HIF and hepcidin : crossing links between infection, iron metabolism and cancer ? – HIF hepcidin

Given the links between oxygen transport and iron metabolism, associations between the physiology of hypoxic response, and the control of iron availability need to take place. The transcription factor HIF (Hypoxia Inducible Factor) is a central mediator of cellular adaptation to critically low oxygen levels (hypoxia) in both normal and compromised tissues. Hepcidin is an antimicrobial peptide secreted by the liver during inflammation playing a key role in mammalian iron homeostasis. We linked the HIF and hepcidin pathways, placing the transcription factor in a central role as sensor and regulator of iron levels in the body (Journal of Clinical Investigation, 2007). We also described that HIF is not only detected at low oxygen concentrations but also during bacterial infection and plays an entirely novel role in innate immunity (Journal of Clinical Investigation, 2005; Journal of Immunology, 2007; Journal of infectious diseases, 2007; Journal of investigative dermatology, 2008). During infection and cancer, an important response for the host is to limit the availability of iron to invading microorganisms or tumoral cells. Iron is thus not only important for physiological processes (erythropoiesis…) but also plays an important role in many pathogenesis, including bacterial infection and tumorigenesis. Altogether, these data place HIF and hepcidin at the crossing points between infection, iron metabolism and cancer. This proposal will take full advantage the unique reagents I developed or am developing including murine models of conditional knock out of HIF. Our research plan seeks : 1- to characterize the oxygen-independent signaling pathway by which HIF is stabilized in response to infection. Similarly to TLR4, HIF controls a balance between being able to respond sufficiently to activate microbicidal mechanisms essential for killing invading microbes versus risking an over-exuberant inflammatory response. We hypothesize that HIF is of critical importance downstream of TLR in signaling the innate response. 2-to test the hypothesis that HIF and hepcidin may be missing links between infection and cancer. HIF is largely known and studied for its crucial role during cancer development. My finding that bacteria induce HIF stabilization (even under normoxia), suggests that HIF may trigger tumor development in response to infection. We will test the hypothesis linking bacterial infection and cancer, by taking the model of the gastric cancer, whose the initiating event is an infection by Helicobacter Pylori. Although the link between inflammation and gastric cancer is admitted, the molecular mechanisms at the base of this transition are still not established. Several arguments suggest that HIF could have an important role in the etiology of gastric cancer 1) during the chronic inflammatory response 2) the transition to the gastric cancer and 3) development of the tumor. Macrophages infiltrate tumors, standing for up to 80% of the total tumoral mass. Presence of Tumor-Associated-Macrophages (TAMs) is correlated to a poor prognosis in cancer, including gastric cancer. Our data showing that hepcidin is expressed in myeloid cells in response to infection (Blood, 2006) prompt us to hypothesize that hepcidin could be expressed by the Tumor-Associated-Macrophages (TAMs) and enhance tumor growth by providing iron to the proliferating cells. A combination of in vitro approaches and in vivo studies in infected murine models of conditional inactivation of HIF and hepcidin in the myeloid or the stomach lineages will be conducted. 3- to investigate the role of HIF-1 in iron absorption. Chronic hypoxia or iron deficiency increased iron absorption by the duodenum, but the mechanisms involved in this process have not been elucidated yet. Several groups have shown an increase of duodenal expression of the iron importer DMT1 and the iron exporter ferroportin at the apical and basolateral surfaces respectively, under hypoxia or iron deficiency. It is reasonable to suspect that activation of HIF-1α in intestinal epithelium is a mediator of this effect. Conditional inactivation of HIF-1 and vHL (the negative regulator of HIF) in the intestine are being generated. A detailed understanding of the regulation of iron-related proteins (including the iron transporters, DMT1 and ferroportin) is indeed a prerequisite in the development of therapeutics for iron diseases, which pose a major problem worldwide.