Proposed model of novel role of AQP1 in tumor biology. Tumor cells increase glycose consumption to produce lactic acid, which results in excess H+ production and intracellular acidosis. The increase in glycolytic intermediates may up-regulate AQP1, LDH, and cathepsin B through the E-box/ChoRE. Excess H+ and HCO3
- are catalyzed by intracellular CAII to produce H2O and CO2. The reaction-generated H2O is transported to extracellular space to aviod cytotoxic edema by up-regluated AQP1. CO2 may or may not leave the cells through AQP1. Membrane-bound extracellular CA IX and XII may regenerate H+ from extracellular H2O and CO2, thus leading to shutting H+ from the intracellular to the extracellular space to keep the acidification of the extracellular compartment. The acid extracellular environment promotes cells to release cathepsin B, a proteolytic enzyme involved in tumor invasion. AQP1 can induce the activity of RhoA and Rac to increase tumor migration and metastasis. The detailed role of AQP1 in this pathway need more studies.