The literature data regarding the risk of colorectal cancer (CRC) in the context of hormone therapy (HT), including both estrogen–progestogen combinations and estrogen alone, are inconclusive. The precise relationship underlying the action of progesterone (P4) and progesterone receptors in CRC has yet to be determined. We characterized the expression profiles of both nuclear and membrane progesterone receptors and their potential cofactors in CRC tissues. Additionally, we analyzed the P4 and NENF treatment effects on the cell proliferation and invasion of DLD-1 and HT-29 colorectal cancer cells. We observed a weak expression of the nuclear P4 receptor (PGR), but an abundant expression of the P4 receptor membrane component 1 (PGRMC1) and neuron-derived neurotrophic factor (NENF) in the CRC tissues. P4 treatment stimulated the proliferation of the DLD-1 and HT-29 CRC cells. The co-treatment of P4 and NENF significantly increased the invasiveness of the DLD-1 and HT-29 cells. A functional analysis revealed that these effects were dependent on PGRMC1. AN immunocytochemical analysis demonstrated a cytoplasmic co-localization of PGRMC1 and NENF in the CRC cells. Moreover, the concentration of serum NENF was significantly higher in CRC patients, and P4 treatment significantly increased the release of NENF in the DLD-1 cells. P4 or NENF treatment also significantly increased the IL-8 release in the DLD-1 cells. Our data may provide novel insights into the action of P4 and PGRMC1/NENF in CRC progression, where NENF may act as a potential PGRMC1 co-activator in non-classical P4 signaling. Furthermore, NENF, as a secreted protein, potentially could serve as a promising circulating biomarker candidate for distinguishing between colorectal cancer patients and healthy individuals, although large-scale extensive studies are needed to establish this.
关于激素治疗（包括雌激素-孕激素联合疗法及单纯雌激素疗法）与结直肠癌风险关系的文献数据尚无定论。孕酮及其受体在结直肠癌中的作用机制尚未明确。本研究系统分析了结直肠癌组织中核孕酮受体与膜孕酮受体及其潜在辅助因子的表达谱，并探究了孕酮与神经元衍生神经营养因子对DLD-1和HT-29结直肠癌细胞增殖与侵袭的影响。结果显示：结直肠癌组织中核孕酮受体表达微弱，而孕酮受体膜组分1与神经元衍生神经营养因子呈现高表达。孕酮处理可促进DLD-1和HT-29细胞增殖，孕酮与神经元衍生神经营养因子联合处理则显著增强两种细胞的侵袭能力。功能分析表明这些效应依赖于孕酮受体膜组分1。免疫细胞化学分析显示孕酮受体膜组分1与神经元衍生神经营养因子在结直肠癌细胞质中共定位。临床样本分析发现结直肠癌患者血清神经元衍生神经营养因子浓度显著升高，且孕酮处理能明显促进DLD-1细胞释放该因子。此外，孕酮或神经元衍生神经营养因子处理均可显著提升DLD-1细胞白细胞介素-8的释放水平。本研究为阐明孕酮及孕酮受体膜组分1/神经元衍生神经营养因子在结直肠癌进展中的作用机制提供了新视角：神经元衍生神经营养因子可能作为非经典孕酮信号通路中孕酮受体膜组分1的潜在共激活因子。作为分泌型蛋白，神经元衍生神经营养因子有望成为区分结直肠癌患者与健康人群的循环生物标志物，但其临床应用价值仍需通过大规模深入研究予以验证。
肿瘤(癌症)患者之家