Expression and Prognostic Value of Id-4 in Patients with Esophageal Squamous Cell Carcinoma

Background: Our previous study demonstrated that Id-1 may promote the tumorigenicity of esophageal squamous cell carcinoma (ESCC). Id-4 is another member of Id family, which is rare to be studied in ESCC. In this study, we investigated the expression of Id-4 in human ESCC specimens and determined whether Id-4 expression was associated with the clinicopathologic characteristic and the prognosis of ESCC patients. Methods: We examined Id-4 expression using immunohistochemistry in 92 ESCC tissues and adjacent normal tissues. The association between Id-4 expression and clinical parameters and survival was evaluated by statistical analysis. Cox regression analyses were conducted to identify prognostic factors associated with overall survival (OS). In addition, we explored the functional mechanism of Id-4 in ESCC. Results: Id-4 expression was significantly downregulated in ESCC tissues compared with adjacent normal tissues. The expression of Id-4 was associated negatively with pT stage (p=0.002), AJCC stage (p=0.008) and histologic differentiation (p<0.001). OS was more unfavorable in patients with low expression of Id-4 than those with high expression of ESCC patients (p=0.007). In subgroup analysis, low expression of Id-4 could reveal unfavorable OS of patients with pT1b/T2 stage (p=0.024) or with pN0/N1 stage (p=0.004). By univariate analysis, pT stage and Id-4 expression showed statistically significant associations with OS (p=0.025, p=0.01, respectively). By multivariate analysis, Id-4 expression was an independent prognostic factor in ESCC (p =0.038). In addition, we observed that Id-4 could decrease the levels of the p-Smad2, p-Smad3 and TGF-beta 1 in both Eca109 and TE1 cells, indicating Id-4 may inactivate the TGF-beta signaling pathway. Conclusion: Low expression of Id-4 suggested unfavorable prognosis for ESCC patients and could identify the prognosis in patients of early-stage tumors. The potential mechanism for Id-4's tumor suppressor role in ESCC may be related to its inhibitory effect on TGF-beta signaling pathway. Thus, we believe that Id-4 may be a promising prognostic marker and a therapeutic target in ESCC.