A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs
BackgroundNecroptosis is a form of regulatory cell death (RCD) that attracts and activates immune cells, resulting in pro-tumor or anti-tumor effects. The purpose of this study was to investigate genes associated with necroptosis, to construct a risk score for predicting overall survival in patients...
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.870264/full |
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| author | Zedong Li Zedong Li Jianyu Fang Sheng Chen Hao Liu Jun Zhou Jiangsheng Huang Sushun Liu Yu Peng |
| author_facet | Zedong Li Zedong Li Jianyu Fang Sheng Chen Hao Liu Jun Zhou Jiangsheng Huang Sushun Liu Yu Peng |
| author_sort | Zedong Li |
| collection | DOAJ |
| description | BackgroundNecroptosis is a form of regulatory cell death (RCD) that attracts and activates immune cells, resulting in pro-tumor or anti-tumor effects. The purpose of this study was to investigate genes associated with necroptosis, to construct a risk score for predicting overall survival in patients with hepatocellular carcinoma, and to find potentially effective drugs.MethodsThe three algorithms ssGSEA, EPIC, and ESTIMATE were used to quantify the immune cell infiltration of the samples, differentially expressed genes (DEGs) analysis, and weighted gene co-expression network analysis were used to screen necroptosis related genes. Variables were screened according to random survival forest analysis, and combinations with significant p-values and a low number of genes were defined as prognostic signatures by using log-rank test after gene combination. Based on the sensitivity data of PRISM and CTRP2.0 datasets, we predicted the potential therapeutic agents for high-NRS patients.ResultsSeven genes such as TOP2A were used to define necroptosis-related risk score (NRS). The prognostic value of risk score was further validated, where high NRS was identified as a poor prognostic factor and tended to have higher grades of histologic grade, pathologic stage, T stage, BCLC, CLIP, and higher AFP. Higher NRS was also negatively correlated with the abundance of DCs, Neutrophils, Th17 cells, Macrophages, Endothelial, and positively correlated with Th2 cells. Necroptosis is often accompanied by the release of multiple cytokines, and we found that some cytokines were significantly correlated with both NRS and immune cells, suggesting that necroptosis may affect the infiltration of immune cells through cytokines. In addition, we found that TP53 mutations were more common in samples with high NRS, and these mutations may be associated with changes in NRS. Patients with high NRS may be more sensitive to gemcitabine, and gemcitabine may be an effective drug to improve the prognosis of patients with high NRS, which may play a role by inhibiting the expression of TOP2A.ConclusionsWe constructed a necroptosis-related scoring model to predict OS in HCC patients, and NRS was associated with immune response, TP53 mutation, and poor clinical classification in HCC patients. In addition, gemcitabine may be an effective drug for high-NRS patients. |
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| institution | Directory Open Access Journal |
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| language | English |
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| publishDate | 2022-03-01 |
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| spelling | doaj.art-be0f9277d4d441d7b18c587e4f9072b62022-12-22T00:03:56ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-03-011310.3389/fimmu.2022.870264870264A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic DrugsZedong Li0Zedong Li1Jianyu Fang2Sheng Chen3Hao Liu4Jun Zhou5Jiangsheng Huang6Sushun Liu7Yu Peng8Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, ChinaClinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, ChinaBackgroundNecroptosis is a form of regulatory cell death (RCD) that attracts and activates immune cells, resulting in pro-tumor or anti-tumor effects. The purpose of this study was to investigate genes associated with necroptosis, to construct a risk score for predicting overall survival in patients with hepatocellular carcinoma, and to find potentially effective drugs.MethodsThe three algorithms ssGSEA, EPIC, and ESTIMATE were used to quantify the immune cell infiltration of the samples, differentially expressed genes (DEGs) analysis, and weighted gene co-expression network analysis were used to screen necroptosis related genes. Variables were screened according to random survival forest analysis, and combinations with significant p-values and a low number of genes were defined as prognostic signatures by using log-rank test after gene combination. Based on the sensitivity data of PRISM and CTRP2.0 datasets, we predicted the potential therapeutic agents for high-NRS patients.ResultsSeven genes such as TOP2A were used to define necroptosis-related risk score (NRS). The prognostic value of risk score was further validated, where high NRS was identified as a poor prognostic factor and tended to have higher grades of histologic grade, pathologic stage, T stage, BCLC, CLIP, and higher AFP. Higher NRS was also negatively correlated with the abundance of DCs, Neutrophils, Th17 cells, Macrophages, Endothelial, and positively correlated with Th2 cells. Necroptosis is often accompanied by the release of multiple cytokines, and we found that some cytokines were significantly correlated with both NRS and immune cells, suggesting that necroptosis may affect the infiltration of immune cells through cytokines. In addition, we found that TP53 mutations were more common in samples with high NRS, and these mutations may be associated with changes in NRS. Patients with high NRS may be more sensitive to gemcitabine, and gemcitabine may be an effective drug to improve the prognosis of patients with high NRS, which may play a role by inhibiting the expression of TOP2A.ConclusionsWe constructed a necroptosis-related scoring model to predict OS in HCC patients, and NRS was associated with immune response, TP53 mutation, and poor clinical classification in HCC patients. In addition, gemcitabine may be an effective drug for high-NRS patients.https://www.frontiersin.org/articles/10.3389/fimmu.2022.870264/fullnecroptosishepatocellular carcinomagemcitabineTOP2Aregulated cell death |
| spellingShingle | Zedong Li Zedong Li Jianyu Fang Sheng Chen Hao Liu Jun Zhou Jiangsheng Huang Sushun Liu Yu Peng A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs Frontiers in Immunology necroptosis hepatocellular carcinoma gemcitabine TOP2A regulated cell death |
| title | A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs |
| title_full | A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs |
| title_fullStr | A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs |
| title_full_unstemmed | A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs |
| title_short | A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs |
| title_sort | risk model developed based on necroptosis predicts overall survival for hepatocellular carcinoma and identification of possible therapeutic drugs |
| topic | necroptosis hepatocellular carcinoma gemcitabine TOP2A regulated cell death |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.870264/full |
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