HDC downregulation induced by chronic stress promotes ovarian cancer progression via IL-6/STAT3/S100A9 pathway

Depression is prevalent in ovarian cancer patients and contribute to the progression of the disease. However, the underlying mechanism remains unclear. In vivo , we established a comorbidity mouse model of ovarian cancer and depression. We found that chronic stress induced depression-like behaviors and promoted inoculated ovarian tumor growth in mice. Histidine decarboxylase (HDC) level was downregulated both in tumor tissue and in plasma of model mice. Exogenous histamine (HIS) treatment significantly alleviated chronic stress-induced depression-like behaviors and inhibited ovarian tumor growth, as well as decreased serum levels of inflammatory factors IL-6 and IL-17A, stress hormones norepinephrine (NE) and cortisol (COR), and 5-hydroxytryptamine (5-HT). Furthermore, HIS treatment regulated the immune response, particularly by increasing the percentage of CD3 ⁺ T cells, CD8 ⁺ cytotoxic T (Tc) cells, and decreasing the secretion of IL-17A. In vitro research of A2780 and ES-2 cell lines, NE and COR treatment down-regulated HDC expression and promoted cancer cells proliferation, migration, and invasion. HIS treatment reversed these effects. Preliminary mechanism research showed that chronic stress downregulated HDC expression and promoted ovarian cancer progression via IL-6/STAT3/S100A9 pathway. HIS may be a potential molecule for treating comorbidity of ovarian cancer and depression.