Risk Stratification by Tissue GAD1 Expression Level in Curatively Resected Esophageal Squamous Cell Carcinoma

To improve patient management, new biomarkers are required that stratify prognosis. Here we focused on glutamic acid decarboxylase 1 (GAD1), which is associated with proliferation of lung cancer cells, and investigated its expression and function in esophageal squamous cell carcinoma (ESCC).

We evaluated changes in the proliferative potential of ESCC cell lines using small interfering RNA-mediated GAD1 knockdown techniques. We analyzed GAD1 protein expression using a tissue microarray (TMA) and measured GAD1 mRNA expression to evaluate correlations between the expression level of each tissue and postoperative outcomes of two independent cohorts (the TMA and mRNA cohorts) of patients who underwent radical esophagectomy.

GAD1 knockdown reduced cell proliferation. In the TMA cohort, high GAD1 expression significantly correlated with lymph node metastasis and advanced stage. Disease-free survival was significantly shorter in the group with high GAD1 expression, as was overall survival. Multivariate analysis of overall survival showed that positivity for GAD1 was an independent prognostic factor for poor survival. In the mRNA cohort, GAD1 mRNA expression in ESCC tissues was significantly up-regulated compared with that in adjacent noncancerous mucosal tissues. When patients were divided into high- and low-expression groups according to the median GAD1 mRNA expression level in ESCC tissues, overall survival was significantly shortened in the high GAD1 expression group. The incidence of initial hematogenous recurrence was significantly higher in the group with high GAD1 expression.

GAD1 expression mediates the proliferative potential of ESCC cells, and a high level may serve as a useful prognostic biomarker for patients with ESCC.