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Hypoxia-Induced Aquaporin-3 Changes Hepatocellular Carcinoma Cell Sensitivity to Sorafenib by Activating the PI3K/Akt Signaling Pathway

Authors Malale K, Fu J, Qiu L, Zhan K, Gan X, Mei Z

Received 30 December 2019

Accepted for publication 12 May 2020

Published 9 June 2020 Volume 2020:12 Pages 4321—4333

DOI https://doi.org/10.2147/CMAR.S243918

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Beicheng Sun


Kija Malale,1 Jili Fu,2 Liewang Qiu,1 Ke Zhan,1 Xiuni Gan,3 Zhechuan Mei1

1Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Nursing, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

Correspondence: Xiuni Gan
Department of Nursing, The Second Affiliated Hospital of Chongqing Medical University, 76, Linjiang Road, Yuzhong District, Chongqing 400010, People’s Republic of China
Tel +86 138 83309318
Fax +86 023 63711527
Email ganxn@163.com
Zhechuan Mei
Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, 76, Linjiang Road, Yuzhong District, Chongqing 400010, People’s Republic of China
Tel +86 136 08338519
Fax +86 236 3711527
Email meizhechuan@cqmu.edu.cn

Purpose: Hypoxia-induced changes are primarily activated in patients with hepatocellular carcinoma (HCC) and long-term sorafenib exposure, thereby reducing the sensitivity to the drug. Aquaporin-3 (AQP3), a member of the aquaporin family, is a hypoxia-induced substance that affects the chemosensitivity of non-hepatocellular tumors. However, its expression and role in the sensitivity of hypoxic HCC cells to sorafenib-induced apoptosis remain unclear. The purpose of this study was to detect changes in AQP3 expression in hypoxic HCC cells and to determine whether these changes alter the sensitivity of these cells to sorafenib.
Materials and Methods: Huh7 and HepG2 hypoxic cell models were established and AQP3 expression was detected using quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Furthermore, the role of AQP3 in cell sensitivity to sorafenib was evaluated via flow cytometry, Western blotting, and a CCK-8 assay.
Results: The results of qPCR and Western blotting showed that AQP3 was overexpressed in the Huh7 and HepG2 hypoxic cell models. Furthermore, AQP3 protein levels were positively correlated with hypoxia-inducible factor-1α (HIF-1α) levels. Compared with cells transfected with lentivirus-GFP (Lv-GFP), hypoxic cells transfected with lentivirus-AQP3 (Lv-AQP3) were less sensitive to sorafenib-induced apoptosis. However, the sensitivity to the drug increased in cells transfected with lentivirus-AQP3RNAi (Lv-AQP3RNAi). Akt and Erk phosphorylation was enhanced in Lv-AQP3-transfected cells. Compared with UO126 (a Mek1/2 inhibitor), LY294002 (a PI3K inhibitor) attenuated the AQP3-induced insensitivity to sorafenib observed in hypoxic cells transfected with Lv-AQP3. Combined with LY294002-treated cells, hypoxic cells transfected with Lv-AQP3RNAi were more sensitive to sorafenib.
Conclusion: The study results show that AQP3 is a potential therapeutic target for improving the sensitivity of hypoxic HCC cells to sorafenib.

Keywords: AQP3, hypoxia, hypoxic HCC cells, hypoxia-inducible factor 1α, PI3K/Akt and Erk signaling pathways, sorafenib resistance

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