Department of Surgery, RCSI University of Medicine and Health Sciences, ERC Beaumont Hospital, D09 YD60 Dublin, Ireland.
Department of Molecular Medicine, RCSI University of Medicine and Health Sciences, ERC Beaumont Hospital, D09 YD60 Dublin, Ireland.
Int J Mol Sci. 2022 Oct 20;23(20):12581. doi: 10.3390/ijms232012581.
Women consistently show lower incidence and mortality rates for colorectal cancer (CRC) compared to men. Epidemiological evidence supports a pivotal role for estrogen in protecting women against CRC. Estrogen protective effects in CRC have been mainly attributed to the estrogen receptor beta (ERβ) however its expression is lost during CRC progression. The role of the G-protein coupled membrane estrogen receptor (GPER/GPER1/GPR30), which remains expressed after ERβ loss in CRC, is currently under debate. We hypothesise that estrogen can protect against CRC progression via GPER by modulating the Wnt/β-catenin proliferative pathway which is commonly hyperactivated in CRC. We sought evidence of sexual dimorphism within the Wnt/β-catenin pathway by conducting Kaplan-Meier analyses based on gene expression of the Wnt receptor (Frizzled 1) in multiple public domain CRC patient data sets. High expression of was associated with poor relapse-free survival rates in the male but not the female population. In female-derived HT29 CRC cell lines, we show that β-catenin nuclear translocation was not affected by treatment with the GPER agonist G1. However, G1 prevented the Wnt pathway-induced upregulation of the oncogene. These novel findings indicate a mechanistic role for GPER in protecting against CRC progression by selectively reducing the tumorigenic effects of hyperactive Wnt/β-catenin signalling pathways in CRC.
与男性相比，女性的结直肠癌（CRC）发病率和死亡率始终较低。流行病学证据支持雌激素在保护女性免受 CRC 影响方面发挥关键作用。CRC 中雌激素的保护作用主要归因于雌激素受体β（ERβ），然而其表达在 CRC 进展过程中丢失。目前，关于 G 蛋白偶联膜雌激素受体（GPER/GPER1/GPR30）的作用存在争议，该受体在 CRC 中 ERβ丢失后仍保持表达。我们假设雌激素可以通过调节 Wnt/β-连环蛋白增殖途径来保护 CRC 进展，该途径在 CRC 中通常过度激活。我们通过对多个公共领域 CRC 患者数据集中 Wnt 受体（卷曲蛋白 1）的基因表达进行 Kaplan-Meier 分析，来寻找 Wnt/β-连环蛋白途径中存在性别二态性的证据。在男性而非女性人群中，表达水平高与无复发生存率降低相关。在来源于女性的 HT29 CRC 细胞系中，我们表明，GPER 激动剂 G1 处理不会影响β-连环蛋白核易位。然而，G1 可防止 Wnt 通路诱导的致癌基因上调。这些新发现表明，GPER 通过选择性减少 CRC 中过度活跃的 Wnt/β-连环蛋白信号通路的致瘤作用，在保护 CRC 进展方面发挥机制作用。
