Abstract
The ALYREF protein acts as a crucial epigenetic regulator in several cancers. However, the specific expression levels and functional roles of ALYREF in cancers are largely unknown, including for hepatocellular carcinoma (HCC). In a pan-cancer tissue analysis that included HCC, we assessed the expression of ALYREF compared to normal tissues using The Cancer Genome Atlas database. Associations between ALYREF gene expression and the clinical characteristics of HCC patient samples were assessed using the UALCAN database. Kaplan-Meier plots were performed to assess HCC patient prognosis, and the TIMER database was used to explore associations between ALYREF expression and immune-cell infiltrations. The same methods were used to assess eIF4A3 expression in HCC patient samples. In addition, ALYREF- and elF4A3-related differentially expressed genes (DEGs) were determined using LinkedOmics, associated protein functionalities were predicted for positively associated DEGs, and both the TargetScan and miRDB databases were used to predict potential upstream miRNAs for control of ALYREF and eIF4A3 expression. We found that ALYREF gene expression was dysregulated in several cancers and was significantly elevated in HCC patient tissue samples and HCC cell lines. The overexpression of ALYREF was significantly related to both advanced tumor-node-metastasis stages and poor HCC prognosis. Furthermore, we found that eIF4A3 expression was significantly correlated with ALYREF expression, and that upregulated eIF4A3 was significantly associated with poor HCC patient outcomes. In the protein-protein interaction network, we identified eight hub genes based on the positively associated DEGs in common between ALYREF and eIF4A3, and the high expression levels of these hub genes were positively associated with patient clinical outcomes. In addition, we identified miR-4666a-5p and miR-6124 as potential regulators of ALYREF and eIF4A3 expression. These findings suggest that increased ALYREF expression may function as a novel biomarker for both HCC diagnosis and prognosis predictions.
Highlights
It is estimated that over 18.1 million cancer patients, and 9.6 million liver cancer patients, died in 2008 globally [1], with primary liver cancer being the seventh most frequent malignancy in the world
The results demonstrated that Aly/REF nuclear export factor (ALYREF) was dysregulated in tumor tissues compared to normal tissues (Figure 1A), including primary liver cancer (Figure 1B)
The results showed that ALYREF expression in patients with TP53 mutations was upregulated compared to that seen in patient samples without TP53 mutations (Figure 1D)
Summary
It is estimated that over 18.1 million cancer patients, and 9.6 million liver cancer patients, died in 2008 globally [1], with primary liver cancer being the seventh most frequent malignancy in the world. Hepatocellular carcinoma (HCC) is the most prominent histological type of liver cancer and accounts for 75–90% of all cases [3]. Accumulating evidence indicates that the m5C modification status of RNA is associated with the pathogenesis of numerous types of cancers [6,7,8,9], and the aberrant regulation of m5C changes contributes to the pathogenesis of both tumor and non-tumor diseases [8, 10]. Studies have shown that m5Crelated regulators play essential roles in tumor progression in HCC [11, 12]. Research into m5C modifications has provided evidence for the epigenetic m5C regulation of lncRNA related to HCC tumorigenesis and progression [13]. The specific genomic distribution of m5C-related genes for HCC remains unclear
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