Hypoxia-inducible factor-2α (HIF-2α) modulates WNT signaling by maintaining the levels of both SMAD4 and β-catenin during PanIN progression.109 Moreover, hypoxic conditions in pancreatic tumors stabilize HIF-2α, which interacts with β-catenin, leading to elevated canonical WNT/β-catenin activity while favoring tumor progression.110. This evidence concerns the gene SMAD4 and neoplasm.