RNA sequencing of HGC - 27 and AGS cells that were treated with estradiol.

Although it is established that chronic psychological stress significantly contributes to tumor development, the molecular mechanisms linking it to gastric cancer (GC) progression remain incompletely understood. In this work, we analyzed depression-related gene expression profiles in relation to clinical prognosis and identified estradiol (E2) and NOTCH3 as key factors involved in GC progression under depression conditions. The impact of depression on GC was verified using a chronic unpredicted stress (CUS)-stimulated tumor bearing mouse model. Furthermore, the underlying molecular mechanisms were elucidated through various biological techniques, including western blotting, immunofluorescence, flow cytometry and immunohistochemistry. Depression significantly promoted GC growth in our mouse model, accompanied by decreased estrogen levels and an upregulation of NOTCH3 expression. Notably, exogenous estrogen supplementation effectively mitigated depression-induced tumor growth. In vitro studied consistently demonstrated that E2 treatment suppressed NOTCH3 expression in HGC and YTN3 cell lines, with NOTCH3 regulating intracellular ROS levels by modulating SOD2 activity to affect cell proliferation. This work identified the estrogen-regulated NOTCH3 as a key link between chronic stress and GC, offering promising therapeutic strategies to enhance the outcome for GC patients suffering from comorbid depression.