Abstract
PurposeGamma-glutamyl transpeptidase (GGT) family genes play crucial roles in the formation and progression of several solid tumors. However, the expression patterns and the prognostic significance of GGT members in hepatocellular carcinoma (HCC) remain unknown. This study was designed to determine the expression profiles of GGT family members in HCC and validate the prognostic value of serum GGT protein in patients with HCC.MethodWe comprehensively searched public resources based on the LIHC dataset to determine the expression patterns, prognostic significance, DNA methylation status, immune infiltration, and biological pathways of GGT family genes in HCC. Subsequently, we validated the prognostic value of serum GGT protein in 85 patients with early-stage HCC subjected to curative hepatectomy from the Renmin Hospital of Wuhan University.ResultsExcept for GGT1, other GGT family members (GGT5, GGT6, and GGT7) were found to be differentially expressed in primary HCC samples (N = 371) and normal control tissues (N = 50). Furthermore, a positive relationship was not only observed between GGT1 and GGT5 (Spearman coefficient: 0.24, P = 5.143 × 10−6) but also between GGT5 and GGT6 (Spearman coefficient: 0.38, P = 1.24 × 10−13). The expression of GGT1, GGT5, and GGT7 was correlated with overall survival (OS), and GGT7 was associated with disease-free survival (DFS) in patients with HCC. Negative associations between DNA methylation and expression of mRNA were observed for GGT1 (Spearman coefficient: −0.38, P = 6.24e-14), GGT6 (Spearman coefficient: −0.29, P = 1.23e-8), and GGT7 (Spearman coefficient: −0.34, P=6.7e-11). GGT family genes were well correlated with the infiltration levels of immune cells in HCC, especially CD4+ T cells, macrophages, and dendritic cells. Finally, when validated with clinical data from the Renmin cohort, a high expression of serum GGT protein was identified as a strong prognostic element of unfavorable OS (HR = 3.114, P = 0.025), but not of DFS (HR = 1.198, P = 0.05) in patients with HCC subjected to curative hepatectomy.ConclusionTo our knowledge, this is the first comprehensive analysis of the expression patterns and clinical value of GGT family genes in patients with HCC. Our study laid the foundation for the clinical application of the GGT protein in the survival assessment of patients with HCC.
Highlights
Liver cancer is the fourth leading cause of cancer-related mortalities worldwide, after lung cancer, colorectal cancer, and stomach cancer [1]
The mRNA expression data for Gamma-glutamyl transpeptidase (GGT) family genes (GGT1, GGT5, GGT6, and GGT7) from 371 primary Hepatocellular carcinoma (HCC) samples and 50 normal control samples were analyzed via UALCAN web tool
High expression of GGT1 mRNA was correlated with inferior overall survival (OS) (HR = 1.4, P = 0.049, Figure 2A) in patients with HCC; this correlation disappeared for disease-free survival (DFS) (HR = 1.2, P = 0.15, Figure 2B)
Summary
Liver cancer is the fourth leading cause of cancer-related mortalities worldwide, after lung cancer, colorectal cancer, and stomach cancer [1]. Identifying serum biomarkers that are specific to the survival outcomes of patients with HCC is quite desirable. As the overexpression of AFP is only observed in approximately 50% of patients with HCC, identifying other serum biomarkers is imperative. Several clinical studies have revealed the association between serum GGT and overall survival (OS) in patients with HCC [14,15,16,17], the overall prognostic effect of serum GGT remains uncertain in patients with HCC. The expression profiles of GGT family genes in liver tissues and the prognostic values of GGT family genes in patients with HCC have never been investigated. The primary goal of this study was to investigate the expression profiles, prognostic role, DNA methylation, immune infiltration, and potential biological pathways of GGT family members in HCC via mining data from publicly accessible datasets. The second aim was to validate the prognostic value of serum GGT protein in patients with HCC based on our cohort
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