Fig. 1. The interaction between CD44v6 and HA.

HA interacts with the ectodomain of the CD44v6 molecule to facilitate CRC colonization, invasion, and metastasis. Furthermore, HA promotes the phosphorylation of the cytoplasmic domain of CD44v6, which then activates Ras and FAK through Src, thus resulting in activation of MAPK/ERK signaling pathway (red line). Likewise, the interaction between HA and CD44v6 also activates the PI3K/Akt signaling pathway, which increases the resistance of CRC cells to apoptosis (yellow line). Moreover, the interaction between HA and CD44v6 increases the production of MMP2/9, which degrades ECM along with promoting maturation of TGFβ (see ref. ⁶¹). After acting on its receptor, Smad3 will stabilize β-catenin intracellularly together with activated Akt. Then, the expression of EMT-related genes along with the gene encoding CD44v6 increase (see ref. ⁷¹). As a result, the invasive and metastatic capabilities of CRC cells are improved (green line). In addition, the CD44v6 supports the expression of the gene encoding HA synthases in a feedback manner, which further strengthens the above-mentioned effects