Targeting Hypoxia-Inducible Factor-1α for the Management of Hepatocellular Carcinoma

Abstract

Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as well as a hypoxic tumor, due to the liver being a relatively hypoxic environment compared to other organs. Trans-arterial chemoembolization (TACE) and trans-arterial embolization (TAE) are locoregional therapies that are part of the treatment guidelines for HCC but can also exacerbate hypoxia in tumors, as seen with HIF-1α upregulation post-hepatic embolization. Hypoxia-activated prodrugs (HAPs) are a novel class of anticancer agent that are selectively activated under hypoxic conditions, potentially allowing for the targeted treatment of hypoxic HCC. Early studies targeting hypoxia show promising results; however, further research is needed to understand the effects of HAPs in combination with embolization in the treatment of HCC. This review aims to summarize current knowledge on the role of hypoxia and HIF-1α in HCC, as well as the potential of HAPs and liver-directed embolization.

Effect of RNA interference with HIF-1α on the growth of pulmonary artery endothelial cells in broiler chickens

“…Cellular signaling pathways involving HIF-1α have been identified as universal biosensors and regulators in a variety of living cells under various hypoxic conditions ( Carmeliet et al, 1998 ). It has been indicated that HIF-1a regulates the cellular response to hypoxia and leads to excessive angiogenesis ( Huynh et al, 2023 ). And when hypoxia occurs, the catabolism of HIF-1α decreases, while its synthesis rate remains unchanged or increases through transcriptional or translational regulatory pathways, the concentration of HIF-1α increases rapidly, and the success of hypoxia modeling can be judged by whether the expression of HIF-1α is elevated ( Fallah and Rini, 2019 ).…”

Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment

“…In addition, inhibition of PD-L1 mediated by the hypoxia-inducible factor (HIF) pathway is an important strategy to enhance cancer immune responses. For example, inhibition of HIF-1α synthesis suppresses PD-L1 expression and induces lysosomal degradation of PD-L1, thereby enhancing the ability of CTL to kill cancer cells ( Huynh et al, 2023 ). In addition, regulating iron metabolism, activating autophagy, or activating nitric oxide synthase 2 (NOS2), thereby promoting TAM metabolic reprogramming towards glycolysis and arginine catabolism, are effective strategies for targeting TAMs for malignancies ( Jayaprakash et al, 2018 ; Muliaditan et al, 2018 ).…”

Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation

“…The targeting of HIFs has been recognized as a prospective strategy for enhancing cancer therapies [ 8 , 9 , 10 ]. A number of small molecular inhibitors targeting HIF have been developed and incorporated into various drug delivery systems.…”