Study Of The Correlation Between ITIH1 Expression And Prognosis In Hepatocellular Carcinoma

ObjectiveAlthough previous pan-cancer studies have reported patterns of ITIHs expression in a variety of cancers,their analysis was limited to a small number of tumor types.We thus comprehensively analyzed the expression profiles and clinical significances of ITIHs in a broader spectrum of cancers from TCGA.Methods1.The expression patterns of ITIHs in different tissues of healthy people were analyzed using RNA sequencing from the genotype-Tissue Expression Project（GTEx）、FANTOM5 and HPA database,The expression patterns of ITIHs in liver tissues of healthy people were analyzed using single-cell RNA sequencing,The expression patterns of ITIHs indifferent cancer cell lines was analyzed by RNA sequencing from the Encyclopedia of Cancer Cell Lines（CCLE）;2.Draw on the richness of pan-cancer datasets from the TCGA project,we compared ITIHs expression between tumor and adjacent normal tissue across 20 cancer types,including 7900 tumor samples and 724 normal tissue samples.Normal tissues from 27 tumor types in the GTEx dataset were used as controls and combined with the TCGA dataset.Using exo RBase,we further explored the expression pattern of ITIHs in human blood exosomes from the following specimens: normal person,coronary heart disease,colorectal cancer,hepatocellular carcinoma,pancreatic adenocarcinoma and whole blood;3.Using the “Stage Plot” module of GEPIA2 to investigate whether ITIHs expressions might differ between different pathologic stages in pan-cancers.Using the “Gene Outcome” module of TIMER2.0 to analyze the association between ITIHs expression and clinical outcomes across 33 cancer types;4.Moreover,we confirmed the remarkable downregulation of ITIH1 in hepatocellular carcinoma in five GEO datasets（GSE1898,GSE39791,GSE45436,GSE6764,and GSE84598）;5.Using c Bio Portal database to evaluate the gene characteristics of ITIH1 in cancer,Using the GSCA database,we further examined the correlation between ITIH1 DNA methylation and expression in pan-cancers.We used the “Gene” module of TIMER2.0 to explore the association between gene expression and immune response in TCGA datasets;6.We used the “Similar Gene Detection” module of GEPIA2 to derive genes that were co-expressed with ITIH1 based on TCGA pan-cancer datasets,and the genes with Pearson correlation coefficients more than 0.4 were considered most related to ITIH1,Next,we performed Gene Ontology（GO）analysis and Kyoto Encyclopedia of Genes and Genomes（KEGG）pathway analysis of ITIH1-related genes using the STRING database.ResultsOur results showed that ITIHs were primarily down-regulated in tested cancers;The ITIH members were associated with either survival advantage or disadvantage,depending on the cancer type tested and the genes queried;we for the first time demonstrated that ITIH1 had substantially decreased expression in liver hepatocellular carcinoma compared with corresponding normal tissue,and its down-regulation adversely impacted patient outcome,Moreover,ITIH1 expression was consistently declining during the progression of hepatocellular carcinoma;Through the analysis of epigenetic characteristics,the expression of ITIH1 was negatively correlated with DNA methylation,suggesting that the dysregulation of ITIH1 expression may be mediated partly by DNA methylation.Further analysis revealed that ITIH1 may be involved in cellular metabolic processes.ConclusionsOur findings established ITIH1 as a potential diagnostic and prognostic biomarker for hepatocellular carcinoma,clarify the functional role of ITIH1 in cancers,and suggest a strong correlation between ITIH1 expression and metabolic pathways.