Nuclear IL‐33/SMAD signaling axis promotes cancer development in chronic inflammation

Interleukin (IL)‐33 cytokine plays a critical role in allergic diseases and cancer. IL‐33 also has a nuclear localization signal. However, the nuclear function of IL‐33 and its impact on cancer is unknown. Here, we demonstrate that nuclear IL‐33‐mediated activation of SMAD signaling pathway in epithelial cells is essential for cancer development in chronic inflammation. Using RNA and ChIP sequencing, we found that nuclear IL‐33 repressed the expression of an inhibitory SMAD, Smad6, by interacting with its transcription factor, RUNX2. IL‐33 was highly expressed in the skin and pancreatic epithelial cells in chronic inflammation, leading to a markedly repressed Smad6 expression as well as dramatically upregulated p‐SMAD2/3 and p‐SMAD1/5 in the epithelial cells. Blocking TGF‐β/SMAD signaling attenuated the IL‐33‐induced cell proliferation in vitro and inhibited IL‐33‐dependent epidermal hyperplasia and skin cancer development in vivo. IL‐33 and SMAD signaling were upregulated in human skin cancer, pancreatitis, and pancreatitis‐associated pancreatic cancer. Collectively, our findings reveal that nuclear IL‐33/SMAD signaling is a cell‐autonomous tumor‐promoting axis in chronic inflammation, which can be targeted by small‐molecule inhibitors for cancer treatment and prevention.