For example, in human melanoma cells, HA-CD44 signaling has been shown to upregulate the expression of TfR on the cell surface, facilitating iron uptake by binding transferrin loaded with Fe3+ and mediating its endocytosis.35 Interestingly, another CSC marker, CD133, has been shown to play a role in facilitating iron uptake by human colorectal cancer cells.36 Recent studies have shown that CD44 directly facilitates intracellular iron uptake by mediating endocytosis of iron-bound HA. This evidence concerns the gene CD44 and colorectal cancer.