<p>Hypoxia-Induced Aquaporin-3 Changes Hepatocellular Carcinoma Cell Sensitivity to Sorafenib by Activating the PI3K/Akt Signaling Pathway</p>
Authors: Kija Malale
Zhechuan Mei
Xiuni Gan
Jili Fu
Ke Zhan
Liewang Qiu
Journal: Cancer Management and Research (2020)
Discipline: CLINICAL MEDICINE
Keywords: AQP3; PI3K/Akt and Erk signaling pathways; hypoxia; hypoxia-inducible factor 1Œ±; hypoxic HCC cells
Affiliations: Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China., Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China., Department of Nursing, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.

Abstract:  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-1Œ± (HIF-1Œ±) 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. 

Retracted: Yes

PubPeer comments:
 Some bands in Figure 1D appear confused. ***  , 
 Figure 5B may have issues as well. ***  , 
 Figs 1D and 3A: an unexpected coincidence.  , 
 Figs 1D and 5A:  , 
 Retracted [2 December 2021] . ---------------------------- The Editor and Publisher of *Cancer Management and Research* wish to retract the published article. Concerns were raised regarding the alleged duplication of Western Blot images in Figures 1D, 3A, 5A and 5B. The authors responded to our initial queries but were unable to provide a satisfactory explanation for the alleged duplication and could not provide satisfactory original data for their study. The Editor advised for the article to be retracted. The authors wish to apologise for this error. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u201cRetractedu201d. ,