Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA.
Am J Physiol Gastrointest Liver Physiol. 2012 Apr 15;302(8):G864-72. doi: 10.1152/ajpgi.00340.2011. Epub 2012 Feb 2.
Beclin-1 has a central role in the regulation of autophagy. Barrett's esophagus (BE) is associated with a significantly increased risk for the development of esophageal adenocarcinoma (EAC). In the current study, we evaluated the role of Beclin-1 and autophagy in the EAC. Biopsies obtained from patients with BE and EAC, tissues from a rat model of BE and EAC, and esophageal cell lines were evaluated for the expression of Beclin-1 by immunohistochemistry, immunoblotting, or RT-PCR. Since reflux of bile acids is important in EAC, we also evaluated the effect of exposure to deoxycholic acid (DCA) on autophagy and Beclin-1 expression. Beclin-1 expression was high in squamous epithelium and nondysplastic BE, whereas its expression was low in dysplastic BE and EAC. The same pattern of expression was observed in rat tissues and in esophageal cell lines. Normal esophageal epithelium and HET-1A cells (derived from normal squamous epithelium) show high levels of Beclin-1, but lower levels of Beclin-1 were found in BE and EAC cell lines (CP-A, CP-C, and OE33). Acute exposure to DCA led to increased Beclin-1 expression and increased autophagy as evaluated by electron microscopy and counting percentage of GFP-LC3-positive BE cells with punctate pattern. In contrast, chronic exposure to DCA did not result in the alteration of Beclin-1 levels or autophagy. In summary, these data suggest that autophagy is initially activated in response to bile acids, but chronic exposure to bile acids leads to decreased Beclin-1 expression and autophagy resistance.
Beclin-1 在自噬的调节中起核心作用。巴雷特食管（BE）与食管腺癌（EAC）的发生风险显著增加相关。在本研究中，我们评估了 Beclin-1 和自噬在 EAC 中的作用。通过免疫组织化学、免疫印迹或 RT-PCR 评估来自 BE 和 EAC 患者的活检组织、BE 和 EAC 大鼠模型的组织以及食管细胞系中 Beclin-1 的表达。由于胆酸反流在 EAC 中很重要，我们还评估了暴露于脱氧胆酸（DCA）对自噬和 Beclin-1 表达的影响。Beclin-1 在鳞状上皮和非异型增生的 BE 中表达较高，而在异型增生的 BE 和 EAC 中表达较低。在大鼠组织和食管细胞系中观察到相同的表达模式。正常食管上皮和 HET-1A 细胞（源自正常鳞状上皮）显示高水平的 Beclin-1，但 BE 和 EAC 细胞系（CP-A、CP-C 和 OE33）中 Beclin-1 水平较低。急性暴露于 DCA 导致 Beclin-1 表达增加和自噬增加，通过电子显微镜和计数具有点状模式的 GFP-LC3 阳性 BE 细胞的百分比来评估。相比之下，慢性暴露于 DCA 不会导致 Beclin-1 水平或自噬的改变。总之，这些数据表明，自噬最初是对胆酸的反应而被激活，但慢性暴露于胆酸会导致 Beclin-1 表达和自噬抵抗降低。
