Aqp3, short for aquaporin 3 (Gill blood group), is an aquaglyceroporin in the AQP family. It transports water, glycerol, small solutes, and hydrogen peroxide across the plasma membrane. Aqp3 is involved in multiple biological processes, such as regulating cell proliferation, migration, invasion, and autophagy, and plays a role in pathways like PDPK1-AKT-MTOR, PI3K/Akt, and AMPK/SIRT1 [2,3,4]. It is also important in maintaining redox status, inflammatory response, and tumor microenvironment regulation [1,4,5]. Genetic models, especially knockout (KO) mouse models, are valuable for studying its functions.

In hepatocellular carcinoma cells, SCFFBXW5-mediated degradation of AQP3 suppresses autophagic cell death via the PDPK1-AKT-MTOR axis, as FBXW5 knockdown induces AQP3 expression, leading to PDPK1 degradation and inactivation of the AKT-MTOR pathway [2]. In breast cancer cell lines, AQP3-silencing shows that AQP3 can modulate PI3K/Akt activation in a cell-line-dependent manner [3]. In a mouse model of cholelithiasis, AQP3 is significantly down-regulated, and its overexpression activates the AMPK/SIRT1 signaling pathway, reducing inflammatory injury of gallbladder mucosal epithelial cells and repressing gallstone formation [4]. In lung adenocarcinoma, AQP3 promotes M2 macrophage polarization through the PPAR-γ/NF-κB axis, affecting tumor growth and migration via modulating IL-6 production. Aqp3 knockout mice models further confirm its role in mediating M2 macrophage polarization, modulating glucose metabolism in tumors, and regulating related pathways [5]. In rosacea, AQP3 deletion blocks the development of rosacea-like skin inflammation in model mice, as AQP3 is essential for the activation of NF-κB signaling in keratinocytes and promotes Th17 differentiation in CD4+ T cells [6]. In sepsis, AQP3 mRNA expression increases during sepsis and is correlated with lymphocyte count, with high AQP3 expression associated with increased survival [7]. In porcine intramuscular adipocytes, knockdown of AQP3 by siRNA suppresses adipogenic gene expression, represses Akt phosphorylation, reduces lipid accumulation, and decreases cell proliferation [8]. In lung adenocarcinoma cells, AQP3-mediated H2O2 uptake inactivates PTEN, activates the AKT/mTOR pathway, inhibits autophagy, and promotes proliferation. AQP3 depletion retards subcutaneous tumorigenesis in vivo [9].

In conclusion, Aqp3 is crucial in various biological processes and disease conditions. Studies using KO/CKO mouse models have revealed its roles in cancer development, autophagy regulation, inflammatory-related diseases like cholelithiasis and rosacea, and in sepsis. These findings provide valuable insights into the functions of Aqp3 and potential therapeutic targets for related diseases.

References:

1. Milković, Lidija, Čipak Gašparović, Ana. 2021. AQP3 and AQP5-Potential Regulators of Redox Status in Breast Cancer. In Molecules (Basel, Switzerland), 26, . doi:10.3390/molecules26092613. https://pubmed.ncbi.nlm.nih.gov/33947079/

2. Liang, Yupei, Chen, Ping, Wang, Shiwen, Wei, Wenyi, Jia, Lijun. 2024. SCFFBXW5-mediated degradation of AQP3 suppresses autophagic cell death through the PDPK1-AKT-MTOR axis in hepatocellular carcinoma cells. In Autophagy, 20, 1984-1999. doi:10.1080/15548627.2024.2353497. https://pubmed.ncbi.nlm.nih.gov/38726865/

3. Mlinarić, Monika, Lučić, Ivan, Milković, Lidija, Soveral, Graça, Čipak Gašparović, Ana. 2023. AQP3-Dependent PI3K/Akt Modulation in Breast Cancer Cells. In International journal of molecular sciences, 24, . doi:10.3390/ijms24098133. https://pubmed.ncbi.nlm.nih.gov/37175840/

4. Wang, Ganggang, Zhang, Hao, Zhou, Zhijie, Ma, Zenghui, Wang, Xiaoliang. 2023. AQP3-mediated activation of the AMPK/SIRT1 signaling pathway curtails gallstone formation in mice by inhibiting inflammatory injury of gallbladder mucosal epithelial cells. In Molecular medicine (Cambridge, Mass.), 29, 116. doi:10.1186/s10020-023-00712-8. https://pubmed.ncbi.nlm.nih.gov/37641009/

5. Lin, Guofu, Lin, Lanlan, Chen, Xiaohui, Zeng, Yiming, Xu, Yuan. 2024. PPAR-γ/NF-kB/AQP3 axis in M2 macrophage orchestrates lung adenocarcinoma progression by upregulating IL-6. In Cell death & disease, 15, 532. doi:10.1038/s41419-024-06919-9. https://pubmed.ncbi.nlm.nih.gov/39060229/

6. Chen, Mengting, Peng, Qinqin, Tan, Zixin, Shi, Wei, Deng, Zhili. 2023. Targeting Aquaporin-3 Attenuates Skin Inflammation in Rosacea. In International journal of biological sciences, 19, 5160-5173. doi:10.7150/ijbs.86207. https://pubmed.ncbi.nlm.nih.gov/37928265/

7. Thon, Patrick, Rahmel, Tim, Ziehe, Dominik, Koos, Björn, Rump, Katharina. 2024. AQP3 and AQP9-Contrary Players in Sepsis? In International journal of molecular sciences, 25, . doi:10.3390/ijms25021209. https://pubmed.ncbi.nlm.nih.gov/38279209/

8. Wang, Xiaoyu, Yang, Jing, Yao, Ying, Yang, Gongshe, Li, Xiao. 2020. AQP3 Facilitates Proliferation and Adipogenic Differentiation of Porcine Intramuscular Adipocytes. In Genes, 11, . doi:10.3390/genes11040453. https://pubmed.ncbi.nlm.nih.gov/32331274/

9. Wang, Yawei, Chen, Di, Liu, Yu, Piao, Hai-Long, Liu, Hong-Xu. 2021. AQP3-mediated H2 O2 uptake inhibits LUAD autophagy by inactivating PTEN. In Cancer science, 112, 3278-3292. doi:10.1111/cas.15008. https://pubmed.ncbi.nlm.nih.gov/34091997/