Background: It is established that depression significantly contributes to tumor development, yet its molecular link to gastric cancer progression remains unclear. Methods: In this study, we examined depression-related gene expression profiles in relation to clinical prognosis and identified estradiol and the NOTCH3 gene as critical factors involved in gastric cancer progression in the context of depression. Using a chronic unpredictable stress-induced tumor-bearing mouse model, we validated the impact of depression on tumor development. Additionally, the underlying molecular mechanisms were explored through a range of biological techniques, including Western blotting, immunofluorescence, flow cytometry and immunohistochemistry. Results: Depression significantly accelerated gastric cancer growth in our mouse model, characterized by decreased estradiol levels and increased NOTCH3 expression. Importantly, exogenous estradiol supplementation effectively counteracted depression-induced tumor growth. Consistently, in vitro studies showed that estradiol treatment suppressed NOTCH3 expression in HGC-27 and YTN3 cell lines. Furthermore, NOTCH3 was shown to modulate intracellular reactive oxygen species levels by regulating SOD2 activity, thereby influencing cell proliferation. Conclusions: This work identified the estrogen/NOTCH3 signaling as a key link between depression and gastric cancer development, offering promising therapeutic strategies to improve outcomes for patients suffering from psychological disorders.
背景：已有研究证实抑郁显著促进肿瘤发展，但其与胃癌进展的分子关联机制尚未明确。方法：本研究通过分析抑郁相关基因表达谱与临床预后的关联，发现雌二醇和NOTCH3基因是抑郁影响胃癌进展的关键因子。采用慢性不可预知应激诱导的荷瘤小鼠模型，验证了抑郁对肿瘤发展的影响。同时通过蛋白质印迹、免疫荧光、流式细胞术及免疫组织化学等多种生物学技术探究其分子机制。结果：抑郁状态显著加速小鼠模型中胃癌的生长，其特征表现为雌二醇水平下降及NOTCH3表达升高。关键的是，外源性补充雌二醇能有效逆转抑郁诱导的肿瘤生长。体外实验同样证实，雌二醇处理可抑制HGC-27和YTN3细胞系中NOTCH3的表达。进一步研究发现，NOTCH3通过调节SOD2活性调控细胞内活性氧水平，从而影响细胞增殖。结论：本研究揭示了雌激素/NOTCH3信号通路是连接抑郁与胃癌发展的关键桥梁，为改善伴有心理障碍患者的临床预后提供了潜在治疗策略。
肿瘤(癌症)患者之家