Estrogen Receptor β Induces Antiinflammatory and Antitumorigenic Networks in Colon Cancer Cells
Estrogen Receptor β Induces Antiinflammatory and Antitumorigenic Networks in Colon Cancer Cells
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DOI：
10.1210/me.2010-0452
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发表时间：
2011-06-01
影响因子：
--
通讯作者：
Williams, Cecilia
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文献类型：
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作者：
Edvardsson, Karin;Stroem, Anders;Williams, Cecilia
多项研究表明雌激素可以预防结肠癌的发展。雌激素受体β（ERβ）是结直肠上皮中表达的主要雌激素受体，是介导保护作用的主要候选者。我们之前已经证明ERβ的表达可以减少异种移植物中结直肠癌的生长。人们对 ER beta 的作用及其对结肠癌基因转录的影响知之甚少。为了剖析 ER β 介导的过程并研究细胞特异性机制，我们在三种结直肠癌细胞系（SW480、HT29 和 HCT-116）中重新表达 ER β，并结合基因通路分析和 ER β 染色质结合位点的互相关进行全基因组表达研究。尽管诱导的基因调控是细胞特异性的，但功能类别的过度代表性分析表明，相同的生物学主题，包括细胞凋亡、细胞分化和细胞周期的调控，在所有三种细胞系中都受到影响。新发现包括 ER β 介导的 IL-6 和下游网络的强烈下调，对结肠癌发生中涉及的炎症机制具有重大影响。我们还发现了所提出的核受体共调节因子 PROX1 和 ER beta 之间的串扰，证明 ER beta 既调节又与 PROX1 共享靶基因。通过功能研究进一步探讨了 ER beta 对细胞凋亡的影响，这表明其 DNA 修复能力有所增强。我们得出的结论是，ER beta 的重新表达会诱导转录组变化，通过几个平行途径，在所有三种细胞系中汇聚成抗肿瘤能力。我们认为增强 ER β 作用有可能成为预防和/或治疗结肠癌的新治疗方法。 （分子内分泌学25：969-979，2011）
Several studies suggest estrogen to be protective against the development of colon cancer. Estrogen receptor beta (ER beta) is the predominant estrogen receptor expressed in colorectal epithelium and is the main candidate to mediate the protective effects. We have previously shown that expression of ER beta reduces growth of colorectal cancer in xenografts. Little is known of the actions of ER beta and its effect on gene transcription in colon cancers. To dissect the processes that ER beta mediates and to investigate cell-specific mechanisms, we reexpressed ER beta in three colorectal cancer cell lines (SW480, HT29, and HCT-116) and conducted genome-wide expression studies in combination with gene-pathway analyses and cross-correlation to ER beta-chromatin-binding sites. Although induced gene regulation was cell specific, overrepresentation analysis of functional classes indicated that the same biological themes, including apoptosis, cell differentiation, and regulation of the cell cycle, were affected in all three cell lines. Novel findings include a strong ER beta-mediated down-regulation of IL-6 and downstream networks with significant implications for inflammatory mechanisms involved in colon carcinogenesis. We also discovered cross talk between the suggested nuclear receptor coregulator PROX1 and ER beta, demonstrating that ER beta both regulates and shares target genes with PROX1. The influence of ER beta on apoptosis was further explored using functional studies, which suggested an increased DNA-repair capacity. We conclude that reexpression of ER beta induces transcriptome changes that, through several parallel pathways, converge into antitumorigenic capabilities in all three cell lines. We propose that enhancing ER beta action has potential as a novel therapeutic approach for prevention and/or treatment of colon cancer. (Molecular Endocrinology 25: 969-979, 2011)