Cathelicidin LL-37 inhibits angiogenesis and migration in gastric cancer via inhibition of NF-κB/IL-6 signaling.

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, often diagnosed at advanced stages with limited therapeutic options. Cathelicidin LL-37, an antimicrobial peptide, has demonstrated context-dependent roles in cancer progression. This study aimed to elucidate the function and underlying mechanism of LL-37 in GC, with a focus on angiogenesis and metastasis. METHODS: The effects of LL-37 were investigated in GC cell lines (HGC27, MKN74, AGS, HSC-39, NCI-N87) and mouse models. In vitro assays included the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, wound healing assay, Transwell assay, tube formation assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (RT-qPCR), western blot, immunofluorescence staining, and chromatin immunoprecipitation (ChIP). Metastasis and xenograft models were established in nude mice to assess the anti-tumor efficacy of LL-37 in vivo. RESULTS: LL-37 significantly suppressed the viability of multiple GC cell lines and downregulated the expression of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGFA). Functionally, LL-37 inhibited angiogenesis, migration, and invasion of GC cells, and attenuated transforming growth factor (TGF)-β-induced pro-metastatic effects. These inhibitory effects were reversed by IL-6 overexpression. Mechanistically, LL-37 inactivated the nuclear factor-κB (NF-κB) pathway, as evidenced by reduced p65 phosphorylation, impaired nuclear translocation, and decreased binding to the IL-6 promoter. The NF-κB inhibitor BAY 11-7082 mimicked the suppressive effects of LL-37. In vivo, LL-37 administration markedly reduced lung metastasis and decreased the levels of IL-6, VEGFA, and phospho-p65 in xenograft tumors. CONCLUSION: LL-37 inhibits angiogenesis, migration, and invasion in GC by suppressing the NF-κB/IL-6 signaling axis. This work provides a rationale for considering LL-37 as a potential therapeutic candidate.