Proposed model of novel roles of AQP3 and AQP5 in tumor biology. AQP5 are exclusively selective for water while AQP3 can transport water and other small neutral solutes such as glycerol. AQP3 increases intracellular glycerol content which is transported to mitochondria to form ATP. Mitochondrial ATP formation provides energy for tumor cell proliferation. AQP3 can directly or indirectly reduce the natural degradation of HIF-1α/ HIF-2α to increase the expression of vascular endothelial growth factor (VEGF), which is a critical regulator in tumor angiogenesis and vessel maturation. AQP3 may directly or indirectly activate AKT to increase MMPs, resulting in tumor invasion. AQP5 induces activation of the epidermal growth factor receptor (EGFR), extracellular receptor kinase (ERK1/2) pathway to faciliate tumor cell proliferation and metastasis. In addition, AQP5 is phosphorylated on Ser156 and bind the the SH3 domain of Src to promote EMT activity in tumor cells. The roles of AQP3 and AQP5 in these pathways are not fully elucidated and still need further exploration.