barrett's esophagus (P < .001). The mRNA expression in cancer tissues (0.49) was also higher than in matching normal squamous esophagus specimens (0.009, P < .001). There was no significant difference between the mRNA expression levels in Barrett's esophagus and adenocarcinoma. There was no CDX2 protein expression in normal squamous esophagus, but moderate to strong protein expression was seen in all Barrett's tissues and in a majority of the dysplasia and adenocarcinoma cells. Relative median PITX1 mRNA expression was decreased in Barrett's esophagus (8.02 for all specimens), compared with normal esophagus specimens (47.46 for all specimens, P < .001), and was further reduced in cancer specimens (2.21), compared with either Barrett's esophagus or normal esophagus (both P < .001). Wilcoxon testwas used for all P values shown.
CDX2 mRNA and CDX2 protein expression are upregulated in Barrett's IM tissues, compared with normal squamous esophagus, and remain elevated in dysplasia and adenocarcinoma tissues. In contrast, PITX1 mRNA expression is decreased in Barrett's esophagus, compared with matching normal squamous esophagus specimens, and is further decreased in Barrett's-associated cancer. These descriptive findings suggest a possible role for these genes in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence.
CDX2（尾型相关同源盒基因2）和PITX1（垂体同源盒1）基因在人类发育过程中发挥着重要作用。仅在小鼠胃中强制表达Cdx2会导致胃肠化生（IM）。本研究旨在探究这些关键形态发生基因在巴雷特食管多阶段癌变模型中的表达模式。
通过逆转录聚合酶链反应测定了从19例巴雷特食管患者和20例食管腺癌患者收集的巴雷特食管肠化生标本（n = 21）、发育异常标本（n = 18）、腺癌标本（n = 20）以及匹配的正常鳞状食管组织标本（n = 39）中相对于对照基因β-肌动蛋白的CDX2和PITX1信使核糖核酸（mRNA）表达水平。通过免疫组织化学评估了正常鳞状食管标本（n = 13）、肠化生标本（n = 10）、发育异常标本（n = 8）和腺癌标本（n = 5）中的CDX2蛋白表达。
在巴雷特食管患者中，巴雷特食管组织中的CDX2 mRNA相对表达中位数（0.83）比匹配的正常鳞状食管（0.004）高约200倍（P <.001）。癌组织中的mRNA表达（0.49）也高于匹配的正常鳞状食管标本（0.009，P <.001）。巴雷特食管和腺癌中的mRNA表达水平之间无显著差异。正常鳞状食管中无CDX2蛋白表达，但在所有巴雷特食管组织以及大多数发育异常和腺癌细胞中可见中度至强蛋白表达。与正常食管标本（所有标本为47.46）相比，巴雷特食管中PITX1 mRNA相对表达中位数降低（所有标本为8.02，P <.001），与巴雷特食管或正常食管相比，癌标本中的PITX1 mRNA相对表达中位数进一步降低（2.21，P均<.001）。所示的所有P值均采用Wilcoxon检验。
与正常鳞状食管相比，巴雷特食管肠化生组织中CDX2 mRNA和CDX2蛋白表达上调，且在发育异常和腺癌组织中仍保持升高。相比之下，与匹配的正常鳞状食管标本相比，巴雷特食管中PITX1 mRNA表达降低，在巴雷特食管相关癌中进一步降低。这些描述性发现表明这些基因在巴雷特食管化生-发育异常-腺癌序列中可能发挥作用。
