Effect Of Long-chain Non-coding RNA-FENDRR On Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma(HCC)is a common primary liver malignancy,while its incidence is increasing globally,including in developed countries.Through the development of hepatic inflammation and fibrosis,HCC mediates liver damage,which ultimately leads to liver structural dysfunction in cirrhosis.Dysplastic lesions(<1 mm)and dysplastic nodules(DNs)(?1 mm)are considered precancerous lesions.HCC exhibits different morphological subtypes,including hepatocytes and cholangiocarcinoma(4-5%),pseudo-core hepatocellular carcinoma,clear cell HCC,fibrin layer HCC,granulocyte colony-stimulating factor HCC,neutral granules,cell infiltrates,lymphocyte-rich HCC,combined dual phenotype HCC,mucin-like HCC,sarcomatoid HCC,hard liver HCC,and fatty liver HCC.Recurrent somatic mutations in specific genes are recognized as potential drivers of carcinogenesis,and the underlying cause of liver cancer appears to influence the occurrence of specific mutations.There are many factors that affect the pathogenesis and regulation of hepatocellular carcinoma,including both coding and non-coding RNA.Among them,long non-coding RNAs(lncRNAs)are a gene of more than 200 nucleotides,and their differential expression affects cell growth and differentiation,and plays a significant role in chromatin organization and regulation.Many lncRNAs have recently been identified with the help of high throughput sequencing and microarrays.Most of them are abnormally expressed in tumors such as HCC,breast cancer,lung cancer,and colorectal cancer.A large number of studies have shown that FENDRR plays an important regulatory role in the development of HCC.Therefore,we explore the molecular mechanism of the regulation of FENDRR in HCC through comprehensive analysis,and provide a more solid theoretical basis for follow-up research and clinical diagnosis.Research content1.lncRNA involved in the regulation of the progression of hepatocellular carcinoma:Based on the sequencing data of two sets of hepatocellular carcinoma samples in the GEO database,this study explored the differential expr ession of lncRNA during the development and progression of hepatocellular carcinoma,and then verified the changing expression of key IncRNA via qPCR We used the online software STRING(https://string-db.org/)to find the interaction between the target genes of the predicted key genes,and applied the "string APP" in Cytoscape to create an interactive network diagram.The candidate lncRNA-related target genes were uploaded to the DAVID Online Bioinformatics Analysis Tool(http://david.abcc.ncifcrf.gov/)for GO functional annotation and KEGG pathway analysis.2.Further identication of the regulation mechanism of FENDRR hepatocellular carcinoma based on TCGA database:This study used the TCGA database to screen differentially expressed mRNA between hepatocellular carcinoma tissues and paracancerous tissues,and then identified target genes for FENDRR among these mRNA.Subsequently,four stages of hepatocellular carcinoma-associated mRNA were screened and matched to the target gene of FENDRR.The target gene for FENDRR associated with HCC development was finally screened.We performed enrichment analysis to these genes in order to identify the molecular regulatory mechanisms of FENDRR.Then,the target gene was divided into co-expression modules by co-expression analysis,and the module's hub gene was screened and identified as the core regulator of FENDRR.The survival analysis of hepatocellular carcinoma-related prognosis of hub gene was performed.3.CeRNA mechanism formed by FENDRR regulating the development of hepatocellular carcinoma:This study established the ceRNA network with the relationship between FENDRR and miRNA and the targeted regulation of miRNA and mRNA in hepatocellular carcinoma in GEO and TCGA databases,and screened as well as verified the genes of four different periods of HCC involved FENDRR-related ceRNA networks.Results1.lncRNA involved in the regulation of the progression of hepatocellular carcinoma:In the HCC data of GSE115018,200 significantly differentially expressed lncRNAs were screened,including 129 up-regulated lncRNAs and 71 down-regulated lncRNAs.775 significantly differentially expressed lncRNAs were screened from the HCC data of GSE98269,including 507 up-regulated lncRNAs and 268 down-regulated lncRNAs.Among them,the difference in FENDRR is the most significant.QPCR experiments Verified that FENDRR was indeed lowly expressed in hepatocellular carcinoma tissues.We performed a predictive analysis of the downstream target genes regulated by FENDRR to obtain 2251 target genes,And further enrichment analysis to module gene by PPI clustering into 5 interaction modules,finding that most biological functions and signaling pathways in which FENDRR target genesparticipated,were related to the progression of hepatocellular carcin oma.2.Further identification of the regulation mechanism of FENDRR hepatocellular carcinoma based on TCGA database:According to transcriptome sequencing of hepatocellular carcinoma and paracancerous tissues in the TCGA database,a total of 10821 mRNAs were related to cancer,and 1207 of these genes belong to the gene regulated by FENDRR.There 11,414 genes were related to stage I including 1221 target genes of FENDRR;11948 genes were related to stage II including 1289 target genes;11827 genes are related to phase III,including 1286 target genes,7534 genes were related to stage IV including 910 FENDRR target genes.Enrichment analysis found that these genes are mainly involved in the metabolism of organisms,biological functions,ECM receptor interactions,TGF-beta signaling pathways and PPAR signaling pathways.Some genes are regulated by methylation and exhibit high and low expression.WGCNA analysis clustered these genes into two co-expression modules,and the module's hub gene was associated with prognosis in HCC patients.3.CeRNA mechanism formed by FENDRR regulating the development of hepatocellular carcinoma:After a series of data and predictive analysis,in the ceRNA network,19 target genes regulated by FENDRR were obtained,which had significant regulatory effects on HCC.Among them,14 genes exist in the 4 developmental period of hepatocellular carcinomas while 4 genes exist both in the first and third periods,and PPM1 E exists in the second period,which indicates that the ENDRNA network of FENDRR also has a certain influence on the different stages of HCC.ConclusionsIn conclusion,in this study we explored the molecular regulation mechanism of lncRNA FENDRR related to HCC from two large databases,enriched the understanding and direction of lncRNA regulation of HCC disease progression,and underlied a new theoretical foundation and experimental target for the regulation mechanism of HCC staging through the identification and analysis of FENDRR-related ceRNA.