Furthermore, CRC cells with AQP9 overexpression displayed enhanced activation of RAS and downstream PI3K/AKT and ERK signaling, which have been shown to regulate cell differentiation and cell cycle arrest via inhibition of GSK3β and upregulation of p21.40, 41 Substantial evidences have indicated that p21 can promote cell differentiation and cellular senescence.42 Hence, this could also explain our clinical finding that AQP9 level is associated with tumor differentiation grade (Table 1). This evidence concerns the gene GSK3B and colorectal carcinoma.