Dvl2 facilitates the coordination of NF-κB 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 to sporadic colorectal cancer (CRC). Although inflammatory NF-κB signaling was activated by proinflammatory cytokines (such as TNFα) in early-stage of CAC, Wnt/β-catenin signaling later appears to function as a key regulator of CAC progression. However, the exact mechanism responsible for the cross-regulation between these two pathways remains unclear. Here, we found reciprocal inhibition between NF-κB and Wnt/β-catenin signalings in CAC samples, and the Dvl2, an adaptor protein of Wnt/β-catenin signaling, is responsible for NF-κB inhibition. Mechanistically, Dvl2 interacts with the C-terminus of TNFRI and mediates TNFRI endocytosis, leading to NF-κB 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 level and restrains colony formation of cancer cells. These findings demonstrate a unique role for Dvl2 in TNFRI endocytosis, which facilitates the coordination of NF-κB and Wnt to promote CAC progression.