Aqp8, an aquaporin protein, belongs to a family of small membrane-spanning proteins involved in fluid transport, cell signalling, and reproduction [5,7]. It not only transports water but also facilitates the bidirectional transport of hydrogen peroxide (H2O2) across cellular membranes, acting as a peroxiporin [1]. In pancreatic β-cells, Aqp8 is crucial for regulating H2O2 homeostasis, which is associated with cell growth and insulin secretion, thus being important for diabetes mellitus pathogenesis [1].

In animal models, Aqp8-deficient mice exhibit impaired hepatic bile formation, characterized by the secretion of concentrated bile and a higher tendency for gallstone formation [6]. In contrast, Aqp8 overexpression in insulin-producing RINm5F cells leads to increased proliferation and insulin content, highlighting its role in H2O2-related processes [1]. In glioma cell lines, knockdown of Aqp8 using CRISPR/Cas9 technology inhibits cell proliferation, migration, and invasion, and affects the ROS/PTEN/AKT and Wnt signalling pathways [2,3,4]. In buffalo granulosa cells, knockdown of Aqp8 by shRNA induces apoptosis and cell cycle arrest at the G2/M stage [5]. In colorectal cancer, over-expression of Aqp8 restrains cell proliferation, migration, and invasion, and in vivo studies using nude mice xenograft models confirm its role in inhibiting cancer growth and metastasis [8,9].

In conclusion, Aqp8 plays essential biological functions in multiple processes such as H2O2 transport, cell proliferation, apoptosis, and bile formation. Gene knockout and knockdown models, including mouse models, have been instrumental in revealing its role in diseases like diabetes, glioma, colorectal cancer, and gallstone formation. These findings provide insights into potential therapeutic targets for these diseases.

References:

1. Krüger, Christina, Waldeck-Weiermair, Markus, Kaynert, Jonas, Michel, Thomas, Elsner, Matthias. 2021. AQP8 is a crucial H2O2 transporter in insulin-producing RINm5F cells. In Redox biology, 43, 101962. doi:10.1016/j.redox.2021.101962. https://pubmed.ncbi.nlm.nih.gov/33892285/

2. Hao, Zhang, Huajun, Sheng, Zhen, Guo, Qingqian, Xia, Shujuan, Zhu. 2023. AQP8 promotes glioma proliferation and growth, possibly through the ROS/PTEN/AKT signaling pathway. In BMC cancer, 23, 516. doi:10.1186/s12885-023-11025-8. https://pubmed.ncbi.nlm.nih.gov/37280594/

3. Cai, Ziling, Shen, Zihao, Zhao, Jing, Sheng, Huajun, Zhu, Shujuan. 2023. AQP8 may affect glioma proliferation and growth by regulating GSK-3β phosphorylation and nuclear transport of β-catenin. In International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 83, 333-345. doi:10.1002/jdn.10261. https://pubmed.ncbi.nlm.nih.gov/37081713/

4. Shen, ZiHao, Sheng, HuaJun, Zhao, Jing, Huang, Juan, Zhu, ShuJuan. 2024. AQP8 Modulates Mitochondrial H2O2 Transport to Influence Glioma Proliferation. In Cancer investigation, 42, 345-356. doi:10.1080/07357907.2024.2352467. https://pubmed.ncbi.nlm.nih.gov/38742677/

5. Cao, Lihua, Li, Sheng, Huang, Shihai, Shi, Deshun, Li, Xiangping. 2021. AQP8 participates in oestrogen-mediated buffalo follicular development by regulating apoptosis of granulosa cells. In Reproduction in domestic animals = Zuchthygiene, 56, 812-820. doi:10.1111/rda.13921. https://pubmed.ncbi.nlm.nih.gov/33639021/

6. Huo, Xiaokui, Yu, Zhenlong, Zhao, Feng, Ma, Xiaochi, Ma, Tonghui. 2024. Hepatocyte aquaporin 8-mediated water transport facilitates bile dilution and prevents gallstone formation in mice. In Journal of hepatology, 82, 464-479. doi:10.1016/j.jhep.2024.09.023. https://pubmed.ncbi.nlm.nih.gov/39326676/

7. Verkman, A S, Mitra, A K. . Structure and function of aquaporin water channels. In American journal of physiology. Renal physiology, 278, F13-28. doi:. https://pubmed.ncbi.nlm.nih.gov/10644652/

8. Zhang, Hui, Du, Wen Bo, Guo, Xiao Min, Cheng, Jun Mei, Wei, Li Jing. 2020. Identification of the AQP8-miR-92a network associated with the aggressive traits of colorectal cancer. In Biochemical and biophysical research communications, 527, 218-225. doi:10.1016/j.bbrc.2020.04.055. https://pubmed.ncbi.nlm.nih.gov/32446370/

9. Wu, De Qing, Yang, Zi Feng, Wang, Ke Jian, Li, Yong, Jian, Zhi Xiang. 2018. AQP8 inhibits colorectal cancer growth and metastasis by down-regulating PI3K/AKT signaling and PCDH7 expression. In American journal of cancer research, 8, 266-279. doi:. https://pubmed.ncbi.nlm.nih.gov/29511597/