Diminished Estrogen Induced Mitochondrial Protection and Immunosuppressive Microenvironment in Gastric Cancer with Depression.

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.