Herrera Luis J, El-Hefnawy Talal, Queiroz de Oliveira Pierre E, Raja Siva, Finkelstein Sydney, Gooding William, Luketich James D, Godfrey Tony E, Hughes Steven J
Department of Surgery, University of Pittsburgh and the Hillman Cancer Center, Pittsburgh, PA 15261, USA.
Neoplasia. 2005 Jan;7(1):75-84. doi: 10.1593/neo.04367.
The hepatocyte growth factor (HGF) receptor, Met, has established oncogenic properties; however, its expression and function in esophageal adenocarcinoma (EA) remain poorly understood. We aimed to determine the expression and potential alterations in Met expression in EA. Met expression was investigated in surgical specimens of EA, Barrett's esophagus (BE), and normal esophagus (NE) using immunohistochemistry (IHC) and quantitative reverse transcriptase polymerase chain reaction. Met expression, phosphorylation, and the effect of COX-2 inhibition on expression were examined in EA cell lines. IHC demonstrated intense Met immunoreactivity in all (100%) EA and dysplastic BE specimens. In contrast, minimal immunostaining was observed in BE without dysplasia or NE specimens. Met mRNA and protein levels were increased in three EA cell lines, and Met protein was phosphorylated in the absence of serum. Sequence analysis found the kinase domain of c-met to be wild type in all three EA cell lines. HGF mRNA expression was identified in two EA cell lines. In COX-2-overexpressing cells, COX-2 inhibition decreased Met expression. Met is consistently overexpressed in EA surgical specimens and in three EA cell lines. Met dysregulation occurs early in Barrett's dysplasia to adenocarcinoma sequence. Future study of Met inhibition as a potential biologic therapy for EA is warranted.
肝细胞生长因子（HGF）受体Met具有明确的致癌特性；然而，其在食管腺癌（EA）中的表达及功能仍知之甚少。我们旨在确定EA中Met的表达情况以及Met表达的潜在改变。采用免疫组织化学（IHC）和定量逆转录聚合酶链反应，对EA、巴雷特食管（BE）和正常食管（NE）的手术标本中的Met表达进行了研究。在EA细胞系中检测了Met的表达、磷酸化以及COX-2抑制对表达的影响。免疫组织化学显示，所有（100%）EA和发育异常的BE标本中均有强烈的Met免疫反应性。相比之下，在无发育异常的BE或NE标本中观察到的免疫染色较弱。三种EA细胞系中Met的mRNA和蛋白水平均升高，且在无血清的情况下Met蛋白发生了磷酸化。序列分析发现，所有三种EA细胞系中c-met的激酶结构域均为野生型。在两种EA细胞系中检测到了HGF mRNA的表达。在COX-2过表达的细胞中，COX-2抑制降低了Met的表达。Met在EA手术标本和三种EA细胞系中持续过度表达。Met失调在Barrett发育异常至腺癌的序列中早期出现。有必要进一步研究将Met抑制作为EA潜在生物治疗方法的可能性。
