| Purpose and significance1.To analyze the clinical factors about the progression of HCC affected by depression,and to analyze the correlation with prognosis.2.To explore the influence of depression on HCC patients from the genetic level furtherly,gene expression profile chip technology was used to compare the gene expression profile of surgical tissue samples of HCC patients with or without depression,and to detect the differentially expressed genes related to HCC and depression.Bioinformatics was used to analyze the signal transduction pathways involved in differential genes and the possible interaction between them,and to explore the key inflammatory regulatory factors and immune signaling pathways related to depression.3.To analyze the correlation between depression-related differential genes and tumor immune microenvironment regulation and the prognosis of HCC,and to explore the mechanism that depression affects the prognosis of HCC.To identify the importance of depression in the process of HCC.The results will provide a theoretical basis for the evaluation of depression and developping intervention for HCC patients with depression,provide a new idea for improving the effect of targeted therapy and immunotherapy for HCC patients,and promote the transformation of tumor psychological nursing from traditional nursing to precise nursing.MethodsPart I: It was a retrospective cohort study.A total of 251 patients who were diagnosed with HCC and underwent hepatectomy for the first time in the affiliated tumor hospital of Guangxi medical university were selected,including95 patients with depression and 156 without.Demographic and sociological data and clinical case data were collected,and follow-up was conducted accordance with the standard for the diagnosis and treatment of primary liver cancer(2018)untill October 15,2018.Spearman method was used to analyze the correlation between depression and the clinical and pathological factors that may affect the prognosis of patients with HCC,and Cox proportional risk regression model was used to analyze the factors affecting the prognosis of HCC patients.Part II: 10 HCC patients were selected from each group in the first part by the tendency matching method.The gene expression profiles of surgical cancer tissue samples of the two groups were compared by the gene chip technology and bioinformatics analysis,the genes with more than twice differentially expressed were detected.GO,KEGG and STRING software were used to analyze the gene function,signal pathway and internetwork of differential genes.Part Ⅲ: Download RNA-Seq transcriptome data of HCC patients from TCGA database.The Limma program in R language was used to cluster the patients according to the high,medium and low immune values,and GSVA was used to convert the RNA-Seq expression profile data into immunophenotypic.Kaplan-meier method was used to analyze the relationship between different levels of immune values and OS of liver cancer patients,anova was used to analyze the relationship between depression-related differential genes in three groups of patients with different immune levels,and Cox regression model was used to analyze the relationship between depression-related differential genes and OS of liver cancer patients.Results1.Analysis of factors influencing the prognosis of HCC: Results showed that 164 patients(65 in the depression group and 99 in the non-depression group)occured recurrence or metastasis,and 47(22 in the depression group and 25 in the non-depression group)died of HCC.DFS and OS in the depression group were lower than those in the non-depression group(P < 0.05).DFS and OS were significantly reduced in patients with high level of Child-puph,high BCLC stage,and large vessel invasion,with statistically significant differences(P< 0.05).Cox regression analysis showed that Child-puph,BCLC stage and depression were independent risk factors for the prognosis of HCC.2.Effects of depression on immune inflammatory response in patients with HCC: Levels of serum CRP,hs-CRP,ALT and AST in the depression group were all higher than those in the non-depression group,with a statistically significant difference(P<0.05),and depression was positively correlated with levels of serum CRP and hs-CRP(P<0.05).According to the subgroup analysis of postoperative recurrence,the level of hs-CRP of depressed patients in the non-relapse group was significantly higher than that in the non-depressed group,and the levels of CRP,hs-CRP,ALT and AST of depressed patients in the relapse group were all higher than that in the non-depressed group,with statistically significant differences(P<0.05).Levels of serum AST,CRP and hs-crp were negatively correlated with DFS,and level of serum hs-CRP was negatively correlated with OS(P<0.05).Three months after surgery,the levels of NK cell in the depressed group were significantly lower than those in the non-depressed group,with a statistically significant difference(P<0.05).3.Analysis of gene expression profile characteristics related to HCC and depression: by comparing the gene expression profiles of surgical cancer tissue samples of patients in the two groups,a total of 286 differentially expressed genes were selected(P<0.05),among which 131 genes were up-regulated and155 genes were down-regulated.GO analysis and KEGG enrichment analysis of differentially expressed genes were conducted in the DAVID database.The differentially expressed genes were mainly involved in the body’s immunity,metabolism of three major nutrients and drug metabolism,among which the immune-related signaling pathway was the intestinal immune network signaling pathway that produced Ig A.The co-expression network of differentially expressed genes was analyzed by using STRING software,and it was found that the degrees of CXCL12,CXCR4,CXCL13,TIMP2,FOS,CD40 and CCL25 genes were relatively higher in the immune-regulation-related pathways.4.Relationship between the levels of liver cancer patients’ immune score and OS: the immune scores of liver cancer patients with different levels in the three groups were compared,and the difference was statistically significant(P <0.05).Survival analysis showed that there was no statistically significant difference between the low group and the high group,the middle group and the high group(P >0.05).However,the middle group was better than that in the low group,and the difference was statistically significant(P < 0.05).5.The relationship between depression-related differential genes and level s of immune score: depression-related differential genes were compared among the three groups,the expression of CXCR4 and CXCL13 genes were statistically significant(P<0.05).The expression of CXCL12 and FOS both in the low and middle groups and in the low and high groups were statistically significant(P <0.05).The expression of TIMP2 and CD40 both in the middle and high groups and in the low and high groups were statistically significant(P<0.05).CCL25 was only different between the low and high groups(P < 0.05).6.Relationship between depression-related differential genes and OS :Cox regression analysis showed that high level of FOS,CXCR4,CXCL13,CD40 expressions and low level of CXCL12 expression were independent risk factors for patients with liver cancer.The level of CCL25,TIMP2 expressions had no statistically relationship with OS of liver cancer patients(P > 0.05).Conclusions1.Child-puph,BCLC stage and depression were independent risk factors for the prognosis of HCC.Depression can mediate the increased levels of serum CRP and hs-CRP and the decreased level of NK cells in patients with HCC to reduce the immune function of the body and enhance the inflammatory response,leading to the aggravation of liver function injury,causing adverse effects on the prognosis of patients with HCC.2.Depression affects the tumor microenvironment by regulating the changes of gene expressions in the liver tumor tissues.The process is related to the changes in gene expression at multiple levels such as immunity,metabolism of three major nutrients and drug metabolism,among which the intestinal immune network signaling pathway producing Ig A may play an important role.3.Depression can up-regulate CXCL12,CXCR4,CXCL13 and CD40 genes,down-regulate TIMP2,FOS and CCL25 genes,causing dysregulation of the secretion of inflammatory factors in the micro-environment of tumor tissue,to inhibit tumor immunity,and affect the prognosis of patients.The results provide a theoretical basis for the formulation of individualized and targeted precise nursing measures for patients with HCC and promote the development of liver cancer nursing discipline. |
PDF Full Text Request