Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma
BackgroundTreatment of cancer with pyroptosis is an emerging strategy. Molecular subtypes based on pyroptosis-related genes(PRGs) seem to be considered more conducive to individualized therapy. It is meaningful to construct a pyroptosis molecular subtypes-related prognostic signature (PMSRPS) to pre...
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| Format: | Article |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1111494/full |
| _version_ | 1811173341281648640 |
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| author | Qian Huang Qian Huang Xingyu Peng Qingqing Li Qingqing Li Jinfeng Zhu Ju Xue Hua Jiang Hua Jiang |
| author_facet | Qian Huang Qian Huang Xingyu Peng Qingqing Li Qingqing Li Jinfeng Zhu Ju Xue Hua Jiang Hua Jiang |
| author_sort | Qian Huang |
| collection | DOAJ |
| description | BackgroundTreatment of cancer with pyroptosis is an emerging strategy. Molecular subtypes based on pyroptosis-related genes(PRGs) seem to be considered more conducive to individualized therapy. It is meaningful to construct a pyroptosis molecular subtypes-related prognostic signature (PMSRPS) to predict the overall survival (OS) of patients with pancreatic adenocarcinoma(PAAD) and guide treatment.MethodsBased on the transcriptome data of 23 PRGs, consensus clustering was applied to divide the TCGA and GSE102238 combined cohort into three PRGclusters. Prognosis-related differentially expressed genes(DEGs) among PRGclusters were subjected to LASSO Cox regression analysis to determine a PMSRPS. External cohort and in vitro experiments were conducted to verify this PMSRPS. The CIBERSORT algorithm, the ESTIMATE algorithm and the Immunophenoscore (IPS) were used to analyze the infiltrating abundance of immune cells, the tumor microenvironment (TME), and the response to immunotherapy, respectively. Wilcoxon analysis was used to compare tumor mutational burden (TMB) and RNA stemness scores (RNAss) between groups. RT-qPCR and in vitro functional experiments were used for evaluating the expression and function of SFTA2.ResultsBased on three PRGclusters, 828 DEGs were obtained and a PMSRPS was subsequently constructed. In internal and external validation, patients in the high-risk group had significantly lower OS than those in the low-risk group and PMSRPS was confirmed to be an independent prognostic risk factor for patients with PAAD with good predictive performance. Immune cell infiltration abundance and TME scores indicate patients in the high-risk group have typical immunosuppressive microenvironment characteristics. Analysis of IPS suggests patients in the high-risk group responded better to novel immune checkpoint inhibitors (ICIs) than PD1/CTLA4. The high-risk group had higher TMB and RNAss. In addition, 10 potential small-molecule compounds were screened out. Finally, we found that the mRNA expression of SFTA2 gene with the highest risk coefficient in PMSRPS was significantly higher in PAAD than in paracancerous tissues, and knockdown of it significantly delayed the progression of PAAD.ConclusionsPMSRPS can well predict the prognosis, TME and immunotherapy response of patients with PAAD, identify potential drugs, and provide treatment guidance based on individual needs. |
| first_indexed | 2024-04-10T17:45:21Z |
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| id | doaj.art-5a2e2d033ee14cdfb2464866d9ebc90e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T17:45:21Z |
| publishDate | 2023-02-01 |
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| spelling | doaj.art-5a2e2d033ee14cdfb2464866d9ebc90e2023-02-03T04:59:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-02-011410.3389/fimmu.2023.11114941111494Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinomaQian Huang0Qian Huang1Xingyu Peng2Qingqing Li3Qingqing Li4Jinfeng Zhu5Ju Xue6Hua Jiang7Hua Jiang8Department of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, ChinaDepartment of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, ChinaDepartment of Pathology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, ChinaDepartment of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaBackgroundTreatment of cancer with pyroptosis is an emerging strategy. Molecular subtypes based on pyroptosis-related genes(PRGs) seem to be considered more conducive to individualized therapy. It is meaningful to construct a pyroptosis molecular subtypes-related prognostic signature (PMSRPS) to predict the overall survival (OS) of patients with pancreatic adenocarcinoma(PAAD) and guide treatment.MethodsBased on the transcriptome data of 23 PRGs, consensus clustering was applied to divide the TCGA and GSE102238 combined cohort into three PRGclusters. Prognosis-related differentially expressed genes(DEGs) among PRGclusters were subjected to LASSO Cox regression analysis to determine a PMSRPS. External cohort and in vitro experiments were conducted to verify this PMSRPS. The CIBERSORT algorithm, the ESTIMATE algorithm and the Immunophenoscore (IPS) were used to analyze the infiltrating abundance of immune cells, the tumor microenvironment (TME), and the response to immunotherapy, respectively. Wilcoxon analysis was used to compare tumor mutational burden (TMB) and RNA stemness scores (RNAss) between groups. RT-qPCR and in vitro functional experiments were used for evaluating the expression and function of SFTA2.ResultsBased on three PRGclusters, 828 DEGs were obtained and a PMSRPS was subsequently constructed. In internal and external validation, patients in the high-risk group had significantly lower OS than those in the low-risk group and PMSRPS was confirmed to be an independent prognostic risk factor for patients with PAAD with good predictive performance. Immune cell infiltration abundance and TME scores indicate patients in the high-risk group have typical immunosuppressive microenvironment characteristics. Analysis of IPS suggests patients in the high-risk group responded better to novel immune checkpoint inhibitors (ICIs) than PD1/CTLA4. The high-risk group had higher TMB and RNAss. In addition, 10 potential small-molecule compounds were screened out. Finally, we found that the mRNA expression of SFTA2 gene with the highest risk coefficient in PMSRPS was significantly higher in PAAD than in paracancerous tissues, and knockdown of it significantly delayed the progression of PAAD.ConclusionsPMSRPS can well predict the prognosis, TME and immunotherapy response of patients with PAAD, identify potential drugs, and provide treatment guidance based on individual needs.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1111494/fullpancreatic cancerpyroptosis molecular subtypesprognostic signaturetumor immune microenvironmenttumor stemnesschemotherapeutic drug sensitivity |
| spellingShingle | Qian Huang Qian Huang Xingyu Peng Qingqing Li Qingqing Li Jinfeng Zhu Ju Xue Hua Jiang Hua Jiang Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma Frontiers in Immunology pancreatic cancer pyroptosis molecular subtypes prognostic signature tumor immune microenvironment tumor stemness chemotherapeutic drug sensitivity |
| title | Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma |
| title_full | Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma |
| title_fullStr | Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma |
| title_full_unstemmed | Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma |
| title_short | Construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma |
| title_sort | construction and comprehensive analysis of a novel prognostic signature associated with pyroptosis molecular subtypes in patients with pancreatic adenocarcinoma |
| topic | pancreatic cancer pyroptosis molecular subtypes prognostic signature tumor immune microenvironment tumor stemness chemotherapeutic drug sensitivity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1111494/full |
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