Study On The Key Molecules Affecting Liver Metastasis Of Pancreatic Cancer And The Mechanism Of Mistletoe Anti Metastasis Based On Systematic Pharmacology

Background: pancreatic cancer is a malignant tumor with a high mortality rate.The 5year survival rate is less than 5%,and the incidence of liver metastases is more than 50%.Liver metastasis of pancreatic cancer is the result of interaction and regulation of multiple genes,transcripts and proteins.The development of modern multi group technology provides a solid foundation for further studying the molecular mechanism of liver metastasis of pancreatic cancer,and also helps modern medicine understand the mechanism of liver metastasis from pancreatic cancer at molecular mechanism level,thus improving the prevention and treatment of liver metastases from pancreatic cancer.Mistletoe,first published in Shennong herbal classic,has the functions of tonifying liver and kidney,strengthening muscles and bones,dispelling wind and dampness,dredging meridians,eliminating carbuncle and detoxification,and benefiting blood.Studies have shown that mistletoe venom,plant agglutinin,polysaccharides,alkaloids,polyphenols and flavonoids can play an anti-cancer role in mistletoe,but mistletoe is less effective in the treatment of liver metastases from pancreatic cancer.This study is divided into two parts.Part 1 Objective: the purpose of this study was to establish the liver metastasis related gene prognostic index(lmpi)of pancreatic ductal adenocarcinoma(PAAD),and to reveal the molecular and immune characteristics of PAAD subgroup defined by lmpi and the benefits of immunotherapy.Methods: Based on the PAAD data set of cancer genome map(n = 170),the hub gene related to liver metastasis was identified by weighted gene coexpression network analysis.Five genes were identified by Cox regression method to construct lmpi and verified.Subsequently,the molecular and immune characteristics of lmpi defined subgroups and the benefits of immunotherapy were analyzed.Functional analysis showed that 78 hub liver metastasis related genes in black module were significantly enriched in complement and coagulation cascade,retinol metabolism,steroid hormone biosynthesis,fat digestion and absorption and PPAR signaling pathway.Then,lmpi was constructed based on five prognostic genes(mogat3,asgr1,TRPM8,sgsm1 and loc101927851).Results: compared with patients in lmpi low-risk group,patients in lmpi high-risk group had lower overall survival rate,more driver gene mutations occurred simultaneously or mutually exclusive,and less benefits of immunotherapy.In addition,high lmpi score was associated with high permeability of Th17;Low irgpi scores were associated with high infiltration of CD4 naive cells,CD8 T cells,TC,Th2,TFH,TGD and NK cells.Conclusion: lmpi is an independent prognostic index to distinguish the prognosis,molecular and immune characteristics of PAAD and immunotherapy.Part 2 Objective: To study the main active components,targets and pathways of mistletoe in the treatment of liver metastases from pancreatic cancer by using network pharmacology.Methods: firstly,the components of various traditional Chinese medicines in the compound were searched in tcmsp,ETCM and other databases.Further,with ESOL class and silicon it class as above solid,GI absorption as high,in line with Lipinski principle as the threshold,the effective active components were screened,and the corresponding action targets of each active component were searched in tcmsp.The target of the obtained mistletoe was uploaded to the HM vs.PT and PT vs.N differential genes obtained from the GSE151580 data.The data were uploaded to the VENNY database,and the database was analyzed to obtain the common target map of mistletoe with pancreatic cancer with liver metastasis and without metastasis of the pancreatic cancer.The Wayne plot was obtained.For the common targets of the three,go function enrichment analysis and KEGG pathway enrichment analysis were performed in David database.The common target of uploading mistletoe with pancreatic cancer with liver metastasis and without metastasis was STRING database,with a set reliability score > 0.4,and a protein interaction network diagram(PPI network diagram)was obtained.A network graphical tool,Cytoscape 3.6.0,was used to map the relationship between mistletoe and the common target of pancreatic cancer with liver metastasis and without metastasis of the pancreatic cancer.Use autodock software to do molecular docking for common targets and their corresponding components.Swissadme was used to analyze 30 active components in mistletoe and their pharmacokinetic parameters.Results: 30 effective components of mistletoe were screened out.60 common targets of mistletoe and pancreatic cancer liver metastasis and pancreatic cancer were obtained.GO functional enrichment analysis and KEGG pathway analysis showed that the target of mistletoe was mainly related to biological oxidation,pancreatic secretion,peanut four acid metabolism,the activity of the active ligand receptor interaction and porphyrin metabolism.Conclusion: through the network pharmacological study of mistletoe,we found that mistletoe is an important active ingredient,target protein and signal pathway in the treatment of pancreatic cancer with liver metastasis,which provides an important basis for further exploration of mistletoe in the treatment of pancreatic cancer.