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.

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