Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer
BackgroundProstate cancer (PCa) is the most common malignant tumor of the male urinary system. Cuproptosis, as a novel regulated cell death, remains unclear in PCa. This study aimed to investigate the role of cuproptosis-related genes (CRGs) in molecular stratification, prognostic prediction, and cl...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1162653/full |
| _version_ | 1797835627943690240 |
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| author | Jili Zhang Shaoqin Jiang Shaoqin Jiang Di Gu Wenhui Zhang Xianqi Shen Min Qu Chenghua Yang Yan Wang Xu Gao |
| author_facet | Jili Zhang Shaoqin Jiang Shaoqin Jiang Di Gu Wenhui Zhang Xianqi Shen Min Qu Chenghua Yang Yan Wang Xu Gao |
| author_sort | Jili Zhang |
| collection | DOAJ |
| description | BackgroundProstate cancer (PCa) is the most common malignant tumor of the male urinary system. Cuproptosis, as a novel regulated cell death, remains unclear in PCa. This study aimed to investigate the role of cuproptosis-related genes (CRGs) in molecular stratification, prognostic prediction, and clinical decision-making in PCa. MethodsCuproptosis-related molecular subtypes were identified by consensus clustering analysis. A prognostic signature was constructed with LASSO cox regression analyses with 10-fold cross-validation. It was further validated in the internal validation cohort and eight external validation cohorts. The tumor microenvironment between the two risk groups was compared using the ssGSEA and ESTIMATE algorithms. Finally, qRT-PCR was used to explore the expression and regulation of these model genes at the cellular level. Furthermore, 4D Label-Free LC-MS/MS and RNAseq were used to investigate the changes in CRGs at protein and RNA levels after the knockdown of the key model gene B4GALNT4.ResultsTwo cuproptosis-related molecular subtypes with significant differences in prognoses, clinical features, and the immune microenvironment were identified. Immunosuppressive microenvironments were associated with poor prognosis. A prognostic signature comprised of five genes (B4GALNT4, FAM83D, COL1A, CHRM3, and MYBPC1) was constructed. The performance and generalizability of the signature were validated in eight completely independent datasets from multiple centers. Patients in the high-risk group had a poorer prognosis, more immune cell infiltration, more active immune-related functions, higher expression of human leukocyte antigen and immune checkpoint molecules, and higher immune scores. In addition, anti-PDL-1 immunotherapy prediction, somatic mutation, chemotherapy response prediction, and potential drug prediction were also analyzed based on the risk signature. The validation of five model genes' expression and regulation in qPCR was consistent with the results of bioinformatics analysis. Transcriptomics and proteomics analyses revealed that the key model gene B4GALNT4 might regulate CRGs through protein modification after transcription.ConclusionThe cuproptosis-related molecular subtypes and the prognostic signature identified in this study could be used to predict the prognosis and contribute to the clinical decision-making of PCa. Furthermore, we identified a potential cuproptosis-related oncogene B4GALNT4 in PCa, which could be used as a target to treat PCa in combination with cuproptosis. |
| first_indexed | 2024-04-09T14:56:44Z |
| format | Article |
| id | doaj.art-b8ffa391352f4afd87a35a1aee76c20b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-09T14:56:44Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-b8ffa391352f4afd87a35a1aee76c20b2023-05-02T05:05:57ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-05-011310.3389/fonc.2023.11626531162653Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancerJili Zhang0Shaoqin Jiang1Shaoqin Jiang2Di Gu3Wenhui Zhang4Xianqi Shen5Min Qu6Chenghua Yang7Yan Wang8Xu Gao9Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Fujian Union Hospital, Fujian Medical University, Fuzhou, Fujian, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Urology, Changhai Hospital, Second Military Medical University, Shanghai, ChinaBackgroundProstate cancer (PCa) is the most common malignant tumor of the male urinary system. Cuproptosis, as a novel regulated cell death, remains unclear in PCa. This study aimed to investigate the role of cuproptosis-related genes (CRGs) in molecular stratification, prognostic prediction, and clinical decision-making in PCa. MethodsCuproptosis-related molecular subtypes were identified by consensus clustering analysis. A prognostic signature was constructed with LASSO cox regression analyses with 10-fold cross-validation. It was further validated in the internal validation cohort and eight external validation cohorts. The tumor microenvironment between the two risk groups was compared using the ssGSEA and ESTIMATE algorithms. Finally, qRT-PCR was used to explore the expression and regulation of these model genes at the cellular level. Furthermore, 4D Label-Free LC-MS/MS and RNAseq were used to investigate the changes in CRGs at protein and RNA levels after the knockdown of the key model gene B4GALNT4.ResultsTwo cuproptosis-related molecular subtypes with significant differences in prognoses, clinical features, and the immune microenvironment were identified. Immunosuppressive microenvironments were associated with poor prognosis. A prognostic signature comprised of five genes (B4GALNT4, FAM83D, COL1A, CHRM3, and MYBPC1) was constructed. The performance and generalizability of the signature were validated in eight completely independent datasets from multiple centers. Patients in the high-risk group had a poorer prognosis, more immune cell infiltration, more active immune-related functions, higher expression of human leukocyte antigen and immune checkpoint molecules, and higher immune scores. In addition, anti-PDL-1 immunotherapy prediction, somatic mutation, chemotherapy response prediction, and potential drug prediction were also analyzed based on the risk signature. The validation of five model genes' expression and regulation in qPCR was consistent with the results of bioinformatics analysis. Transcriptomics and proteomics analyses revealed that the key model gene B4GALNT4 might regulate CRGs through protein modification after transcription.ConclusionThe cuproptosis-related molecular subtypes and the prognostic signature identified in this study could be used to predict the prognosis and contribute to the clinical decision-making of PCa. Furthermore, we identified a potential cuproptosis-related oncogene B4GALNT4 in PCa, which could be used as a target to treat PCa in combination with cuproptosis.https://www.frontiersin.org/articles/10.3389/fonc.2023.1162653/fullprostate cancercuproptosisunsupervised clusteringtumor microenvironmentsignature |
| spellingShingle | Jili Zhang Shaoqin Jiang Shaoqin Jiang Di Gu Wenhui Zhang Xianqi Shen Min Qu Chenghua Yang Yan Wang Xu Gao Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer Frontiers in Oncology prostate cancer cuproptosis unsupervised clustering tumor microenvironment signature |
| title | Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer |
| title_full | Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer |
| title_fullStr | Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer |
| title_full_unstemmed | Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer |
| title_short | Identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis-related genes in prostate cancer |
| title_sort | identification of novel molecular subtypes and a signature to predict prognosis and therapeutic response based on cuproptosis related genes in prostate cancer |
| topic | prostate cancer cuproptosis unsupervised clustering tumor microenvironment signature |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1162653/full |
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