Abstract
BackgroundThis study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment.MethodsAberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed.ResultsTotally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo.ConclusionsThis study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy.
Highlights
This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment
By Principal component analysis (PCA), we removed three hepatoblastoma samples “GSM1948566”, “GSM1948577”, “GSM1948562” that were close to normal liver tissues
1364 differentially expressed genes were screened for hepatoblastoma than normal samples, including 756 up- and 608 down-regulated genes (Fig. 1D)
Summary
This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment. Hepatoblastoma represents a predominant pediatric liver cancer [1]. This malignancy mainly occurs in the first three years after birth [2]. Combination of surgery and chemotherapy is a typical treatment strategy. Despite overall survival rate up to 80%, patients in advanced stages are usually refractory to typical therapy [3]. Some subjects present poor prognostic factors such as non-chemotherapy resistance and metastases, thereby reducing survival time [4]. It is of significance for revealing the mechanisms of hepatoblastoma and probing novel therapeutic targets for hepatoblastoma subjects
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