Hypoxia-regulated gene network in drug resistance and cancer progression

Abstract

Hypoxia is a common phenomenon of solid tumors and contributes to aggressive phenotype and treatment failure. Hypoxia-inducible factor (HIF), a versatile transcription factor that regulates more than 5% of total human genes, not only plays important roles in controlling physiological processes, but is also a crucial mediator in hypoxia-induced tumor progression and chemoresistance. Overexpression of HIF-1α is detected in a wide spectrum of cancers via different kinds of mechanisms, including reduced oxygen concentration, loss-of-function of tumor suppressor gene, activating mutation of oncogenes, and hyperactivation of protein kinase signaling pathways. HIF-regulated genes involve in many pathological processes such as metabolic switch, drug efflux, angiogenesis, cell proliferation, and anti-apoptosis, which ultimately leads to increased tumor growth and drug resistance. Due to the common failure of classic chemotherapeutic agents in treating hypoxic cancers, novel strategies have been developed to target tumors under hypoxic conditions including inhibition of HIF activity and administration of bioreductive drugs. These new strategies may provide more effective and specific methods in targeting hypoxic tumors.