Dataset Information

Expression Status and Prognostic Significance of Gamma-Glutamyl Transpeptidase Family Genes in Hepatocellular Carcinoma

ABSTRACT:

Purpose

Gamma-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.

Method

We 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.

Results

Except 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.

Conclusion

To 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.

SUBMITTER: Tian S

PROVIDER: S-EPMC8426663 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEarly prediction of recurrence and death risks is significant to the treatment of hepatocellular carcinoma (HCC) patients. We aimed to develop and validate prognosis nomogram models based on the gamma-glutamyl transpeptidase (GGT)-to-platelet (PLT) ratio (GPR) for HCC and to explore the relationship between the GPR and inflammation-related signaling pathways.MethodsAll data were obtained from 2000 to 2012 in the Affiliated Hospital of Qingdao University. In the training cohort, factors included in the nomograms were determined by univariate and multivariate analyses. In the training and validation cohorts, the concordance index (C-index) and calibration curves were used to assess predictive accuracy, and receiver operating characteristic curves were used to assess discriminative ability. Clinical utility was evaluated using decision curve analysis. Moreover, improvement of the predictive accuracy of the nomograms was evaluated by calculating the decision curve analysis, the integrated discrimination improvement, and the net reclassification improvement. Finally, the relationship between the GPR and inflammation-related signaling pathways was evaluated using the independent-samples t-test.ResultsA larger tumor size and higher GPR were common independent risk factors for both disease-free survival (DFS) and overall survival (OS) in HCC (P < 0.05). Good agreement between our nomogram models' predictions and actual observations was detected by the C-index and calibration curves. Our nomogram models showed significantly better performance in predicting the HCC prognosis compared to other models (P < 0.05). Online webserver and scoring system tables were built based on the proposed nomogram for convenient clinical use. Notably, including the GPR greatly improved the predictive ability of our nomogram models (P < 0.05). In the validation cohort, p38 mitogen-activated protein kinase (P38MAPK) expression was significantly negatively correlated with the GPR (P < 0.01) and GGT (P = 0.039), but was not correlated with PLT levels (P = 0.063). And we found that P38MAPK can regulate the expression of GGT by quantitative real-time PCR and Western blotting experiments.ConclusionsThe dynamic nomogram based on the GPR provides accurate and effective prognostic predictions for HCC, and P38MAPK-GGT may be a suitable therapeutic target to improve the prognosis of HCC patients.