Aquaporin 3 promotes the stem-like properties of gastric cancer cells via Wnt/GSK-3β/β-catenin pathway.

Yangchun Zhou,Haijian Zhao,Lizong Shen,Xuqiang Dong,Jianfei Wen,Shoulin Wang,Zhihong Zhang,Yao Wang

doi:10.18632/oncotarget.7664

Yangchun Zhou, Haijian Zhao + Show 6 more

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https://doi.org/10.18632/oncotarget.7664

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Abstract

Cancer stem cells (CSCs) are believed to contribute to the tumor growth in gastric carcinoma (GC), a common lethal malignancy. This study investigated the effect of aquaporin 3 (AQP3) on stem-like properties of human GC cells. Elevated AQP3 expression was associated with CD44 expression in human GC specimens. Expression of AQP3 and that of CD44 positively correlated with Lauren classification, lymph node metastasis, and lymphovascular invasion. Altering the AQP3 expression had pronounced effects on the tumorigenic potential and self-renewal capacity of the gastric cancer cell lines SGC7901, MGC803, and AGS, both in vitro and in vivo. Overexpression of AQP3 induced CD44 expression and activation of the β-catenin signaling pathway, whereas silencing AQP3 expression using short hairpin RNA had the opposite effect. Furthermore, pharmacological inhibition of GSK-3β using LiCl impaired the effect of AQP3 knockdown in CSCs, whereas the inhibition of the Wnt/β-catenin pathway by XAV939 blocked the effect of AQP3 overexpression. These results demonstrate that AQP3 promotes stem-like properties of human GC cells by activating the Wnt/GSK-3β/β-catenin signaling pathway.

Highlights

Gastric carcinoma (GC) remains as a common lethal malignancy worldwide [1]
aquaporin 3 (AQP3) expression correlates with CD44 expression in GC tissues
The results showed that elevated expression of AQP3 in cancer tissues was associated with the Lauren classification (P = 0.034), lymph node metastasis (P = 0.006), and lymphovascular invasion (P = 0.024)

Summary

Introduction

Gastric carcinoma (GC) remains as a common lethal malignancy worldwide [1]. Multistep and multi-factorial processes involving various genetic and molecular alterations, including the activation of various oncogenes and the inactivation of tumor suppressor genes, are involved in the development of GC [3,4,5]. Mounting evidence suggests that most human cancers, including gastric cancer, are driven by a rare population of cancer cells, the cancer stem cells (CSCs), that display stem cell-like properties [6]. CSCs have the ability to initiate tumor growth and sustain tumor self-renewal. CD44 is an important cell surface marker of breast, pancreatic, colorectal, and prostate cancers [7,8,9,10]. Recent studies have identified CD44 as the most significant marker of gastric CSCs [11, 12]

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