Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer
Abstract Background Gastric cancer (GC), an aggressive malignant tumor with poor overall survival worldwide, urgently requires novel diagnostic and therapeutic targets. The dyskeratosis congenita 1 (DKC1) gene has been reported to have diverse biological functions and prognostic values in several ty...
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BMC
2025-07-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-025-03926-4 |
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| author | Tengkai wang Hui Zhang Yaoyao Feng Yinrong Yang |
| author_facet | Tengkai wang Hui Zhang Yaoyao Feng Yinrong Yang |
| author_sort | Tengkai wang |
| collection | DOAJ |
| description | Abstract Background Gastric cancer (GC), an aggressive malignant tumor with poor overall survival worldwide, urgently requires novel diagnostic and therapeutic targets. The dyskeratosis congenita 1 (DKC1) gene has been reported to have diverse biological functions and prognostic values in several types of human cancers. However, the specific role and molecular mechanism of DKC1 in GC have received less attention. Methods Multi-omics analysis integrated The Cancer Genome Atlas (TCGA) data with validation in GC specimens and GC cell lines. DKC1 expression was quantified via immunohistochemistry, real-time polymerase chain reaction (qRT-PCR), and western blotting. Functional impacts on proliferation (CCK-8/cell cycle analysis), migration (Transwell), apoptosis (Annexin V/PI staining), and chemosensitivity (5-fluorouracil [5-FU] IC50) were assessed. RNA sequencing of DKC1-silenced AGS cells informed pathway enrichment (Gene Set Enrichment Analysis [GSEA]/Kyoto Encyclopedia of Genes and Genomes [KEGG]) to predict the underlying mechanism. Results DKC1 expression was increased and displayed a remarkable diagnostic value in GC. High DKC1 expression correlated with advanced histologic grade and diffuse-type Lauren classification in GC patients. Functional studies revealed that DKC1 effectively promoted GC cell proliferation and migration while suppressing apoptosis in vitro. RNA-seq analysis and rescue experiments confirmed that DKC1 regulated GC progression via the NF-κB signaling pathway. Critically, DKC1 knockdown synergistically enhanced 5-FU efficacy through cell cycle dysregulation. Conclusions DKC1 was identified as a regulator of GC development through the NF-κB pathway. It displayed a dual role as a diagnostic biomarker and therapeutic target. Elevated DKC1 expression correlated with aggressive clinicopathological features and a good diagnostic value in GC. Furthermore, DKC1 knockdown synergistically enhanced 5-FU efficacy. These data suggested that DKC1 is a potential tumor diagnostic biomarker and a therapeutic target for GC. |
| format | Article |
| id | doaj-art-7e10fdbbb7324d0b8562a64b72b14f8d |
| institution | Kabale University |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-7e10fdbbb7324d0b8562a64b72b14f8d2025-08-20T03:46:20ZengBMCCancer Cell International1475-28672025-07-0125111310.1186/s12935-025-03926-4Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancerTengkai wang0Hui Zhang1Yaoyao Feng2Yinrong Yang3Department of Gastroenterology, Qilu Hospital of Shandong UniversityDepartmant of pathology, Qingdao Chengyang People’s HospitalDepartment of Gastroenterology, Qilu Hospital of Shandong UniversityDepartment of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao)Abstract Background Gastric cancer (GC), an aggressive malignant tumor with poor overall survival worldwide, urgently requires novel diagnostic and therapeutic targets. The dyskeratosis congenita 1 (DKC1) gene has been reported to have diverse biological functions and prognostic values in several types of human cancers. However, the specific role and molecular mechanism of DKC1 in GC have received less attention. Methods Multi-omics analysis integrated The Cancer Genome Atlas (TCGA) data with validation in GC specimens and GC cell lines. DKC1 expression was quantified via immunohistochemistry, real-time polymerase chain reaction (qRT-PCR), and western blotting. Functional impacts on proliferation (CCK-8/cell cycle analysis), migration (Transwell), apoptosis (Annexin V/PI staining), and chemosensitivity (5-fluorouracil [5-FU] IC50) were assessed. RNA sequencing of DKC1-silenced AGS cells informed pathway enrichment (Gene Set Enrichment Analysis [GSEA]/Kyoto Encyclopedia of Genes and Genomes [KEGG]) to predict the underlying mechanism. Results DKC1 expression was increased and displayed a remarkable diagnostic value in GC. High DKC1 expression correlated with advanced histologic grade and diffuse-type Lauren classification in GC patients. Functional studies revealed that DKC1 effectively promoted GC cell proliferation and migration while suppressing apoptosis in vitro. RNA-seq analysis and rescue experiments confirmed that DKC1 regulated GC progression via the NF-κB signaling pathway. Critically, DKC1 knockdown synergistically enhanced 5-FU efficacy through cell cycle dysregulation. Conclusions DKC1 was identified as a regulator of GC development through the NF-κB pathway. It displayed a dual role as a diagnostic biomarker and therapeutic target. Elevated DKC1 expression correlated with aggressive clinicopathological features and a good diagnostic value in GC. Furthermore, DKC1 knockdown synergistically enhanced 5-FU efficacy. These data suggested that DKC1 is a potential tumor diagnostic biomarker and a therapeutic target for GC.https://doi.org/10.1186/s12935-025-03926-4DKC15-FUGastric cancerNFκBTherapeutic target |
| spellingShingle | Tengkai wang Hui Zhang Yaoyao Feng Yinrong Yang Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer Cancer Cell International DKC1 5-FU Gastric cancer NFκB Therapeutic target |
| title | Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer |
| title_full | Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer |
| title_fullStr | Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer |
| title_full_unstemmed | Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer |
| title_short | Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer |
| title_sort | targeting dkc1 nf κb axis suppresses tumorigenesis and enhances 5 fu sensitivity in gastric cancer |
| topic | DKC1 5-FU Gastric cancer NFκB Therapeutic target |
| url | https://doi.org/10.1186/s12935-025-03926-4 |
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