PERK/eIF2α轴介导小胶质细胞极化促进乳腺癌并发抑郁症的机制研究

BackgroundBreast cancer is one of the major chronic diseases that seriously threatens the health of women around the worldand the incidence is on the rise. Depression is the most common psychological comorbidity in breast cancer patients and can promote the progression of breast cancer. PKR-like endoplasmic reticulum kinasePERK/eukaryotic initiation factor 2eIF2-mediated microglial polarization plays a key role in the occurrence and development of depression and breast cancerbut the mechanism of action in breast cancer complicated by depression is still unclear. ObjectiveTo explore the mechanism of PERK/eIF2 axis-mediated microglial polarization in promoting depression in breast cancer. MethodsAnimal experiments were conducted from May 2022 to December 2022. A total of 30 mice were randomly divided into control groupcontrol grouptumor-bearing group4T1 groupmodel groupmodel groupagonist groupCCT020312 groupand inhibitor groupISRIB groupwith 6 mice in each groupand the tumor volume was calculated for 21 days. Sugar-water preference test and open-field test were used to evaluate depressive-like behavior in mice. Hematoxylin-eosinHE staining was used to evaluate tumor morphology and hippocampal neuronal morphology. ImmunofluorescenceIF was used to observe the levels of CD86/ionic calcium-binding adapter molecule 1Iba-1 and CD206/Iba-1 in hippocampus. Western blot was used to detect the protein levels of PERKeIF2activating transcription factor 4ATF4 and C/EBP homologous protein CHOPwhich are key factors in the PERK/eIF2 axis of hippocampal tissue. ResultsThe sugar water preferencetotal exercise distancetimes in the central areaand distance from central district in the model group were lower than those in the control groupand the depression-like behavior was higher than that in the control groupand the difference was statistically significantP<0.05. The tumor volume in the model group was higher than that in the 4T1 groupand the tumor volume in the CCT020312 group was higher than that in the model groupand the differences were statistically significantP<0.05. The sugar water preference and reduction of total exercise distancetimes in the central areaand distance from central district in the CCT020312 group were lower than those in the model groupwhile those in the ISRIB group were higher than the model groupand the difference was statistically significantP<0.05The results of HE staining showed that the tumor cells in the 4T1 groupmodel group and the CCT020312 group were tightly arrangedwith a large nucleocytoplasmic ratio and more nuclear division imageswhile the tumor cells in the were tightly arrangedwith a large nucleocytoplasmic ratio and most obvious nuclear division in CCT020312 group. In the ISRIB grouplarge areas of plaque-like necrosis and cell debris appeared in the tumor tissueswhich became larger along the interspace of living cells and reduced mitosis.The neurons atrophied in the 4T1 groupand neurons in the Model group and CCT020312 groups showed different degrees of atrophycytoplasmic concentration increasingnuclear hyper staining and cell necrosiswith the CCT020312 group being the most obvious. The ISRIB group showed a decrease in cytoplasmic concentration and the number of nuclear hyperchromations. The results of immunofluorescence staining showed that the protein levels of CD86/Iba-1 and CD206/Iba-1 in the model group were higher than those in the 4T1 groupthe levels of CD86/Iba-1 protein in the CCT020312 group were higher than those in the model groupand the levels of CD206/Iba-1 protein were lower than those in the model groupthe levels of CD206/Iba-1 protein in the ISRIB group were higher than those in the Model groupand the levels of CD86/Iba-1 protein were lower than those in the Model groupand the difference was statistically significantP<0.05. The results of Western blot showed that the levels of PERKeIF2ATF4 and CHOP in the CCT020312 group were higher than those in the model groupand the levels of the above proteins in the ISRIB group were lower than those in the model groupand the differences were statistically significantP<0.05. ConclusionThe mechanism of depression complicated by breast cancer may be related to the PERK/eIF2 axis-mediated imbalance of microglial polarization and the induction of hippocampal neuron inflammation.