Low expression of AQP9 and its value in hepatocellular carcinoma

Abstract

Background: The mortality rate for liver cancer is high worldwide. The etiology of liver cancer has altered with the high incidence rate of non-alcoholic fatty liver disease (NAFLD) although effective vaccination strategies have been developed. Therefore, it is important to discover new biomarkers for diagnosis and prognosis. Aquaporin 9 (AQP9) has been reported in some cancers, especially in liver cancer, although its role in this malignancy remains to be clarified. In this study, we conducted a bioinformatics analysis to clarify the function of AQP9 in liver cancer.Methods: Immunohistochemistry, real-time qPCR, western blot analysis were applied to detect AQP9 expression in tissue samples or cells. Online databases were used to analyze the correlation of AQP9 expression and clinical factors. LinkedOmics and gene set enrichment analysis (GSEA) were used to analyze the functional network of AQP9 in hepatocellular carcinoma (HCC). Four authoritative databases were used to predict the candidate microRNAs that bind to AQP9. Finally, we used the Tumor Immune Estimation Resource (TIMER) to assess the correlation of AQP9 and immune cell infiltration in HCC.Results: All analysis were revealed AQP9 is significantly decreased in HCC tissues and cells. AQP9 was negatively correlated with different tumor stage, grade, and weight, as well as lymph node metastasis, sex, and histological subtypes. AQP9 can be used to predict the prognosis of HCC patients. GSEA revealed that AQP9 was significantly involved in most significant hallmark pathways. LinkedOmics was used to analyze the relationship of AQP9 with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Mechanistically, mir-23a-3p and mir-330-3p may downregulate AQP9 expression in HCC. AQP9 was found to be specifically correlated with immune cell infiltration and play a major role in the liver cancer microenvironment.Conclusions: In this study, we found that AQP9 was significantly decreased in HCC, with low AQP9 levels indicating a poor outcome. GSEA analysis and LinkedOmics revealed that AQP9 was significantly involved in the most significant hallmarks pathways. Mir-23a-3p and mir-330-3p may inhibit AQP9 expression in HCC. Our results also suggest that AQP9 is important in tumor immunity in the liver cancer.

Identification of Specific Biomarkers and Pathways in the Treatment Response of Infliximab for Inflammatory Bowel Disease: In-Silico Analysis

“…They are considerably small (26–34 kD) and very hydrophobic, with intrinsic membrane proteins, and AQP9 specifically contains two additional peptide spans compared to the other subtypes. The AQPs family is found in the plasma membranes of various cells and functions to transport fluid across the cell membrane [ 32 ]. In a study that aimed to obtain and characterize a dataset of significant DEGs of treatment naïve UC patients compared to healthy controls, 1480 DEGs were found in UC patients.…”

The Multifaceted Role of Aquaporin-9 in Health and Its Potential as a Clinical Biomarker

“…Majority of the primary hepatic cancer burden pertains to HCC, with liver cancer representing the sixth most common oncologic condition and the second-leading cause of death from malignant neoplasm around the world [ 99 ]. AQP9 was shown to be consistently downregulated in HCC tissues and cells compared to normal liver tissues and hepatocyte cell lines, respectively [ 30 , 31 , 32 , 33 , 34 , 35 ]. Interestingly, AQP9-overexpressing human HCC SMMC-7721 cells displayed increased expression of E-cadherin and decreased expression of N-cadherin in vitro and in xenografted tumors that were positively correlated with decreased levels of phosphoinositide 3-kinase (PI3K) and p-Akt.…”

“…The microRNAs mir-23a-3p and mir-330-3p were correlated with AQP9 inhibition upon HCC. Moreover, AQP9 was shown to be critical in tumor immunity in liver cancer [ 32 ].…”

“…Leukocytes are another major site of expression for this AQP. In recent years, AQP9 implication in a variety of disorders, including liver injury [ 28 ], inflammation [ 29 ], cancer [ 30 , 31 , 32 , 33 , 34 , 35 ], and altered immune response [ 36 , 37 , 38 ], revealed AQP9 as a promising drug target and a diagnostic/prognostic biomarker in clinical medicine.…”

Integrated multiple microarray studies by robust rank aggregation to identify immune-associated biomarkers in Crohn's disease based on three machine learning methods

“…Several studies have reported that AQP9 is a promising biomarker in CD patients 12 , 67 , 68 . Interestingly, AQP9 has also been reported as a prognostic indicator of many cancers in recent years and is related to immune infiltration 69 – 72 . Similar to CD, AQP9 expression is significantly increased in colon cancer 69 .…”