Table 1.

Hypoxia and sorafenib resistance in HCC

Cell lines/animal models/human samples	Effects on HIF after sorafenib treatment	Global effects	References
HCCs from patients HepG2, Huh7, PLC-5, Hep3B, and SK-Hep-1 cells BALB/c mice inoculated with Hep3B or Huh7 and orthotopic Huh7 hepatic tumors	↑ HIF-1α	↑ GLUT-1, MDR1, and VEGF Activation of NF-κB	32
Human HCC samples HepG2, SMMC-7721, BEK-7402, Hep3B, and Huh7 cells BALB/c nude mice subcutaneous model with HepG2 cells	↑ HIF-1α	↑ GLUT-1, MDR1, and VEGF	44
Sorafenib-resistant Huh7 cells (Huh7R) Tumor xenograft model by subcutaneously injecting Huh7 and Huh7R cells in BALB/c nude mice	↑ HIF-1α	↑ Galectin-1	45
HCC samples HepG2, SMMC-7721, MHCC-LM3, and CSQT-2 cells DEN-induced HCC in C57BL/6 mice Mouse xenograft model derived from SMMC-7721 cells	↑ HIF-1α	↑ GLUT-1, HK2, PDK1, LDHA, and VEGF	46
HCC-LM3 and Bel-7402 cells BALB/c nu/nu injected with HCC-LM3 cells	↑ HIF-1α	↑ GLUT-1 and HK2	47
HepG2 and Huh7 cells BALB/c mice with Huh7 subcutaneously injected	↓ HIF-1α ↑ HIF-2α	Activation of TGF-α/EGFR	26
HepG2 and Huh7 cells BALB/c mice with Huh7 subcutaneously injected	↓ HIF-1α ↑ HIF-2α	↑ VEGF and cyclin D1 ↓ LDHA	25
HepG2, Huh7, and SK-Hep-1 cells Mice HCC nodules Orthotopic HCC mouse models with SK-Hep-1 cells	↑ HIF-2α	↑ AR	25
HepG2, Huh7, Bel-7402, and SMMC-7402 cells BALB/c mice subcutaneously inoculated with HepG2	↓ HIF-1α ↑ HIF-2α	↑ β-catenin/c-Myc/PCNA	34
HCC cells	↑ HIF-2α	–	49
MHCC97H cells BALB/c mice subcutaneously injected with MHCC97H cells	↑ HIF-2α	↓ TIP30	50

AR androgen receptor, c-Myc Myc proto-oncogene protein, DEN diethylnitrosamine, EGFR epidermal growth factor receptor, GLUT-1 glucose transporter 1, HCC hepatocellular carcinoma, HIF hypoxia-inducible factor, HK2 hexokinase 2, LDHA lactate dehydrogenase A, MDR1 multidrug resistance protein 1, PCNA proliferating cell nuclear antigen, PDK1 pyruvate dehydrogenase kinase isoform 1, TGF-α transforming growth factor α, TIP30 oxidoreductase HTATIP2, VEGF vascular endothelial growth factor