Receptor-interacting serine/threonine-protein kinase 1 promotes the progress and lymph metastasis of gallbladder cancer

Receptor-interacting serine/threonine-protein kinase 1 (RIP-1) is highly expressed in gallbladder cancer, and is very important in promoting tumor proliferation and invasion. The underlying mechanism in this promotion is the RIP-1-nuclear factor κ-B (NF-κB) and activator protein 1 (AP-1)-vascular endothelial growth factor-C (VEGF-C) signaling pathways. However, the precise mechanisms by which RIP-1 regulates VEGF-C expression are still unknown. The current study aims to clarify the detailed mechanisms by which RIP-1 upregulates VEGF-C expression. In the current study, the authors constructed various VEGF-C promoter deletions, VEGF-C promoter mutations and RIP-1 overexpression plasmids, and silenced RIP-1 with a small interfering RNA. Promoter analysis, an electrophoretic mobility shift assay, a chromatin immunoprecipitation assay was then performed, and an orthotopic transplantation model in nude mice was established by modified methods previously used. The authors also found that the core region for luciferase activity in the VEGF-C promoter was −332 to −190 nt, in which there are two overlapping AP-1 sites and an NF-κB site. RIP-1 was demonstrated to activate transcription factors NF-κB and AP-1 to combine with the core region and enhance VEGF-C promoter activity. In conclusion, the current study illustrated the mechanisms by which RIP-1 regulates VEGF-C expression, by activating NF-κB and AP-1 to combine with the −332 to −190 nt area of the VEGF-C promoter. By establishing an orthotopic mouse model of gallbladder cancer tumors, it was further elucidated that RIP-1 promotes gallbladder cancer metastasis. The findings provide evidence that targeting RIP-1 may prove to be useful in the treatment of gallbladder cancer.