Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, 171 21, Solna, Sweden; Department of Biosciences and Nutrition, Karolinska Institutet, 141 83, Huddinge, Sweden.
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA.
Cancer Lett. 2020 Nov 1;492:54-62. doi: 10.1016/j.canlet.2020.06.021. Epub 2020 Jul 23.
Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ERβ) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ERβ mediates this effect. To investigate the functional role of intestinal ERβ during colitis-associated CRC we used intestine-specific ERβ knockout mice treated with azoxymethane and dextran sodium sulfate, followed by ex vivo organoid culture to corroborate intrinsic effects. We explored genome-wide impact on TNFα signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ERβ. Increased tumor formation in males and tumor size in females was noted upon intestine-specific ERβ knockout, accompanied by enhanced local expression of TNFα, deregulation of key NFκB targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ERβ protects against TNFα-induced damage intrinsically, and characterized an underlying genome-wide signaling mechanism in CRC cell lines whereby ERβ binds to cis-regulatory chromatin areas of key NFκB regulators. Our results support a protective role of intestinal ERβ against colitis-associated CRC, proposing new therapeutic strategies.
雌激素可预防结直肠癌（CRC），并且使用完全敲除动物已经证实雌激素受体β（ERβ）对 CRC 具有预防作用。然而，ERβ 通过哪些细胞或器官来发挥这种作用还不清楚。为了研究肠 ERβ 在结肠炎相关 CRC 中的功能作用，我们使用肠特异性 ERβ 敲除小鼠，用氧化偶氮甲烷和葡聚糖硫酸钠处理，然后进行离体类器官培养以验证内在作用。我们使用人类 CRC 细胞系探索了对 TNFα 信号的全基因组影响，并通过染色质免疫沉淀测定来对 ERβ 的调节进行机制表征。肠特异性 ERβ 敲除后，雄性小鼠的肿瘤形成增加，雌性小鼠的肿瘤体积增大，同时伴有 TNFα 的局部表达增强、关键 NFκB 靶基因的失调以及结肠溃疡增加。出乎意料的是，我们发现雄性小鼠的影响尤为明显。我们证实肠 ERβ 可内在地防止 TNFα 诱导的损伤，并在 CRC 细胞系中描述了一个潜在的全基因组信号机制，其中 ERβ 结合到关键 NFκB 调节剂的顺式调控染色质区域。我们的研究结果支持肠 ERβ 可预防结肠炎相关 CRC，并提出了新的治疗策略。
