Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma
Background: Esophageal squamous cell carcinoma (ESCC) is a genetically heterogeneous disease with poor clinical outcomes. Identification of biomarkers linked to DNA replication stress may enable improved prognostic risk stratification and guide therapeutic decision making. We performed integrated si...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-06-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523324000755 |
| _version_ | 1797220271943319552 |
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| author | Dengfeng Zhang Fangchao Zhao Jing Li Pengfei Guo Haitao Liu Tianxing Lu Shujun Li Zhirong Li Yishuai Li |
| author_facet | Dengfeng Zhang Fangchao Zhao Jing Li Pengfei Guo Haitao Liu Tianxing Lu Shujun Li Zhirong Li Yishuai Li |
| author_sort | Dengfeng Zhang |
| collection | DOAJ |
| description | Background: Esophageal squamous cell carcinoma (ESCC) is a genetically heterogeneous disease with poor clinical outcomes. Identification of biomarkers linked to DNA replication stress may enable improved prognostic risk stratification and guide therapeutic decision making. We performed integrated single-cell RNA sequencing and computational analyses to define the molecular determinants and subtypes underlying ESCC heterogeneity. Methods: Single-cell RNA sequencing was performed on ESCC samples and analyzed using Seurat. Differential gene expression analysis was used to identify esophageal cell phenotypes. DNA replication stress-related genes were intersected with single-cell differential expression data to identify potential prognostic genes, which were used to generate a DNA replication stress (DRS) score. This score and associated genes were evaluated in survival analysis. Putative prognostic biomarkers were evaluated by Cox regression and consensus clustering. Mendelian randomization analyses assessed the causal role of PRKCB. Results: High DRS score associated with poor survival. Four genes (CDKN2A, NUP155, PPP2R2A, PRKCB) displayed prognostic utility. Three molecular subtypes were identified with discrete survival and immune properties. A 12-gene signature displayed robust prognostic performance. PRKCB was overexpressed in ESCC, while PRKCB knockdown reduced ESCC cell migration. Conclusions: This integrated single-cell sequencing analysis provides new insights into the molecular heterogeneity and prognostic determinants underlying ESCC. The findings identify potential prognostic biomarkers and a gene expression signature that may enable improved patient risk stratification in ESCC. Experimental validation of the role of PRKCB substantiates the potential clinical utility of our results. |
| first_indexed | 2024-04-24T12:46:54Z |
| format | Article |
| id | doaj.art-79917d2ae0544a398acf9d439b644122 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-04-24T12:46:54Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-79917d2ae0544a398acf9d439b6441222024-04-07T04:35:25ZengElsevierTranslational Oncology1936-52332024-06-0144101948Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinomaDengfeng Zhang0Fangchao Zhao1Jing Li2Pengfei Guo3Haitao Liu4Tianxing Lu5Shujun Li6Zhirong Li7Yishuai Li8Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, ChinaDepartment of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, ChinaDepartment of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, ChinaDepartment of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, ChinaCollege of Life Science, Inner Mongolia University, Hohhot 010000, ChinaDepartment of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, ChinaDepartment of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; Corresponding authors.Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; Corresponding authors.Department of Thoracic Surgery, Hebei Chest Hospital, Shijiazhuang 050000, China; Hebei Provincial Key Laboratory of Pulmonary Diseases, Shijiazhuang 050000, China; Corresponding authors.Background: Esophageal squamous cell carcinoma (ESCC) is a genetically heterogeneous disease with poor clinical outcomes. Identification of biomarkers linked to DNA replication stress may enable improved prognostic risk stratification and guide therapeutic decision making. We performed integrated single-cell RNA sequencing and computational analyses to define the molecular determinants and subtypes underlying ESCC heterogeneity. Methods: Single-cell RNA sequencing was performed on ESCC samples and analyzed using Seurat. Differential gene expression analysis was used to identify esophageal cell phenotypes. DNA replication stress-related genes were intersected with single-cell differential expression data to identify potential prognostic genes, which were used to generate a DNA replication stress (DRS) score. This score and associated genes were evaluated in survival analysis. Putative prognostic biomarkers were evaluated by Cox regression and consensus clustering. Mendelian randomization analyses assessed the causal role of PRKCB. Results: High DRS score associated with poor survival. Four genes (CDKN2A, NUP155, PPP2R2A, PRKCB) displayed prognostic utility. Three molecular subtypes were identified with discrete survival and immune properties. A 12-gene signature displayed robust prognostic performance. PRKCB was overexpressed in ESCC, while PRKCB knockdown reduced ESCC cell migration. Conclusions: This integrated single-cell sequencing analysis provides new insights into the molecular heterogeneity and prognostic determinants underlying ESCC. The findings identify potential prognostic biomarkers and a gene expression signature that may enable improved patient risk stratification in ESCC. Experimental validation of the role of PRKCB substantiates the potential clinical utility of our results.http://www.sciencedirect.com/science/article/pii/S1936523324000755Esophageal squamous cell carcinomaMolecular subtypesDNA replication stress response genesPRKCBMendelian randomizationImmune infiltration |
| spellingShingle | Dengfeng Zhang Fangchao Zhao Jing Li Pengfei Guo Haitao Liu Tianxing Lu Shujun Li Zhirong Li Yishuai Li Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma Translational Oncology Esophageal squamous cell carcinoma Molecular subtypes DNA replication stress response genes PRKCB Mendelian randomization Immune infiltration |
| title | Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma |
| title_full | Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma |
| title_fullStr | Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma |
| title_full_unstemmed | Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma |
| title_short | Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma |
| title_sort | comprehensive single cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma |
| topic | Esophageal squamous cell carcinoma Molecular subtypes DNA replication stress response genes PRKCB Mendelian randomization Immune infiltration |
| url | http://www.sciencedirect.com/science/article/pii/S1936523324000755 |
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