Hypoxia‑inducible factors in hepatocellular carcinoma (Review)

Abstract

Maintenance of an appropriate oxygen concentration is essential for the function of the liver. However, in many pathological conditions, and particularly in the tumor microenvironment, cells and tissues are frequently in a hypoxic state. In the presence of hypoxia, the cells adapt to the low oxygen levels through the hypoxia-inducible factor (HIF) pathway. Overgrowth of tumor cells restricts the diffusion of oxygen in tumors, leading to insufficient blood supply and the creation of a hypoxic microenvironment, and, as a consequence, activation of the expression of HIFs. HIFs possess a wide range of target genes, which function to control a variety of signaling pathways; thus, HIFs modulate cellular metabolism, immune escape, angiogenesis, metastasis, extracellular matrix remodeling, cancer stem cells and other properties of the tumor. Given their crucial role in the occurrence and development of tumors, HIFs are expected to become new targets of precise treatment of hepatocellular carcinoma.

HIF-1α promotes hepatocellular carcinoma metastasis by regulating angiogenesis and epithelial-mesenchymal transition

“…HCC is one of the most common malignant cancers worldwide and a high malignancy solid tumor with hypoxia microenvironment, high-vascular, and traditional-therapy resistance [16,17] . HIF-1α is a key transcription regulator for many genes and promotes tumorigenicity by up-regulating its target genes, which were involved in apoptosis, proliferation, angiogenesis, invasion and metastasis of HCC such as VEGF, Ang-2, Wnt3a, IGF-II, and so on [18,19] .…”

Role of hypoxia inducible factor-1 in cancer stem cells (Review)

“…miR-21 and HIF-1α are positively correlated in multiple tumors, and miR-126 and HIF-1α are significantly negatively correlated in colon cancer, thus indicating that their expression could be used for the early diagnosis and screening of cancer (46,48,49). miR-21 and miR-130b activate EMT through the phosphatase and tensin homolog/Akt/HIF-1α pathway and promote hepatocellular carcinoma metastasis (50). HIF-1α binds to the miR-1275 promoter, which promotes miR-1275 expression and maintains the pluripotency of stem cells by activating the β-catenin and Notch signaling pathways in lung adenocarcinoma (51).…”

“…Studies have found that the PI3K/Akt/mTOR pathway maintains the transcription, translation and biological activity of HIF-1α (54,124). Hypoxia also induces tuftelin 1 in a HIF-1α-dependent manner; subsequently, tuftelin1 activates the Ca 2+ /PI3K/Akt pathway to induce EMT and metastasis in hepatocellular carcinoma (50). HIF-1α promotes the survival of prostate CSCs by inhibiting mTOR and activating Akt phosphorylation, which may be accomplished by the feedback regulation of PI3K via P70-S6K-mediated insulin receptor substrate 1 phosphorylation (125).…”

“…The mitochondrial autophagy regulator NIX interacts with Ras homolog enriched in the brain to activate mTOR/Akt/HIF signaling, and subsequently increase the self-renewal capacity of glioma stem cells (126). The Wnt/β-catenin signaling pathway activates the transcription of HIF-1α, inhibits the apoptosis of hepatocellular carcinoma and promotes the occurrence of EMT, and then triggers the metastasis of hepatocellular carcinoma (50). Conversely, HIF-1α maintains the stemness of esophageal squamous cell carcinoma by activating the Wnt/β-catenin signaling pathway (127).…”

“…Studies have also suggested that the hypoxia/Notch1/SOX2 axis is essential for the development of ovarian CSCs (81). The combination of HIF-1α and notch intracellular domain activates Notch-responsive promoters and increases the expression of Notch downstream genes, such as Hes1 and Hey2, and Hes1 is important in the stemness maintenance and self-renewal of leukemia stem cells (50,81). In addition, studies have suggested that there is negative feedback regulation of the Hes1 expression, which is completed by the combination of Hes1 and N-boxes on the Hes1 promoter (132).…”