Project Summary/Abstract
The overarching goal of the proposed research is to elucidate the initiating mechanisms in the development of
cancer-prone chronic inflammation for cancer prevention and therapy. Chronic inflammatory diseases, such as
chronic dermatitis, pancreatitis, colitis and hepatitis, are major risk factors for cancer. In addition, a tumor-
promoting immune environment, which resembles chronic inflammation, is a key driver of cancer development
across the majority of cancer types. By studying the mediators of the transition from acute to chronic
inflammation, we have demonstrated that interleukin (IL)-33 cytokine is a key initiator of chronic inflammation
that eventually leads to cancer development in the skin, colon and pancreas. Importantly, we have recently
discovered that the nuclear function of IL-33 within the epithelial cells plays an essential role in cancer
development in chronic skin and pancreas inflammation. To develop an effective strategy to suppress cancer-
prone chronic inflammation, we will focus on the mechanism that blocks the initiating steps in the development
of a cancer-prone chronic inflammation. Founded on our innovative discovery that IL-33 is an essential initiator
of cancer-prone chronic inflammation, we aim to determine the mechanism of IL-33 induction in tissues exposed
to inflammatory insults and to develop a novel therapeutic approach to inhibit IL-33 expression for cancer
prevention and therapy. To accomplish this, we will use novel mouse models and clinical samples to (1)
determine the mechanism of IL-33 induction in chronic inflammation triggered by chemical agents, (2) investigate
the role of IL-33 in cancer-prone chronic inflammation associated with a viral infection, and (3) study inhibitor of
IL-33 that can block chronic inflammation and the subsequent cancer development. The outcomes of our
research will establish a fundamental pathway to suppress chronic inflammation-associated cancer and provide
the means to prevent cancer progression and recurrence.