Abstract
Methyltransferase-like 18 (METTL18), a METTL family member, is abundant in hepatocellular carcinoma (HCC). Studies have indicated the METTL family could regulate the progress of diverse malignancies while the role of METTL18 in HCC remains unclear. Data of HCC patients were acquired from the cancer genome atlas (TCGA) and gene expression omnibus (GEO). The expression level of METTL18 in HCC patients was compared with normal liver tissues by Wilcoxon test. Then, the logistic analysis was used to estimate the correlation between METTL18 and clinicopathological factors. Besides, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) were used to explore relevant functions and quantify the degree of immune infiltration for METTL18. Univariate and Multivariate Cox analyses and Kaplan–Meier analysis were used to estimate the association between METTL18 and prognosis. Besides, by cox multivariate analysis, a nomogram was conducted to forecast the influence of METTL18 on survival rates. METTL18-high was associated with Histologic grade, T stage, Pathologic stage, BMI, Adjacent hepatic tissue inflammation, AFP, Vascular invasion, and TP53 status (P < 0.05). HCC patients with METTL18-high had a poor Overall-Survival [OS; hazard ratio (HR): 1.87, P < 0.001), Disease-Specific Survival (DSS, HR: 1.76, P = 0.015), and Progression-Free Interval (PFI, HR: 1.51, P = 0.006). Multivariate analysis demonstrated that METTL18 was an independent factor for OS (HR: 2.093, P < 0.001), DSS (HR: 2.404, P = 0.015), and PFI (HR: 1.133, P = 0.006). Based on multivariate analysis, the calibration plots and C-indexes of nomograms showed an efficacious predictive effect for HCC patients. GSEA demonstrated that METTL18-high could activate G2M checkpoint, E2F targets, KRAS signaling pathway, and Mitotic Spindle. There was a positive association between the METTL18 and abundance of innate immunocytes (T helper 2 cells) and a negative relation to the abundance of adaptive immunocytes (Dendritic cells, Cytotoxic cells etc.). Finally, we uncovered knockdown of METTL18 significantly suppressed the proliferation, invasion, and migration of HCC cells in vitro. This research indicates that METTL18 could be a novel biomarker to evaluate HCC patients’ prognosis and an important regulator of immune responses in HCC.
Highlights
Hepatocellular Carcinoma (HCC) is the fourth most common cause of death of tumor and the seventh most common malignant tumor in 2018 [1]
Using receiver operating characteristic (ROC) curves, we evaluated the diagnostic performance of METTL18 in HCC patients
Results have indicated that expression levels of METTL18 in 371 tumor tissues were higher than that in 160 normal samples (P < 0.001; Figure 1B) and METTL18 expression in 248 tumor tissues was significantly increased compared with 220 normal samples (P < 0.001; Figure 1C)
Summary
Hepatocellular Carcinoma (HCC) is the fourth most common cause of death of tumor and the seventh most common malignant tumor in 2018 [1]. Problems remain in the process of treatment and diagnosis of liver cancer, due to the shortage of efficient biomarkers for cancer type and disease stage. Several serum biomarkers were used to detect the progression and prognosis of hepatocellular carcinoma, such as Alpha-fetoprotein (AFP) and Carcinoembryonic Antigen (CEA) [4, 5]. Both the specificity and sensitivity of these biomarkers in evaluating tumor progression, prognosis, and recurrence are still unsatisfactory. Identification of the reliable and new biomarkers for the diagnosis of HCC is urgently needed to improve the prognosis
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