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 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.