In conclusion, we propose that SB3 (Figure 9), whose expression is significantly associated with the worst clinical outcome in HCC patients [37], potentially acts as a paracrine mediator able to affect the behavior of surrounding normal and cancer cells by differently modulating, independently on hypoxic microenvironment, the expression of HIF-1α and HIF-2α proteins, with HIF-1α facilitating cell survival in a harsh microenvironment by inducing early cellular metabolic switch to glycolytic phenotype and HIF-2α potentially promoting proliferation and tumor progression. This evidence concerns the gene EPAS1 and hepatocellular carcinoma.