Screening Prognostic Markers For Hepatocellular Carcinoma Based On Pyroptosis-Related And Necroptosis-Related LncRNA

Objective:Pyroptosis and necroptosis are two different processes of pro-inflammatory cell death.In cancer patients,they could influence cancer prognosis and treatment by affecting the immune system.In this thesis,with hepatocellular carcinoma(HCC)as a research object,we evaluated the prognostic prediction efficacy of pyroptosis-related lncRNAs(PRlncRNAs)and necroptosis-related lncRNAs(NRlncRNAs)by constructing individualized prognostic risk models based on the within-sample relative expression orderings(REOs)of PRlncRNAs and NRlncRNAs respectively.On this basis,we further explored the relationship between pyroptosis and necroptosis in cancer progression.Methods:In this thesis,with RNA sequencing data of 343 HCC samples downloaded from The Cancer Genome Atlas(TCGA)database as a research object,the dataset was firstly randomly divided into training and validation sets.Secondly,based on the expression levels of reported pyroptosis-related genes(PRGs)and necroptosis-related genes(NRGs)in the training set respectively,clustering analysis was performed to identify lncRNAs with differential expression levels between the sample sets with different expression patterns of PRGs and NRGs as PRlncRNAs and NRlncRNAs.Subsequently,based on the within-sample REOs of PRlncRNAs and NRlncRNAs respectively,the PRlncRNA pairs and NRlncRNA pairs associated with the prognosis of HCC were screened by Cox regression to construct an individualized prognostic risk model for predicting high-and low-risk groups for HCC,followed by gene set enrichment analysis,immune infiltration analysis and others to assess the differences in immune characteristics between high-and low-risk groups.Finally,the molecular mechanisms of the synergistic effect of pyroptosis and necroptosis were explored based on the expression levels of PRGs and NRGs and the PRlncRNA pair and NRlncRNA pair prognostic risk signatures in HCC.Results:In the training set,HCC samples could be significantly clustered into two categories based on the expression levels of genes in the PRG set.There was a significant difference between the overall survival time of two categories of samples(log-rank test,p = 0.026).A total of 104 lncRNAs(defined as PRlncRNAs)were significantly differentially expressed between the two categories of samples.Based on the REOs of PRlncRNAs within every training sample,83 PRlncRNA pairs with REOs significantly associated with HCC prognosis were screened.A prognostic risk model for HCC consisting of 11 PRlncRNA pairs was constructed by LASSO and stepwise Cox regression.The areas under the 1-,3-and 5-year time-dependent receiver operating characteristic curves of the model in the training and validation sets were 0.855,0.891,0.902 and 0.737,0.705,0.797,respectively.Based on the same approach,an HCC prognostic risk model consisting of 17 NRlncRNA pairs was constructed by the REOs of the 118 NRlncRNAs identified within every training sample.The model also had good prognostic ability for HCC.The areas under the 1-,3-and 5-year time-dependent receiver operating characteristic curves of the model in the training and validation sets were 0.852,0.898,0.913 and 0.705,0.767,0.718,respectively.Immune characteristics were significantly different between high-and lowrisk groups predicted for HCC patients based on both models,and immune escape was present in both high-risk groups.Meanwhile,significantly highly expressed PRGs and NRGs in high-risk group implied significant impacts of levels of both pyroptotic and necroptotic processes on the prognosis of HCC.Finally,clustering analysis based on the expression levels of PRGs and NRGs in HCC respectively revealed consistent clustering results in 77.8% of the samples(chi-square test,p < 0.0001).Meanwhile,co-expression of PRGs and NPGs occurred under the regulation of lncRNAs both present in both models,KB-68A7.1 and LINC01554.These results suggest that pyroptosis and necroptosis synergistically affect HCC prognosis.Conclusion:Both PRlncRNA-based and NRlncRNA-based HCC prognostic risk models have good predictive power.Pyroptosis and necroptosis can impact on the prognosis of HCC by affect immune system.Abnormal coexpression of pyroptosis-related and necroptosis-related genes may be caused by the same lncRNAs.The results of this thesis provide a theoretical reference to further explore the role of pyroptosis and necroptosis in the prognosis of HCC.