A Molecular Perspective on HIF-1α and Angiogenic Stimulator Networks and Their Role in Solid Tumors: An Update

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional factor, which plays an important role in cellular reprogramming processes under hypoxic conditions, which facilitate solid tumors' progression. HIF-1α is directly involved in the regulation of the angiogenesis, metabolic reprogramming, and extracellular matrix remodeling of the tumor microenvironment. Therefore, an in-depth study on the role of HIF-1α in solid tumor malignancies is required to develop novel anti-cancer therapeutics. HIF-1α also plays a critical role in regulating growth factors, such as the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, in a network manner. Additionally, it plays a significant role in tumor progression and chemotherapy resistance by regulating a variety of angiogenic factors, including angiopoietin 1 and angiopoietin 2, matrix metalloproteinase, and erythropoietin, along with energy pathways. Therefore, this review attempts to provide comprehensive insight into the role of HIF-1α in the energy and angiogenesis pathways of solid tumors.

Keywords: HIF-1α; VEGF; angiogenesis; angiopoietins; hypoxia; solid tumors.

Figure 1

Diagrammatic representation of the domain structures of HIF. The HIF-1α, HIF-2α, and HIF-3α structural domains along with their transcriptional binding partner, HIF-1β/ARNT, comprise the (HIF-α/HIF-1β) transcriptional complexes. The NH2-terminal region of HIF-α and HIF-1β contains bHLH and PAS domains, which are essential for heterodimerization and DNA binding in the HRE at the target gene loci. HIF-α has two TADs at its COOH-terminus. The ODD domain of HIF-1α, HIF-2α, and HIF-3α contains proline(s) residues. HIF-3 has a LZIP domain in the COOH-terminal region; it also lacks the TAD-C domain, unlike HIF-1α, HIF-2α. Abbreviations: ARNT: aryl hydrocarbon receptor nuclear translocator; bHLS-PAS: basic helix loop helix-per ARNT sim; CBP: CREB-binding protein; FIH: factor-inhibiting hypoxia-inducible factor; HIF: hypoxia-inducible factor; HRE: hypoxia-responsive element; LZIP: leucine zipper; PHD: prolyl hydroxylase domain; TAD: trans-activation domain.

Figure 2

Significance of the HIF-1α-signaling pathway in metabolic reprogramming in solid tumors. In hypoxic scenarios, HIF-1α enhances glucose uptake by positively regulating glycolytic enzymes and inducing the expression of PDK, the negative regulator of PDH, which results in the conversion of pyruvate into lactate instead of acetyl-CoA. This reduction of acetyl-CoA results in the inhibition of the TCA cycle; however, it also causes mitochondrial malfunctioning by inhibiting the activity of aconitase. HIF-1α also produces higher levels of ROS in cancer cells through the inhibition of the TCA cycle and by activating the pentose phosphate pathway. Abbreviations: Acetyl CoA: acetyl coenzyme A; CBP: CREB-binding protein; ETC: electron transport chain; FADH2: flavin adenine dinucleotide; GLUT: glucose transporters; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HIF-1: hypoxia-inducible factor-1; HRE: hypoxia-responsive element; IDH2: isocitrate dehydrogenase 2; KGDH: ketoglutarate dehydrogenase; LDHA: lactate dehydrogenase A; MDH: malate dehydrogenase; MCT4: mono-carboxylate transporter4; NADP: nicotinamide adenine dinucleotide phosphate; NADPH: nicotinamide adenine dinucleotide phosphate hydrogen; PDH: pyruvate dehydrogenase; PDK: pyruvate dehydrogenase kinase; ROS: reactive oxygen species; SDH: succinate dehydrogenase; TCA cycle: tricarboxylic acid cycle.

Figure 3

String analysis data to represent the signaling cascade of HIF-1 with angiogenic stimulators. Abbreviations: ANGPT 2: angiopoietin 2; DCN: decorin; EPOR: erythropoietin receptor; EPO: erythropoietin; EGLN3: elegans gene egl-9 homolog 3; HIF1A: hypoxia-inducible factor 1 alpha; MMP13: matrix metalloproteinase 13; MYOF: myoferlin; NRP: neuropilin; SEMA3F: semaphorin-3F; SEDT2: SET Domain Containing 2; SPARC: secreted protein acidic and rich in cysteine; TGFB: transforming growth factor beta; TGFBR: transforming growth factor beta receptor; TIMP1: tissue inhibitor matrix metalloproteinase 1; TM7SF2: transmembrane 7 Superfamily Member 2; VEGFB: vascular endothelial growth factor B; VHL: Von Hippel–Lindau tumor suppressor protein; WWOX: WW domain containing oxidoreductase.