The prognostic significance of Id proteins in Esophageal Squamous Cell Carcinoma

Abstract

Id protein family, a group of basic helix-loop-helix (bHLH) transcription factors, consist of 4 members namely Id-1 to -4. Different from other bHLH transcription factors, they lack the DNA binding domain and therefore function by negatively regulating other bHLH transcription factors through direct protein binding. Id proteins have been shown to be dysregulated in many different cancer types with prognostic implications. Recently, Id-1 has been shown to be up-regulated in esophageal squamous cell carcinoma (ESCC) cell lines and human specimens. In this study, we aimed to examine, by western blot and immunohistochemistry respectively, the expression level of the 4 Id proteins in 9 esophageal cell lines and 84 ESCC patients, who had undergone esophagectomy with no prior radiochemotherapy of the ESCC. Id proteins expression levels were correlated with clinico-pathological parameters of the cohort. Id proteins expressions were found to be dysregulated in the seven ESCC cell lines compared to the two immortalized esophageal epithelial cell lines. By immunohistochemistry, Id proteins were shown to be up-regulated in ESCC specimens when compared to the normal esophageal epithelium counterpart. High level nuclear expression of Id-1 was significantly associated with M1-stage of ESCC (p = 0.012) and stage IV disease (p = 0.012), and significantly predicted development of distant metastasis within one year after esophagectomy (OR = 4.615, 95%CI = 1.596-13.348, p = 0.005). On the other hand, high level cytoplasmic expression of Id-1 was significantly associated with high tumor stage, pT4 (p = 0.045). High level cytoplasmic expression of Id-2 was significantly associated with poorly differentiated ESCC specimens (p = 0.007) while a high combined nuclear and cytoplasmic staining of Id-2 predicted better survival of the patients (p = 0.041). Id-3 and -4 were not significantly associated with any of the clinico-pathological parameters analyzed. Taken together, our results suggest that high level of Id-1 expression may promote metastasis of ESCC and can act as a marker for development of metastatic ESCC while Id-2 may be useful as a prognostic marker for ESCC patients.