Synergistic DBNDD1–GDF15 Signaling Activates the NF-κB Pathway to Promote Colorectal Cancer Progression

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Colorectal cancer is a highly lethal gastrointestinal tract malignancy whose pathogenesis and molecular drivers are not fully understood. This study focused on searching for genes that are differentially expressed in cancer versus normal mucosa, with the goal of identifying molecular patterns of expression that are mechanistically linked to colorectal cancer pathogenesis. We analyzed 585 colorectal cancer samples and 329 normal samples from the Gene Expression Omnibus database, creating a weighted gene coexpression network analysis across 24,069 genes. Through this approach, five modules associated with colorectal cancer were identified, which were enriched in MAPK signaling and cholesterol metabolism pathways. Using least absolute shrinkage and selection operator (LASSO) regression, we selected 13 hub genes [ABCB5, AOC1, ARHGAP44, CACNG3, dysbindin domain-containing protein 1 (DBNDD1), GAS7, GTF2IRD1, PRSS22, SCN4A, TTC22, DLX6, PDK4, and SLC13A2] from these modules. Survival analysis indicated that higher expression of DBNDD1 correlated with worse overall survival in patients with colorectal cancer. Machine learning validation confirmed the stability of these genetic markers. Experimental validation demonstrated increased levels of DBNDD1 and growth differentiation factor 15 (GDF15) in colorectal cancer, promoting constant NF-κB (RELA) activation via DBNDD1-dependent GDF15 induction. Knocking down DBNDD1 inhibited cell proliferation, migration, and invasion in vitro (DLD1/HCT116 cells), alongside decreased GDF15 expression and reduced p-NF-κB p65-p-I-κB signaling. Additionally, DBNDD1 knockdown resulted in reduced tumor growth in vivo, highlighting that the DBNDD1-GDF15-NF-κB signaling pathway drives colorectal cancer pathogenesis. IMPLICATIONS: This study highlights the crucial role of the DBNDD1-GDF15-NF-κB signaling pathway in colorectal cancer development, positioning DBNDD1 as a promising target for precision medicine strategies aimed at enhancing patient outcomes.