The Hypoxia-Inducible Factor-1α Signaling Pathway and its Relation to Cancer and Immunology

Abstract

Hypoxia-Inducible Factor 1 (HIF-1) is a transcription factor that is present in all metazoans from early embryonic development throughout adult life. It plays a major roles in the different stress responses that are triggered by low Oxygen (O₂) levels and its expression is associated with cell survival. HIF-1 is a heterodimer protein that comprises the subunits HIF-1α and HIF-1β. The HIF-1α subunit is regulated by O₂-dependent hydroxylation of proline and asparagine residues, which results in ubiquitination and subsequent proteasome degradation. It may also be regulated independently of O₂. This review discusses the regulatory mechanisms and biological significance of HIF-1α with regard to cancer development and immune regulation. HIF-1α stabilization under hypoxic conditions is crucial to the survival of established tumors and cancer stem cells. HIF-1α is included in the hallmarks of cancer that are related to energy metabolism, although there is clear evidence that this transcription factor might participate in other hallmarks, such as angiogenesis, invasion and metastasis, self-sufficiency in proliferation signals and even apoptosis evasion. With regard to immunology, HIF-1α regulates Interleukin (IL)-1β, IL-8 and Heme-Oxygenase-1 (HO-1) and despite some conflicting results, HIF-1α is considered to be an important component of innate immune cell-mediated inflammation. With regard to the adaptive immune response, HIF-1α expression is related to Th17 polarization and Treg inhibition. Thus, the HIF-1α signaling pathway has been designated as a promising target for new drugs in several studies.