Abstract:

Objective To screen for regulatory cell death and senescence genes with differential prognostic significances in the gastric cancer through bioinformatics methods， and to analyze the effect of phosphodiesterase 1B （PDE1B） on the survival prognosis of the gastric cancer patients. Methods The gastric cancer gene expression data and clinical data were downloaded from the TCGA Public Database.Fifty gastric cancer patients were randomly selected from the local database， and their clinical informations and paraffin samples， including gastric cancer tissue and adjacent normal tissue， were collected. The R software “limma” package was used to screen differentially expressed genes （DEGs）； univariate COX analysis and Kaplan-Meier survival analysis were used to screen DEGs with predictive survival value. The intersection genes affecting the survival prognosis of gastric cancer patients were obtained， and the gene most associated with clinical pathological features PDE1B was screened. The TCGA Database and Kaplan-Meier survival analysis were used to detect the expression levels of PDE1B mRNA in adjacent normal and gastric cancer tissues and their relationships with survival period of the gastric cancer patients. Gene Ontology （GO） functional and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analyses were used to enrich the biological functions of PDE1B. The CIBERSORT algorithm， Tumor Immunity Database （TISIDB）， and GSCA online website were used to analyze the correlation between PDE1B and tumor microenvironment， immune characteristic molecules， and drug sensitivity. The real-time fluorescence quantitative PCR （RT-qPCR） method was used to detect the PDE1B mRNA expression levels in gastric cancer tissue and adjacent normal tissue of the gastric cancer patients. Results A total of 716 DEGs were screened， among which 505 DEGs were upregulated （P<0.05）， and 211 DEGs were downregulated （P<0.05）. There were 10 intersection genes affecting survival prognosis.The PDE1B mRNA expression level was most closely related to the clinical pathological characteristics of the gastric cancer patients， being associated with age， tumor grade， tumor stage， and tumor T， N， and M stages （P<0.05）. Compared with G1-G2， StageⅠ， T1-T2， N0， and M0 stage gastric cancer patients，the PDE1B mRNA expression levels in G3-G4， StageⅡ-Ⅳ， T3-T4， N1-N3， and M1 stage gastric cancer patients were significantly increased （P<0.05）. Compared with adjacent normal tissue， the PDE1B mRNA expression level in gastric cancer tissue was significantly decreased （P<0.05）. Compared with the patients with low PDE1B expression， the patients with high PDE1B expression had a significantly lower overall survival rate （P<0.01）. PDE1B expression， age， and tumor stage were the risk factors for the prognosis of gastric cancer patients （P<0.05）. After adjusting for gender， age， tumor grade， and tumor stage， PDE1B expression was an independent risk factor affecting the prognosis of the gastric cancer patients （P<0.05）. PDE1B was mainly enriched in the biological process（BP）， such as immunoglobilin production， second-messenger， mediated signaling transduction and calcium ion transport， cellular component（CC）， such as Tlymplocytes receptor complex， plasma membrance signaling receptor complex and collagen-containing extracellular matrix， and molecular function（MF）， such as antigen binding， glycosaminoglycan binding， and extracellular matrix structural constituents. PDE1B was mainly involved in the pathways such as neuroactive ligand-receptor interaction， calcium signaling pathway， cGMP-PKG signaling pathway， and cytokine-cytokine receptor interaction. PDE1B was positively correlated with regulatory T lymphocytes （r=0.488）， myeloid-derived suppressor cells （r=0.474）， and macrophages （r=0.617） （P<0.01）. Compared with the patients with low PDE1B expression， the patients with high PDE1B expression promoted the significant increase of infiltration of regulatory T lymphocytes， monocytes， and M2 macrophages （P<0.05）. The PDE1B mRNA expression levels were positively correlated with the immunosuppressive agents transforming growth factor-β1 （TGF-β1） （r=0.535）， colony-stimulating factor 1 receptor （CSF1R） （r=0.519）， immune activator ectonucleoside triphosphate diphosphohydrolase 1 （ENTPD1） （r=0.593）， and CXC chemokine ligand 12 （CXCL12） （r=0.646） （P<0.01）. The gastric cancer tissue with high PDE1B expression was more sensitive to the drugs such as fluorouracil （-0.3<r <-0.1）， methotrexate （-0.3<r <-0.1）， and decitabine （-0.3<r <-0.1） （P<0.05）. Compared with adjacent normal tissue， the PDE1B mRNA expression levels in gastric cancer tissue were significantly decreased （P<0.01）. Compared with low PDE1B expression group， the overall survival rate patients in of the high PDE1B expression group had a significantly lower was decreased（P<0.05）.Compared with T1-T2 stage gastric cancer patients， the PDE1B mRNA expression level of the T3-T4 stage gastric cancer patients was significantly increased （P<0.01）. Conclusion PDE1B is an independent risk factor for the prognosis of the gastric cancer patients and can serve as an effective indicator of poor prognosis of gastric cancer.

Key words: Stomach neoplasm, Survival prognosis, Phosphodiesterase 1B, Tumor microenvironment, Drug sensitivity