Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances Cyclin D1 expression and promotes human endometrial cancer cell proliferation
Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances Cyclin D1 expression and promotes human endometrial cancer cell proliferation
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DOI：
10.4161/cc.21029
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发表时间：
2012-07-15
期刊：
影响因子：
4.3
通讯作者：
Ando, Sebastiano
中科院分区：
文献类型：
--
作者：
Casaburi, Ivan;Avena, Paola;Ando, Sebastiano
子宫内膜癌在西方发达国家发病率很高，主要原因是高脂肪饮食和肥胖。膳食脂质的加工是由胆汁酸触发的，胆汁酸是在肝脏中合成并储存在胆囊中的两亲性去污剂。胆汁酸除了在膳食脂质吸收和胆固醇稳态中具有公认的作用外，还可以作为具有系统内分泌功能的信号分子。在本研究中，我们研究了初级胆汁鹅去氧胆酸（CDCA）对人子宫内膜癌细胞系 Ishikawa 的生物学效应。低浓度的 CDCA 能够通过激活膜 G 蛋白偶联受体 (TGR5) 依赖性途径，诱导 Cyclin D1 蛋白和 mRNA 表达显着增加，从而刺激 Ishikawa 细胞生长。通过诱变、EMSA 和 ChIP 分析剖析这种效应背后的分子机制，发现 CDCA 诱导的 Cyclin D1 表达需要在 Cyclin D1 基因近端启动子内的环 AMP 响应元件基序上增强转录因子 CREB 的募集。我们的结果提出了一种新的分子机制，解释了高脂饮食和肥胖对子宫内膜的潜在贡献 癌症的生长和进展为预防女性患这种与肥胖相关的癌症风险的策略提供了理论基础。
Endometrial cancer exhibits a strong incidence in western developed countries mainly due to fat-rich diet and obesity. Processing of dietary lipids is triggered by bile acids, amphipathic detergents that are synthesized in the liver and stored in the gallbladder. In addition to their well-recognized role in dietary lipid absorption and cholesterol homeostasis, bile acids can also act as signaling molecules with systemic endocrine functions.In the present study we investigated the biological effects of the primary bile chenodeoxycholic acid (CDCA) on a human endometrial cancer cell line, Ishikawa. Low concentrations of CDCA are able to stimulate Ishikawa cell growth by inducing a significant increase in Cyclin D1 protein and mRNA expression through the activation of the membrane G protein-coupled receptor (TGR5)-dependent pathway. Dissecting the molecular mechanism underlying this effect by mutagenesis, EMSA and ChIP analysis revealed that CDCA-induced Cyclin D1 expression requires the enhanced recruitment of the transcription factor CREB on the cyclic AMP-responsive element motif within the Cyclin D1 gene proximal promoter.Our results suggest a novel molecular mechanism explaining the potential contribution of high-fat diet and obesity to endometrial cancer growth and progression opening the rationale for strategies to prevent the risk of this obesity-related cancer in women.