Division of Cell Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Division of Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
J Pathol. 2020 Jul;251(3):297-309. doi: 10.1002/path.5453. Epub 2020 May 15.
Oestrogen receptor β (ERβ) has been suggested to have anti-proliferative and anti-tumour effects in breast and prostate cancer cells, but other studies have indicated its tumour-promoting effects. Understanding the complex effects of this receptor in different contexts requires further study. We reported that high ERβ expression is independently associated with improved prognosis in female colorectal cancer (CRC) patients. Herein, we investigated the possible anti-tumour effect of ERβ and its selective agonist. CRC patients with high ERβ expression had significantly higher levels of membrane-associated β-catenin, cysteinyl leukotriene receptor 2 (CysLT R), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which have anti-tumour effects, but lower levels of nuclear β-catenin, cysteinyl leukotriene receptor 1 (CysLT R), and cyclooxygenase-2 (COX-2), which have tumour-promoting effects. These interesting findings were further supported by two different publicly available CRC mRNA datasets that showed a significant positive correlation between ERβ expression and 15-PGDH and CysLT R expression and a negative correlation between ERβ expression and β-catenin, CysLT R, and COX-2 expression. We next evaluated ERβ expression in three different colon cancer mouse models; ERβ expression was negatively correlated with tumourigenesis. Furthermore, treatment with the ERβ-agonist ERB-041 reduced CysLT R, active β-catenin, and COX-2 levels but increased phospho-β-catenin, CysLT R, and 15-PGDH levels in HCT-116, Caco-2, and SW-480 colon cancer cells compared to vehicle-treated cells. Interestingly, ERB-041-treated cells showed significantly decreased migration, survival, and colonosphere formation and increased apoptotic activity, as indicated by increased CASPASE-3 and apoptotic blebs. Finally, patients with low ERβ expression had significantly more distant metastasis at the time of diagnosis than patients with high ERβ expression. Therefore, we studied the effects of ERB-041-treated colon cancer cells in a zebrafish xenograft model. We found significantly less distant metastasis of ERB-041-treated cells compared to vehicle-treated cells. These results further support ERβ's anti-tumour role in CRC and the possible use of its agonist in CRC patients. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
雌激素受体 β（ERβ）被认为在乳腺癌和前列腺癌细胞中有抗增殖和抗肿瘤作用，但其他研究表明其具有促进肿瘤的作用。了解该受体在不同环境中的复杂作用需要进一步研究。我们报道高 ERβ 表达与女性结直肠癌（CRC）患者的预后改善独立相关。在此，我们研究了 ERβ 及其选择性激动剂的可能的抗肿瘤作用。高 ERβ 表达的 CRC 患者具有更高水平的膜结合β-连环蛋白、半胱氨酰白三烯受体 2（CysLT R）和 15-羟基前列腺素脱氢酶（15-PGDH），具有抗肿瘤作用，但核β-连环蛋白、半胱氨酰白三烯受体 1（CysLT R）和环氧化酶-2（COX-2）水平较低，具有促肿瘤作用。这一有趣的发现得到了两个不同的公开可用的 CRC mRNA 数据集的进一步支持，该数据集显示 ERβ 表达与 15-PGDH 和 CysLT R 表达之间存在显著正相关，而 ERβ 表达与β-连环蛋白、CysLT R 和 COX-2 表达之间存在显著负相关。我们接下来在三种不同的结肠癌小鼠模型中评估了 ERβ 的表达；ERβ 的表达与肿瘤发生呈负相关。此外，与用载体处理的细胞相比，用 ERβ 激动剂 ERB-041 处理 HCT-116、Caco-2 和 SW-480 结肠癌细胞可降低 CysLT R、活性β-连环蛋白和 COX-2 水平，但增加磷酸化β-连环蛋白、CysLT R 和 15-PGDH 水平。有趣的是，用 ERB-041 处理的细胞表现出明显降低的迁移、存活和集落形成能力，并增加了细胞凋亡活性，表现为 CASPASE-3 和凋亡泡增加。最后，与高 ERβ 表达的患者相比，低 ERβ 表达的患者在诊断时具有明显更多的远处转移。因此，我们在斑马鱼异种移植模型中研究了 ERB-041 处理的结肠癌细胞的作用。我们发现与载体处理的细胞相比，用 ERB-041 处理的细胞远处转移明显减少。这些结果进一步支持 ERβ 在 CRC 中的抗肿瘤作用，以及其激动剂在 CRC 患者中的可能应用。2020 年由 John Wiley & Sons Ltd 代表英国和爱尔兰病理学学会出版的《病理学杂志》的作者。
