HIFHEPC · HIF and hepcidin : missing links between infection, iron metabolism and cancer ?

HIF transcription factors, central mediators of cellular adaptation to critically low oxygen levels (=hypoxia), have been largely studied for their crucial role during cancer development. Our recent findings have unveiled two new major roles of HIF. First, in innate immunity and infection, we demonstrated the key contributions of HIFs in regulating important immune effectors molecules. Second, we highlighted the role of HIFs in iron metabolism as critical regulators of iron absorption in the intestine and in systemic iron homeostasis by regulating the liver synthesis of the iron regulatory hormone, hepcidin.These results open new research areas and our research program, based on unique mouse models of conditional HIFs and hepcidin knockout, will be developed around three main axes.1) define the physiological roles of HIF and hepcidin in different key organs involved in maintaining body iron homeostasis. A detailed understanding of the regulation of iron-related proteins is a prerequisite in the development of therapeutics for iron diseases, which pose a major problem worldwide.2) study the role of hepcidin during bacterial infection and tumorigenesis, two pathological conditions where iron is critically required for the proliferation of the pathogens and for cancer cells to feed their high metabolic activity.3) determine the contribution of HIFs in the initiation of tumor development in response to infection. Indeed, our findings that HIF is stabilized by bacteria, even under normal levels of oxygen, and is an essential component of the inflammation response, let us to speculate that HIFs may be a missing link between infection and cancer by triggering a high chronic inflammatory response. For that, we will use the model of the gastric cancer, whose the initiating event is an infection by Helicobacter Pylori.