Abstract. The prognosis of patients with esophageal cancer remains poor, and the tumor-node-metastasis classification system is not sufficient for predicting patient prognoses. Therefore, the identification of novel predictive markers for esophageal cancer is required. The present study investigated the clinicopathological significance of growth arrest and DNA damage-inducible 45α (GADD45A) and p53 in resectable esophageal squamous cell carcinoma (ESCC). The study consisted of 62 patients with esophageal cancer who underwent surgery between 2001 and 2007. The expression of the GADD45A gene product (GADD45A) and the p53 protein was analyzed by immunohistochemistry. The correlations among GADD45A expression, clinicopathological factors and prognosis were then analyzed in the patients with ESCC. GADD45A and p53 were expressed in 56.5% (35/62) and 48.4% (30/62) of patients, respectively. The expression of GADD45A did not show a marked correlation with that of p53. However, GADD45A expression correlated with pathological stage (stage 0-I vs. stages II-IV; P=0.014) and did not correlate with the tumor (T) or node (N) status. Furthermore, patients who were positive for GADD45A exhibited a significantly higher survival rate than those who were negative for GADD45A (log-rank test, P=0.009). Multivariate analysis indicated that T status, N status and GADD45A expression were significant variables predicting survival (hazard ratio, 2.486; 95% confidence interval, 1.168-5.290; P=0.018). Overall, GADD45A expression significantly affected the survival of patients with ESCC, and the reduced expression of GADD45A was correlated with a poor prognosis following curative surgery in these patients.
IntroductionThe prognosis of esophageal cancer patients remains poor, emphasizing the requirement for the development of novel treatment strategies. At present, the overall 5-year survival rate is <50%, despite the use of multimodality therapies. Numerous patients, even those with early-stage disease, develop local recurrence of tumors or distant metastasis within a short time period after surgery. To develop novel treatment strategies, it is important to understand the biological behavior of esophageal cancer. Recent studies have found that a number of genes and molecules show involvement in the origin and/or progression of esophageal cancer, including tumor protein p53 (1), deleted in esophageal cancer 1 (2), deleted in colorectal cancer (3), deleted in lung cancer 1 (4), cyclin D1 (5), adenomatous polyposis coli (6) and survivin (7). However, the exact mechanisms underlying esophageal squamous cell carcinoma (ESCC) development and progression remain unclear.The p53 gene is required for the proper induction of the G 1 checkpoint and functions to upregulate growth arrest and DNA damage-inducible 45α (GADD45A) and WAF1/p21 expression (8). Additionally, GADD45A is a downstream mediator of p53 and is able to deactivate p53, thereby contributing to cell cycle regulation through binding with cyclin-dependent kinases and proliferating cell nuc...