AQP3 Promotes the Invasion and Metastasis in Cervical Cancer by Regulating NOX4-derived H2O2 Activation of Syk/PI3K/Akt Signaling Axis

Unrestrained chronic inflammation leads to the abnormal activity of NOX4 and the subsequent production of excessive hydrogen peroxide (H₂O₂). Excessive H₂O₂ signaling triggered by prolonged inflammation is thought to be one of the important reasons for the progression of some types of Cancer including cervical Cancer. Aquaporin 3 (AQP3) is a member of the water channel protein family, and it remains unknown whether AQP3 can regulate the transmembrane transport of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)-derived H₂O₂ induced by the stimulation of inflammatory factors to facilitate the malignant progression in cervical Cancer. In this study, cervical Cancer HeLa cell line was respectively treated with diphenyleneiodonium (DPI), N-Acetylcysteine (NAC) or lentivirus-shRNA- AQP3. Plate cloning, cell migration or transwell invasion assays, etc. were performed to detect the invasive and migration ability of the cells. Western blot and CO-IP were used to analyze the mechanism of AQP3 regulating H₂O₂ conduction. Finally, in vivo assays were performed for validation in nude mice. AQP3 Knockdown, DPI or NAC treatments all reduced intracellular H₂O₂ influx, and the activation of Syk/PI3K/Akt signal axis was inhibited, the migration and invasive ability of the cells was attenuated. In vivo assays confirmed that the excessive H₂O₂ transport through AQP3 enhanced the infiltration and metastasis of cervical Cancer. These results suggest that AQP3 activates H₂O₂/Syk/PI3K/Akt signaling axis through regulating NOX4-derived H₂O₂ transport to contribute to the progression of cervical Cancer, and AQP3 may be a potential target for the clinical treatment of advanced cervical Cancer.

AQP3; Akt; Cervical cancer; H2O2; Syk.