Grant: Operating Grant

Mutation in von Hippel-Lindau (VHL) gene causes VHL disease, which is characterized by the development of multiple tumours in multiple organs including the brain, spinal cord, retina, pancreas, adrenal gland, and kidney. We and others have shown that VHL protein promotes the degradation of a transcription factor called hypoxia-inducible factor (HIF). HIF maintains cellular oxygen homeostasis or balance, which is a vital organizing principle for human development and physiology. Moreover, dysregulation of oxygen homeostasis is associated with the development and/or progression of major human diseases, including cardiovascular and chronic pulmonary diseases and cancer. One of the key proteins upregulated by HIF under compromised oxygen availability is erythropoietin (EPO), which binds to EPO receptor (EPOR) to stimulate the production and expansion of oxygen-carrying red blood cells or erythropoiesis. Recently, we discovered for the first time that EPOR protein stability is regulated by oxygen and VHL, which raises the possibility that EPOR regulation is involved in cancer biology. Moreover, over the past two decades, human recombinant EPO has been administered to cancer patients to alleviate the symptoms of anaemia. However, recent randomized controlled trials in cancer patients have indicated that EPO treatment during chemotherapy increases the rate of cancer progression and death. In this proposal, we will elucidate the novel molecular mechanisms governing EPOR signaling and interrogate this new insight in the context of normal erythropoiesis as well as EPO-induced cancer progression model.