Multi-Omic Analyses of the m5C Regulator ALYREF Reveal Its Essential Roles in Hepatocellular Carcinoma

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.

Roles of m5C RNA Modification Patterns in Biochemical Recurrence and Tumor Microenvironment Characterization of Prostate Adenocarcinoma

“…Moreover, increasing evidence has recently proven that RNA modification regulators had the potential to act as the biomarkers for diagnosis and prognostic monitoring in cancer ( 54 – 56 ). The m5C reader ALYREF expression was dysregulated in several cancers, and higher ALYREF expression was associated with poor prognosis in hepatocellular carcinoma ( 57 ). Some studies indicated that m5C writers NSUN3 and NSUN4 were associated with the infiltration of some immune cells, such as CD8+ T cells and neutrophils ( 58 ).…”

ALYREF associated with immune infiltration is a prognostic biomarker in hepatocellular carcinoma

“…Some studies have found that expression of ALYREF is related to the prognosis of HCC patients through public database analysis [13] . Nevertheless, the mechanism of action of ALYREF in HCC is still unclear.…”

“… [8] , [9] , [10] , [11] , [12] . Xue et al [13] have pointed out that ALYREF might be a prognostic factor for HCC. Nevertheless, the specific biological function of ALYREF in HCC and its relationship to the immune system have not been reported.…”

The Mechanism Underlying the ncRNA Dysregulation Pattern in Hepatocellular Carcinoma and Its Tumor Microenvironment

“…Recently, RNA methylation of ncRNAs has gained much attention (50)(51)(52)(53)(54). For instance, M6A, a well-known type of RNA modification at the posttranscriptional level, has been reported to be involved in the expression of miRNAs, circRNAs and lncRNAs in HCC (Table 3 and Figure 1C).…”