Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer

Abstract

BackgroundGastric Cancer is one of the most lethal malignancies worldwide. Gamma-glutamyl transpeptidase (GGT) is an enzyme mainly involved in cellular glutathione homeostasis. We aim to explore the clinical value of GGT in gastric cancer.ResultsAmong 322 patients enrolled, 65/82 patients were determined as GGT positive in serum/tumor, respectively. High tumor GGT expression is significantly associated with lymph node metastasis, histological subtype, and Her2 expression. Kaplan-Meier curve shows that high tumor GGT patients have shorter overall survival (P log-rank=0.001) and progress-free survival (P log-rank =0.001). Patients with both high tumor and serum GGT have the poorest prognosis. The multivariable Cox analysis shows that the hazard ratio of overall survival for high tumor GGT is 1.69 (95% CI 1.19-2.37). High serum GGT is a poor prognostic factor in adjuvant chemotherapy hazard ratio=2.18, 95%CI (1.15-4.47). These findings were further validated in six online datasets. Gene Sets Enrichment Analysis showed that GGT promotes cancer progression through EMT, KRAS, SRC and PKCA pathways.MethodsTumor GGT and serum GGT levels were evaluated with immuno-histochemistry staining and enzymatic assay, respectively. Kaplan-Meier curve and Cox regression model were used to test the association between GGT and gastric cancer prognosis. Independent datasets from Gene Expression Omnibus and Gene Sets Enrichment Analysis were applied to validate the findings and explore the potential mechanisms.ConclusionBoth tumor GGT and serum GGT are poor prognostic factors in gastric cancer. Patients with high tumor and serum GGT levels require more intense treatment and follow-up.

The Predictive Value of Pre-therapeutic Serum Gamma-glutamyl transferase in Efficacy and Adverse Reactions to Neoadjuvant Chemotherapy among Breast Cancer Patients

“…In this study, the investigators hypothesized that GGT might be associated with tumor development. Wang et al [ 20 ] found that the expression of GGT in tumor cells was increased, which could promote the development and invasion of gastric cancer. Moreover, previous studies have confirmed that GGT can affect the sensitivity of tumor cells to drugs [ 17 21 22 ].…”

Serum gamma-glutamyltransferase and the overall survival of metastatic pancreatic cancer

“…For example, GGT may directly participate in the progression of cancer, as studies on melanoma cells found that elevated GGT activity resulted in a growth advantage both in vitro and in vivo [27]. Moreover, a newly published study using geneset enrichment analysis (GSEA) reported that in gastric cancer patients, GGT was significantly associated with EMT, KRAS, SRC and PKCA signaling pathways [13], which are involved in cancer progression and metastasis [28,29].…”

“…Oxidative stress and inflammation are also pathways implicated in cancer development and progression, and positive GGT associations with risks of various cancer types have been demonstrated by several prospective studies [9][10][11][12]. Quite opposite to the abundance of cancer risk studies, relatively few studies have investigated the prognostic role of serum GGT in cancer outcomes: increased serum GGT has been inversely associated with survival in gastric cancer [13], colorectal cancer [14], ovarian cancer [15], breast cancer [16], endometrial cancer [17,18], cervical cancer [19], and renal cell carcinoma [20].…”

Serum gamma-glutamyltransferase and the overall survival of metastatic pancreatic cancer

“…For example, GGT may directly participate in progression of cancer, as studies on melanoma cells found that elevated GGT activity resulted in growth advantage both in vitro and in vivo [27]. Moreover, a newly published study using gene set enrichment analysis (GSEA) reported that in gastric cancer patients, GGT was significantly associated with EMT, KRAS, SRC and PKCA signaling pathways [13], which are involved in cancer progression and metastasis [28,29].…”

“…Oxidative stress and inflammation are also pathways implicated in cancer development and progression, and positive GGT associations with various cancer types have been demonstrated by several prospective studies [9][10][11][12]. Quite opposite to the abundance of cancer risk studies, only a few studies have investigated a prognostic role of serum GGT in cancer outcomes: increased serum GGT has been inversely associated with survival in gastric cancer [13], colorectal cancer [14], ovarian cancer [15], breast cancer [16], endometrial cancer [17,18], cervical cancer [19], and renal cell carcinoma [20].…”