Fig. 2

HIF-1a and HIF-2a upstream and downstream pathways promoting cancer. HIF-1a expression varies with oxygen level in the cellular environment while HIF-2a is constitutively expressed and has some known oncogenic effects. Under normal oxygen conditions, both HIF-1a and HIF-2a are degraded through ubiquitination pathway by proteasome. Under hypoxia (low oxygen) conditions, HIF-1a translocates into the nucleus and forms HIF complex with HIF-1b and p300, leading to many cancer-promoting outcomes, including metabolic adaptation, cell survival, invasion and metastasis, angiogenesis and vascular tone, cellular proliferation, and apoptosis. Abbreviations: ADM = adrenomedullin; ALD = adrenoleukodystrophy protein; ANF = atrial natriuretic factor; Ang2 = Angiopoietin 2; ANGPT = Angiopoietin-related protein; ANP = Atrial natriuretic peptide; BCL-2 = B-cell lymphoma 2; BNIP3 = BCL2/adenovirus E1B 19 kDa interacting protein 3; CATHD = Cathepsin D; c-MET = mesenchymal-epithelial transition factor; C-MYC = Cellular myelocytomatosis oncogene; COS4 = ; EDN1 = Endothelin 1 gene; EGF = Epidermal growth factor; EG-VEGF = endocrine gland derived vascular endothelial growth factor; ENG = Endoglin; ENO = Enolase; EPO = Erythropoietin; ET1 = Endothelin 1; Flt-1 = Fms Related Receptor Tyrosine Kinase 1; FN1 = soluble plasma fibronectin; GAPDH = Glyceraldehyde 3-phosphate dehydrogenase; GPI = Glycosylphosphatidylinositol; HIF = hypoxia inducible factor; HK = Hexokinase; HRE = Hypoxia-response element; HSP90 = Heat shock protein 90; ID2 = Inhibitor Of DNA binding 2; IGF2 = Insulin like growth factor 2; IGF-BP = Insulin-like growth factor-binding protein; iNOS = Inducible nitric oxide synthases; KL = Klotho; KRT = Keratin; LDH-A = Lactate Dehydrogenase A; LEP = Leptin; LRP = Low-density lipoprotein (LDL)-related protein; MMPs = Matrix metalloproteinases; mTORC = mechanistic target of rapamycin complex; NOS = nitric oxide synthases; OH = Hydroxyl group; P4HS = Prolyl 4-hydroxylase; PDGF-B = platelet derived growth factor; PDK1 = Pyruvate Dehydrogenase Kinase 1; PFK2 = Phosphofructokinase 2; PFKFB3 = 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PFKL = ATP-dependent 6-phosphofructokinase, liver type; PGF = Placenta growth factor; PGK1 = Phosphoglycerate Kinase 1; PGM = phosphoglucomutase; PHD = HIF prolyl hydroxylase; PKM2 = Pyruvate kinase isozymes M2; POK1 = Phragmoplast orienting kinesin 1; pVHL = Von Hippel–Lindau tumor suppressor; RTP801 = HIF responsive protein; S6K1 = Ribosomal protein S6 kinase beta-1; TGF = Transforming growth factor; TIMP = Tissue Inhibitor of Metalloproteinase; TPI = Triosephosphate isomerase; Ub = Ubiquitin; uPAR = urokinase plasminogen activator surface receptor; PAI-1 = plasminogen activator inhibitor 1; PI3K = Phosphoinositide-3-kinase; VEGF = Vascular endothelial growth factor; VEGFR2 = Vascular endothelial growth factor receptor 2; VIM = Vimentin; WAF-1 = Wild type p53 activated protein-1