Roles of hypoxia-inducible factor in hepatocellular carcinoma under local ablation therapies

Abstract

Hepatocellular carcinoma (HCC) is one of the most common digestive malignancies. HCC It ranges as the fifth most common cause of cancer mortality worldwide. While The prognosis of metastatic or advanced HCC is still quite poor. Recently, locoregional treatment, especially local ablation therapies, plays an important role in the treatment of HCC. Radiofrequency ablation (RFA) and high-intensity focused ultrasound (HIFU) ablation are the most common-used methods effective and feasible for treating HCC. However, the molecular mechanisms underlying the actions of ablation in the treatments for HCC and the HCC recurrence after ablation still are poorly understood. Hypoxia-inducible factor (HIF), the key gene switch for adaptive responses to hypoxia, has been found to play an essential role in the rapid aggressive recurrence of HCC after ablation treatment. In this review, we summarized the current evidence of the roles of HIF in the treatment of HCC with ablation. Fifteen relevant studies were included and further analyzed. Among them, three clinical studies suggested that HIF-1α might serve as a crucial role in the RAF treatment of HCC or the local recurrence of HCC after RFA. The remainder included experimental studies demonstrated that HIF-1, 2α might target the different molecules (e.g., BNIP3, CA-IX, and arginase-1) and signaling cascades (e.g., VEGFA/EphA2 pathway), constituting a complex network that promoted HCC invasion and metastasis after ablation. Currently, the inhibitors of HIF have been developed, providing important proof of targeting HIF for the prevention of HCC recurrence after IRFA and HIFU ablation. Further confirmation by prospective clinical and in-depth experimental studies is still warranted to illustrate the effects of HIF in HCC recurrence followed ablation treatment in the future.

Dynamic contrast-enhanced magnetic resonance imaging assessment of residual tumor angiogenesis after insufficient microwave ablation and donafenib adjuvant therapy

“…However, the tumor recurrence rate after thermal ablation is still high. Hypoxia and hypoxia-driven angiogenesis play important roles in tumor progression, and the hypoxic environment generated by local ablation may induce the overexpression of a variety of angiogenesis-related cytokines 12 , 13 , among which VEGF is a key factor 14 , 15 . It has been well documented 16 – 18 that VEGF is closely associated with the development and prognosis of malignant tumors such as HCC.…”

Salvigenin Suppresses Hepatocellular Carcinoma Glycolysis and Chemoresistance Through Inactivating the PI3K/AKT/GSK-3β Pathway

“…HCC development, a sophisticated biological process, concerns multiple molecular and cellular signaling pathways [ 29 ]. Conventional treatment strategies are usually accompanied by high recurrence and metastasis rates.…”

Clinical Results, Risk Factors, and Future Directions of Ultrasound-Guided Percutaneous Microwave Ablation for Hepatocellular Carcinoma

“…15,16 Hypoxic microenvironment contributes to the development of malignant phenotype of HCC, including local progression, recurrence, and chemotherapy resistance. 17,18…”