Dvl2 facilitates the coordination of NF-kappa B and Wnt signaling to promote colitis-associated colorectal progression

Colitis-associated colorectal cancer (CAC) arises due to prolonged inflammation and has distinct molecular events compared with sporadic colorectal cancer (CRC). Although inflammatory NF-kappa B signaling was activated by pro-inflammatory cytokines (such as TNF alpha) in early stages of CAC, Wnt/beta-catenin signaling later appears to function as a key regulator of CAC progression. However, the exact mechanism responsible for the cross-regulation between these 2 pathways remains unclear. Here, we found reciprocal inhibition between NF-kappa B and Wnt/beta-catenin signaling in CAC samples, and the Dvl2, an adaptor protein of Wnt/beta-catenin signaling, is responsible for NF-kappa B inhibition. Mechanistically, Dvl2 interacts with the C-terminus of tumor necrosis factor receptor 1 (TNFRI) and mediates TNFRI endocytosis, leading to NF-kappa B signal inhibition. In addition, increased infiltration of the pro-inflammatory cytokine interleukin-13 (IL-13) is responsible for upregulating Dvl2 expression through STAT6. Targeting STAT6 effectively decreases Dvl2 levels and restrains colony formation of cancer cells. These findings demonstrate a unique role for Dvl2 in TNFRI endocytosis, which facilitates the coordination of NF-kappa B and Wnt to promote CAC progression.