To Explore The Association Between Alzheimer’s Disease And Esophageal Cancer Using Transcriptomics Data

Objective: Objective: Although Alzheimer’s disease(AD)and esophageal cancer(EC)are two distinct diseases,some experimental and epidemiological evidences support that these two diseases are associated with each other.To the best of our knowledge,no research has been carried out to explore the potential link between EC and AD using the transcriptomics data so far.In this study,we use gene expression data and bioinformatics methods to investigate the relationship between AD and EC at the level of molecular and biological pathways.Methods:(1)The AD data(Accession No: GSE48350),including four regions(hippocampus,entorhinal cortex,superior frontal gyrus and postcentral gyrus),were downloaded from the GEO(Gene Expression Omnibus)database.Moderated t-tests were used to identify differentially expressed genes between the diseased group and control group,respectively in the four regions of brain.The EC data was downloaded from TCGA(The Cancer Genome Atlas)database and moderated t-tests were used to screen for differentially expressed genes between the tumor tissue and adjacent normal tissue.(2)The R cluster Profiler package was used to carry out pathway enrichment analysis upon identified differentially expressed genes of the two diseases.How the identified genes and pathways of the two diseases overlap were graphically illustrated by Venn diagrams.Through literature mining,we explored the expression regulation of shared pathways in the two diseases.After dividing the differentially expressed genes of Alzheimer’s disease and esophageal cancer into the up-regulated group(log2FC>0)and the down-regulated group(log2FC<0),the R cluster Profiler package was used for enrichment analysis again.Results:(1)In AD dataset,it is found that the hippocampus has the largest number of differentially expressed genes with 3277,28 in the entorhinal cortex,60 in the postcentral gyrus,and 114 in the superior frontal gyrus.The pathological changes of AD mainly occur in the hippocampus,so the differentially expressed genes in the hippocampus are viewed as a focused dataset of AD in this study.In EC dataset,there are 2414 differentially expressed genes.There are 429 shared differentially expressed genes,of which HRAS,CCNB1 and TPI1 have been reported to be associated with AD and EC.HRAS is mutated in esophageal cancer to initiates RAS and cell cycle re-enter,but HRAS is highly expressed in AD.CCNB1,a marker of the G2/M phase of the cell cycle,is low expression in AD,but highly expressed in EC.TPI1,promoting glucose metabolism,is mutated and low expression in AD brain,but highly expressed in EC.(2)The differentially expressed genes of AD and EC are both enriched in 4KEGG pathways and 159 shared GO function annotations(including 139 biological process(BP)terms,12 molecular function(MF)terms and 9 Cell component(CC)terms).PI3K/AKT,one of the KEGG pathways obtained by enrichment analysis,is inhibited when tau protein is highly phosphorylated,but it is activated in EC and promoted EC cell metastasis.There is a number of GO terms(such as GO:0051321,GO:0001844,GO:1900739)related to the cell cycle.Neurons(brain cells)in a physiological state are usually in a resting phase and do not enter the cell cycle.However,in AD,a large number of neurons apoptotic due to cell cycle disorders.Unlike AD,cancer cells in EC repeatedly enter the cell cycle uncontrollably and proliferate malignantly.(3)Given the manifestations of PI3K/AKT,cell cycle pathways and some genes directly related to AD and EC(such as HRAS,CCNB1,TPI1)are in opposite directions,we anticipate that AD and EC are negatively correlated.In order to test this hypothesis,the identified differentially expressed genes of AD and EC are divided into two groups — up-regulated and down-regulated,and then pathway enrichment analyses upon AD up-regulated group and EC down-regulated group,and AD down-regulated group and EC up-regulated group were carried out,respectively.The analysis results show that AD up-regulated differentially expressed genes and EC down-regulated differentially expressed genes shared 6 enriched KEGG pathways and 64 GO terms.In contrast,AD down-regulated differentially expressed genes and EC up-regulated differentially expressed genes shared 10 enriched KEGG pathways and 207 GO functional annotations,Among the shared GO terms,three of them(GO:0090263,GO:0035567,GO: 0060071)are related to the Wnt pathway.The Wnt pathway in AD brain is inhibited through a variety of pathogenic mechanisms,but it is activated to promote the development of EC.Conclusion: Using bioinformatics methods,we found that many overlapped differentially expressed genes(HRAS,CCNB1,TPI1,etc.)and enriched pathways(PI3K/AKT,cell cycle,Wnt pathway)were up-regulated(or activated)in one disease and down-regulated in the other(or inhibition).This provides some evidence to support an inverse association between AD and EC.Large-scale cohort studies and experimental validations are warranted.