Liu Yixin, Tian Sheng, Tan Yujia, Yan Picheng, Liu Pan, Zhu Huiying, Nomura Sachiyo, Huang Tianhe, Wei Yongchang
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
Cancers (Basel). 2025 Aug 26;17(17):2789. doi: 10.3390/cancers17172789.
It is established that depression significantly contributes to tumor development, yet its molecular link to gastric cancer progression remains unclear.
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.
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.
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.
抑郁症对肿瘤发展有显著影响已得到证实，但其与胃癌进展的分子联系仍不清楚。
在本研究中，我们检测了与临床预后相关的抑郁症相关基因表达谱，并确定雌二醇和NOTCH3基因是抑郁症背景下参与胃癌进展的关键因素。使用慢性不可预测应激诱导的荷瘤小鼠模型，我们验证了抑郁症对肿瘤发展的影响。此外，通过一系列生物学技术，包括蛋白质印迹法、免疫荧光法、流式细胞术和免疫组织化学法，探索了潜在的分子机制。
在我们的小鼠模型中，抑郁症显著加速了胃癌的生长，其特征是雌二醇水平降低和NOTCH3表达增加。重要的是，外源性补充雌二醇有效地抵消了抑郁症诱导的肿瘤生长。同样，体外研究表明，雌二醇处理抑制了HGC-27和YTN3细胞系中NOTCH3的表达。此外，NOTCH3被证明通过调节SOD2活性来调节细胞内活性氧水平，从而影响细胞增殖。
这项工作确定雌激素/NOTCH3信号通路是抑郁症与胃癌发展之间的关键联系，为改善患有心理障碍的患者的预后提供了有前景的治疗策略。
