Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer. 2013 Apr 1;119(7):1321-9. doi: 10.1002/cncr.27910. Epub 2012 Dec 20.
Gastroesophageal reflux is a risk factor for esophageal adenocarcinoma, and bile acid and its farnesoid X receptor (FXR) have been implicated in esophageal tumorigenesis. The authors investigated the role of FXR expression and activity in esophageal cancer initiation and growth.
FXR expression in esophageal adenocarcinoma tissues was assessed by immunohistochemistry. Knockdown of FXR expression in esophageal cancer cells in vitro and in nude mice xenografts was suppressed by FXR small hairpin RNA (shRNA) and guggulsterone (a natural FXR inhibitor). Esophageal cancer cells were treated with bile acids to demonstrate their effects on growth-promoting genes.
FXR was expressed in 48 of 59 esophageal adenocarcinoma tissues (81.3%), and this overexpression was associated with higher tumor grade, larger tumor size, and lymph node metastasis; however, was inversely associated with retinoic acid receptor-β2 (RAR-β2 ) expression. Knockdown of FXR expression suppressed tumor cell growth in vitro and in nude mouse xenografts. Guggulsterone reduced the viability of esophageal cancer cells in a time-dependent and dose-dependent manner, whereas this effect was diminished after knockdown of FXR expression. Guggulsterone induced apoptosis through activation of caspase-8, caspase-9, and caspase-3 in tumor cells. FXR mediated bile acid-induced alterations of gene expression, eg, RAR-β2 and cyclooxygenase-2 (COX-2).
Inhibition of FXR by FXR shRNA or guggulsterone suppressed tumor cell viability and induced apoptosis in vitro, and it reduced tumor formation and growth in nude mouse xenografts. FXR also mediated bile acid-induced alterations of cell growth-related genes in esophageal cancer cells.
胃食管反流是食管腺癌的一个危险因素，胆酸及其法尼醇 X 受体 (FXR) 已被牵涉到食管肿瘤发生中。作者研究了 FXR 表达和活性在食管癌发生和生长中的作用。
通过免疫组织化学评估食管腺癌组织中 FXR 的表达。通过 FXR 短发夹 RNA (shRNA) 和古卡斯特酮（一种天然的 FXR 抑制剂）在体外和裸鼠异种移植中抑制食管癌细胞中 FXR 的表达。用胆酸处理食管癌细胞，以证明它们对促进生长基因的影响。
FXR 在 59 个食管腺癌组织中的 48 个（81.3%）中表达，这种过表达与更高的肿瘤分级、更大的肿瘤大小和淋巴结转移有关；然而，与维甲酸受体-β2 (RAR-β2) 的表达呈负相关。FXR 表达的敲低抑制了体外肿瘤细胞生长和裸鼠异种移植中的肿瘤生长。古卡斯特酮以时间和剂量依赖的方式降低食管癌细胞的活力，而在敲低 FXR 表达后，这种作用减弱。古卡斯特酮通过激活肿瘤细胞中的半胱天冬酶-8、半胱天冬酶-9 和半胱天冬酶-3诱导细胞凋亡。FXR 介导胆酸诱导的基因表达改变，例如 RAR-β2 和环氧化酶-2 (COX-2)。
FXR shRNA 或古卡斯特酮抑制 FXR 可抑制肿瘤细胞活力并诱导体外细胞凋亡，并减少裸鼠异种移植中的肿瘤形成和生长。FXR 还介导了食管癌细胞中与细胞生长相关基因的胆酸诱导改变。
