Medication Rule And Action Mechanism Of Traditional Chinese Medicine In The Treatment Of Advanced Gastric Cancer Based On Data Mining Combined With Gene Chip

Objective:Firstly,The study screened out the beneficiaries of the combination of traditional Chinese and Western medicine in the treatment of advanced gastric cancer,and used data mining technology to explore the rule of traditional Chinese medicine prescription for patients with advanced gastric cancer,so as to provide theoretical basis for clinical rational drug use of advanced gastric cancer;Secondly,network pharmacology combined with gene chip technology was used to predict the action mechanism of core drugs in the treatment of gastric cancer,and further explored the correlation between key targets and the prognosis of gastric cancer,so as to open up a new way for the research and development of new drugs for gastric cancer.Methods:Collecting and sorting out patients with advanced gastric cancer in Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine and Cancer Hospital of Huanxing Chao Yang District Beijing from January,2015 to January,2020,and screening the beneficiaries of advanced gastric cancer with integrated traditional Chinese and Western medicine treatment.The definition of the beneficiary population was based on the beneficiary population of the advanced gastric cancer treated with integrated traditional Chinese and Western medicine in the previous Capital Health Development Research Project(Number:2016-1-4171),that was,patients with stage IV survival time ? 11.1 months.The pathological diagnosis refered to the definition of gastric cancer in the WHO(2019)Classification of Digestive System Tumors,and the clinical staging refered to the International Union Against Cancer(UICC)and American Cancer Union(AJCC)gastric cancer TNM staging(8th edition,2016)standards.Finally,135 patients were included,and information such as gender,age,BMI,KPS score and specific prescriptions were collected.TCMICS V3.0 was used to analyze the frequency,four Qi,five flavors,meridian tropism,efficacy and association rules of included prescription drugs,and finally the core drug combination was obtainedAccording to the core drug combination based on the above results,TCMSP database and literature database were searched to obtain the active ingredients,and the potential targets of active compounds were predicted through PubChem database and Swiss target prediction platform.At the same time,the active ingredient targets in TCMSP database were combined to obtain the final drug targets.In this study,the gastric cancer gene chip in the GEO database was used to obtain disease targets,and the Venn online database was used to obtain common targets for drugs and diseases.The PPI network of target was obtained by using String database.The visualization network was constructed by using Cytoscape 3.8.1,and the core target was screened by using its MCODE and BisoGenent plug-in.GO and KEGG enrichment analysis of the common target was carried out by R software.Finally,the Oncomine and Kaplan-Meier Plotter databases were used to explore the expression of key targets in gastric cancer and its relationship with gastric cancer survival.Results:Among the 135 patients included,81 were males,accounting for 60%,54 were females,accounting for 40%,and the ratio of men to women was 3:2.The maximum age is 85 years old,the youngest age is 26 years old,the average age is 59.33 years old,the median age is 59 years old,more than 85%of patients are over 50 years old.The minimum BMI is 12.33kg/m2,the maximum BMI is 33.23kg/m2,and the average of BMI is 21.13kg/m2.The BMI value of more than 50%of patients is within the normal range.Among the 135 patients,there were 127 patients with a KPS score of 70 and above,accounting for 94.07%of the total.Drug statistics showed that the 135 prescriptions involved 251 traditional Chinese medicines.The frequency of the drugs in descending order was Astragalus,Codonopsis,Pinellia,Tangerine Peel,Poria,Gallus gallus,Atractylodes,Licorice,Shenqu,Malt,and so on.The proportions of the four qi in descending order are warm,calm,cold,cool and hot,of which warm,calm and cold account for 94.38%.The proportion of five flavors from high to low is sweet,bitter,pungent,sour and salty,of which sweet,bitter,and pungent account for 90.41%.The spleen meridian(22.47%)accounted for the highest proportion of the meridians,followed by lung(16.86%),stomach(15.78%),liver(13.68%),kidney(10.46%).The efficacy of the medicine is mainly to invigorate the deficiency type,supplemented by the qi-regulating type,the heat-clearing type,and the digestion type.The drug combination is analyzed,and the more frequent drug combinations are Astragalus and Pinellia,Astragalus and Codonopsis,Codonopsis and Pinellia ternata,Codonopsis and Tangerine peel,and so on.According to the cluster analysis,135 prescriptions were divided into three categories.The first category contained 72 similar prescriptions mainly containing Astragalus,Codonopsis,Pinellia Ternata,Tangerine Peel and Poria Cocos,the second category contained 33 similar prescriptions mainly containing Astragalus,Codonopsis,Tangerine peel,Pinellia ternata and Atractylodes macrocephala,and the third category contained 30 similar prescriptions mainly containing Astragalus,Jinejin,Liquorice,Malt and Caulis Spatholobi.Combined with drug frequency,association rules and cluster analysis,it was found that "Astragalus-Codonopsis-Tangerine Peel-Pinellia Ternata-Poria" was the core drug combination of 135 prescriptions.In this study,77 active ingredients of "Astragalus-Codonopsis-Tangerine Peel-Pinellia Ternata-Poria" were found,including 23 from Astragalus,20 from Codonopsis,6 from Tangerine Peel,12 from Pinellia Ternata,14 from Poria,1 from Codonopsis and Pinellia Ternata,1 from Astragalus and Poria.Among them,quercetin,isorhamnetin,kaempferol and Jaranol in Astragalus,luteolin in Codonopsis,and baicalein in Pinellia,Hesperetin and naringenin in Tangerine Peel,and 16?-Hydroxydehydrotrametenolic acid in Poria are the main effective ingredients in the treatment of gastric cancer.Taking gastric cancer sample tissues from the GSE63089 and GSE118916 datasets in the GEO database as the research object,a total of 520 differential genes for gastric cancer were obtained,including 366 up-regulated genes and 154 down-regulated genes.58 common targets for drugs and gastric cancer were obtained from the Venn database,among which NTRK1,TP53,MCM2,CUL3,CDK2,FN1,ESR1,ITGA4,UBC,NPM1,CUL1 and so on are the key targets.GO functions involved in 58 common targets are mainly involved in extracellular matrix metabolism,DNA signal transduction,regulation of mitosis,metalloendopeptidase activity,oxidoreductase activity,chromosome structure and other processes.KEGG pathway is mainly related to cell cycle and cell senescence,p53 signaling pathway,AGE-RAGE signaling pathway in diabetic complications and so onIn oncomine database,there were 10 studies involving 928 samples(500 cases and 428 cases of gastric cancer and normal tissue respectively).The study found that the expression of NTRK1 in gastric cancer tissue and normal tissue was significantly different(P<0.05).In 7 studies involving 291 samples(205 cases and 86 cases of gastric cancer and normal tissues respectively),the study found that the expression difference of TP53 in gastric cancer tissue and normal tissue was statistically significant(P<0.05).12 studies involving 1274 samples(694 cases and 580 cases of gastric cancer and normal tissue respectively),the study found that the expression difference of MCM2 in gastric cancer tissue and normal tissue was statistically significant(P<0.05).In addition,the Kaplan-Meier Plotter database found that the Overall Survival(OS)and First Progression(FP)of the NTRK1,TP53 and MCM2 high expression group were lower than the low expression group,and the differences were statistically different(P<0.05).Conclusions:The traditional Chinese medicine prescription of advanced gastric cancer mainly includes invigorating the spleen and replenishing qi,regulating qi and resolving phlegm,supplemented by clearing away heat and dampness,invigorating the spleen and eliminating food,promoting blood circulation,removing blood stasis and so on.The core prescription is"Astragalus-Codonopsis-Tangerine Peel-Pinellia Ternata-Porian" which reflects the important pathogenesis of "spleen and stomach weakness" of advanced gastric cancer."Astragalus-Codonopsis-Tangerine Peel-Pinellia Ternata-Poria" regulates NTRK1,TP53,MCM2,CUL3 CDK2 and so on through active ingredients such as quercetin,isorhamnetin,kaempferol,luteolin,baicalein,hesperetin,naringenin and so on.At the same time,key targets are involved in the regulation of tumor cell cycle,inflammation and other processes,and regulate cell cycle,p5 3 signaling pathway,AGE-RAGE signaling pathway in diabetic complications,TNF signaling pathway,etc.to play an anti-gastric cancer effect.NTRK1,TP53,and MCM2 are all highly expressed in gastric cancer tissues.The higher the expression level of the them,the shorter the survival time of gastric cancer patients.On the contrary,the lower the expression level,the longer the survival time of patients.