Identification Of Transcriptional Dysregulation Mechanism And Novel Potential Prognositic Biomarker In Esophageal Cancer

Esophageal cancer(EC)is one of common digestive system malignancies worldwide,derived from the surface of esophagus mucous membrane,and mainly has two pathological types,esophageal adenocarcinoma(EAC)and esophageal squamous cell carcinoma(ESCC).EAC accounts for the most of EC in western countries,while ESCC is the predominate type in the developing countries,especially in China.The pathogenesis of EC is concealed,and it is usually detected in the middle-late stage,leading to the poor survival.Therefore,it is necessary to explore the molecular pathological mechanism of EC and identify an improved biomarker for predicting the prognosis of EC patients,which is able to give a survival benefit.Differential co-expression presents that the correlation between the expression levels of two genes is significantly different in disease and control samples,it is not only emerging to complement the shortage of different expression,but also can hint the altered regulatory relationships and cancer-specific dysregulations.Therefore,it is reliable to study the molecular biological mechanism of cancergenesis and identify cancer-related prognostic lncRNAs by using differential co-expression analysis.Firstly,the expression profile was used to identify an improved biomarker for predicting the prognosis of EAC.Differential co-expression analysis and differential expression analysis were performed to identify the EAC related genes.The 5-fold cross-validation was used to assess the prognostic performance of the genes.CRNKL1 was the best one,and could be regarded as a prognostic biomarker to predict the survival of EAC patients.It could significantly stratify EAC patients into high-risk and low-risk groups and was much better than the traditional biomarkers(PTGS2、EGFR、ERBB and TP53).Furthermore,ROC curve also verified that CRNKL1 with the best prognostic effectiveness by comparing with other biomarkers.Our research proposed that CRNKL1 might be a novel and improved prognostic biomarker of EAC,and provided the foundation for ESCC research.Secondly,in order to reveal the molecular biological mechanism of esophagus squamous cell cancergenesis,differential co-expression analysis was used to construct the differential co-expression mRNA-lncRNA network of ESCC,and by using the differentially co-expressed mRNA to construct the differential regulation network.The differential co-expression network presented that most of the gene pairs lost associations in the tumor tissues.The differential regulation network deciphered that transcriptional dysregulation was ubiquitous in ESCC,and most of the differentially regulated links were losing regulation.The differential regulation network was modulated by 37 TFs,among them,TCF3 and TP53 were two critical TFs in ESCC and contributed more than a quarter of loss-of-regulation DRLs.Therefore,the TF was a critical class of regulatory factor in the development of ESCC,and hinted the importance of differentially co-expressed lncRNAs in ESCC.Finally,our study used the differential co-expressed lncRNAs to identify the prognostic lncRNA.The relationship between the lncRNAs and well-known cancer genes and differential expression analysis were performed to filter the differential co-expressed lncRNAs.5-fold cross-validation was used to assess the performance of the prognostic models,and identified two novel lncRNAs(ADAMTS9-AS1 & AP000696.2),which could significantly stratify ESCC patients into high-risk and low-risk groups,and the changes of TF-target regulation in the high-risk patients were significantly higher than that in the low-risk patients.The further study found that they might be essential in the development of ectoderm and epithelial cells,and not only with better prognostic effectiveness than traditional clinical tumor markers(CYFRA21-1,CEA),but also differentially co-expressed with four signal transduction related DCmRNAs(ERBB3,ENSA,KCNK7,MFSD5),which might also associate with the survival of ESCC patients.Our findings proved that the two-lncRNA combination might serve as a novel prognostic biomarker for the prediction of ESCC.In conclusion,we systematically analyzed the expression profile of EC by using differential co-expression analysis,and verified that the abnormal expression of genes was induced by transcriptional dyregulation in EC,and identified a novel EC prognostic biomarker.They did not only play a critical role in EC progression,but also with better predictive ability than traditional EC biomarkers,which might be a new molecular target for predicting and treating EC patients.