PDF(Pubmed)
Abstract：
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.
摘要：
不受约束的慢性炎症导致NOX4的异常活性和随后产生过量的过氧化氢(H2O2)。由长期炎症引发的过量H2O2信号被认为是包括宫颈癌在内的某些类型癌症进展的重要原因之一。水通道蛋白3(AQP3)是水通道蛋白家族中的一员,目前尚不清楚AQP3是否能调节炎症因子刺激诱导的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶4（NOX4）衍生的H2O2的跨膜转运，促进宫颈癌的恶性进展。在这项研究中,分别用二苯基碘（DPI）治疗宫颈癌HeLa细胞系，N-乙酰半胱氨酸(NAC)或慢病毒-shRNA-AQP3。平板克隆,细胞迁移或transwell侵袭试验，等。进行检测细胞的侵袭和迁移能力。Westernblot和CO-IP分析AQP3调节H2O2传导的机制。最后,在裸鼠中进行体内试验验证.AQP3击倒,DPI或NAC治疗均减少了细胞内H2O2流入，Syk/PI3K/Akt信号轴的激活被抑制,细胞的迁移和侵袭能力减弱。体内实验证实，通过AQP3的过量H2O2转运增强了宫颈癌的浸润和转移。这些结果表明，AQP3通过调节NOX4衍生的H2O2转运激活H2O2/Syk/PI3K/Akt信号轴，有助于宫颈癌的进展。AQP3可能是晚期宫颈癌临床治疗的潜在靶点。
