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

Autor: Park JH; Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Ameri AH; Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Dempsey KE; Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Conrad DN; Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Kem M; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Mino-Kenudson M; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Demehri S; Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2021 Apr 01; Vol. 40 (7), pp. e106151. Date of Electronic Publication: 2021 Feb 22.
DOI: 10.15252/embj.2020106151
Abstrakt: 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.
(© 2021 The Authors.)
Databáze: MEDLINE
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