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Targeting DKC1/NF-κB axis suppresses tumorigenesis and enhances 5-FU sensitivity in gastric cancer
Tengkai Wang1,2, Hui Zhang3, Yaoyao Feng1,2
1Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China.
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.
Insights
Dyskeratosis congenita 1 (DKC1) promotes gastric cancer (GC) growth and migration via the NF-κB pathway. Targeting DKC1 offers a dual approach for GC diagnosis and enhances chemotherapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gastric cancer (GC) is an aggressive malignancy with poor survival, necessitating new diagnostic and therapeutic targets.
- The dyskeratosis congenita 1 (DKC1) gene has known roles in various cancers, but its specific function in GC remains under-explored.
Purpose of the Study:
- To investigate the role and molecular mechanism of DKC1 in gastric cancer development.
- To evaluate DKC1 as a potential diagnostic biomarker and therapeutic target for GC.
Main Methods:
- Integrated multi-omics data from TCGA with validation in GC specimens and cell lines.
- Assessed DKC1 expression using immunohistochemistry, qRT-PCR, and western blotting.
- Performed functional assays for proliferation, migration, apoptosis, and chemosensitivity; utilized RNA sequencing and pathway enrichment analysis.
Main Results:
- DKC1 expression is elevated in GC and serves as a diagnostic marker, correlating with advanced features.
- DKC1 promotes GC cell proliferation and migration while inhibiting apoptosis, acting through the NF-κB signaling pathway.
- DKC1 knockdown synergistically enhances 5-fluorouracil (5-FU) efficacy by disrupting the cell cycle.
Conclusions:
- DKC1 regulates GC progression via the NF-κB pathway, acting as both a diagnostic biomarker and therapeutic target.
- Elevated DKC1 expression is linked to aggressive GC and holds significant diagnostic value.
- Targeting DKC1 presents a promising strategy to improve GC treatment outcomes, particularly in combination with 5-FU.
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