RIP1 Contributes to Colorectal Cancer Progression and Lymphatic Remodeling in Association With VEGF-C/NF-κB Pathway

Abstract

Receptor-interacting protein kinase 1 (RIP1) plays a regulatory role in inflammation and cell survival, but its involvement in colorectal cancer (CRC), particularly in relation to lymphatic changes within the tumor microenvironment, remains poorly defined. The expressions of RIP1 and VEGF-C were examined in CRC tissues and adjacent normal samples by qRT-PCR and Western blot. Their correlation was analyzed, and functional assays were conducted using RIP1-silenced and reexpressed HT29 and SW480 cells. Cell proliferation, migration, and colony formation were evaluated, alongside NF-κB reporter activity. Conditioned media from LPS-stimulated CRC cells were applied to assess tube formation by lymphatic endothelial cells. A xenograft model was applied to verify tumor growth and vascular changes in vivo. RIP1 was found to be elevated in CRC tissues and positively associated with VEGF-C expression. Knockdown of RIP1 reduced cell growth, migration, VEGF-C level, and NF-κB activity. These changes were partially reversed by restoring RIP1 overexpression. Conditioned media from RIP1-deficient cells impaired tubule formation in lymphatic endothelial cells. In mice, RIP1 silencing suppressed tumor growth and reduced microvessel density and Ki67-positive cells. RIP1 promotes CRC progression and is associated with elevated VEGF-C expression and NF-κB pathway activation. It may contribute to CRC growth and lymphatic remodeling, suggesting RIP1 as a potential target for CRC intervention.