Effect Of Chronic Stress-induced Depression And Fluoxetine Intervention On Tumor Progression In Tumor-bearing Mice And Metabonomics Study

OBJECTIVEThe aim of this study was to investigate the effects of chronic stress-induced depression on tumor progression,whether the antidepressant fluoxetine has antitumor effects,and the metabolomic changes of fluoxetine in mice with chronic stress-induced depression.METHODSNormal C57 mice were randomly divided into 6 groups:(A)control mice,(B)depression mice,(C)control mice bearnng Lewis lung cancer,(D)depression mice bearing Lewis lung cancer,(E)control mice bearing Lewis lung cancer + fluoxetine treatment,and(F)depression mice bearing Lewis lung cancer + fluoxetine treatment.The mice in the B,D,and F groups were given a chronic unpredictable mild stress(CUMS)for 8 weeks to establish a depression model,and the other groups were fed normally.The depression model was tested with behavioral analysis and sucrose preference test 8 weeks later.Then,mice in groups C,D,E,and F were inoculated with LLC lung cancer tumor cells.Groups D and F were mouse models of comorbid tumors of depression.Mice in groups E and F were administrated fluoxetine on the third day after tumor-bearing,and four control mice,A,B,C,and D,were given normal saline.The body weight is measured regularly.After 14 days of continuous administration,the mice were sacrificed,the tumors were excised,and the volume and weight of the transplanted tumors were determined.Significant differential genes were identified in mouse liver gene sequencing results,and differentially expressed tumor-associated genes were screened and verified by RT-PCR.The expression of the corresponding protein in the liver of mice was detected by Western blotting.RESULTSBlood biochemistry and behavioral testing confirmed the establishment of a chronic stress-induced depression model.Compared with the simple tumor-bearing control group(B),the tumor weight of the depression and tumor-bearing control group(D)was significantly increased,and the tumor volume was increased;while the tumor weight of the tumor-bearing and fluoxetine-treated group(E)mice was the volume is significantly reduced.We found that the tumor weight and volume were significantly reduced in the depression and tumor-bearing+ fluoxetine-treated group(F)compared with the depression and tumor-bearing control group(D).Based on the results of mouse liver gene sequencing,4 mRNA tumor-associated genes(Pttgl,OsbpI5,Aatf,Tnfrsfl8)were screened.Compared with group A mice,the expression of the above 4 mRNA tumor-associated genes in the liver of chronic stress-induced depression mice(group B)was adjusted to varying degrees,and the mice in group F administered with fluoxetine were compared with depression and the expression of 4 mRNAs in the liver of the tumor-bearing group D mice was reduced to varying degrees.The difference metabolites between the depression group and the control group were mainly amino acids,fatty acids and carbohydrates.CONCLUSIONThe expression of tumor-associated genes in mice with chronic stress depression increases,suggesting that chronic stress can promote tumor development.The antidepressant fluoxetine can effectively slow tumor growth and has certain anti-tumor activity,and its mechanism may be related to the inhibition of tumor-related gene expression.Metabolomics studies have found that chronic stress-induced depression and aggravation of tumor progression may be related to energy metabolism disorders such as amino acids and lipid acids.