Aquaporin 9 inhibits hepatocellular carcinoma through up-regulating FOXO1 expression.

Chuan-Fei Li,Zhe-Chuan Mei,Xiao-Feng Chen,Wen-Guang Zhang,Lin Lv,Lie-Wang Qiu,Min Liu

doi:10.18632/oncotarget.10143

Abstract

Aquaporin 9 (AQP9) is the main aquaglyceroporin in the liver. Few studies have been performed regarding the role of AQP9 in liver cancer. Here we report AQP9 expression and function in liver cancer. We found that AQP9 mRNA and protein levels were reduced in human hepatocellular cancer compared to the para-tumor normal liver tissues. Human hepatoma cell line SMMC7721 expressed low basal levels of AQP9. When AQP9 was overexpressed in SMMC7721 cell line, cell proliferation was inhibited due to cell cycle arrest at G1 phase and increased apoptosis. At the molecular level, AQP9 overexpression decreased the protein levels of phosphatidylinositol-3-kinase (PI3K), leading to reduced phosphorylation of Akt. Subsequently, the protein levels of forkhead box protein O1 (FOXO1) were increased, resulting in down-regulation of proliferating cell nuclear antigen (PCNA) expression and up-regulation of caspase-3 expression. AQP9 overexpression inhibited growth of subcutaneously xenografted liver tumors in nude mice. These findings suggest that AQP9 expression is down-regulated in liver cancer compared to the normal liver tissue and restoration of AQP9 expression can inhibit development of liver cancer.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and is the third leading cause of cancer-related deaths after lung and gastric cancers [1]
We found that Aquaporin 9 (AQP9) mRNA and protein levels were reduced in human hepatocellular cancer compared to the para-tumor normal liver tissues
Pathologic diagnosis of normal liver tissues and HCC was confirmed by hematoxin and eosin (H&E) staining (Figure 1A and 1C)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and is the third leading cause of cancer-related deaths after lung and gastric cancers [1]. Aquaporins (AQPs) are transmembrane proteins that mediate water molecules transporting across the cytoplasmic membrane. 13 AQP subtypes (AQP0-AQP12) have been identified in mammalian cells [2]. AQPs are divided into three categories: (1) orthodox aquaporins, including AQP1/2/4/5; (2) aquaglyceroporins, including AQP3/7/9/10; and (3) unorthodox aquaporins, including AQP6/8/11/12 [3]. Aquaglyceroporins are permeable to water, glycerin, urea and other small solutes, and mediates transport of 5-fluorouracil and other anticancer drugs [4]. AQPs are widely distributed in human tissues and have been found to be involved in edema [5], glucose and lipid metabolism [6, 7], and skin physiology [8] as well as cell migration [9]. AQPs play different roles in different tissues and organs

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