It is imperative, therefore, to identify novel biomarkers for early detection, and therapeutic targets if long-term survival of ESCC is to be improved. The 14-3-3 proteins comprise a family of highly conserved small acidic proteins expressed in all eukaryotic organisms. In mammals, seven isoforms, are implicated in diverse biological processes including protein trafficking, metabolism, cell cycle progression, cell differentiation, senescence, apoptosis, DNA repair and malignant transformation. Of these seven mammalian isoforms, 14-3-3s is uniquely expressed in epithelial cells and is linked most directly to cancer. Because it is a negative regulator of cell cycle and since there is reciprocal modulation between 14-3-3s and p53, 14-3-3s has been suggested as a potential tumor suppressor. Recently, downregulation of 14-3-3s has been reported in various cancers of epithelial origin, including breast, lung, colon, liver, stomach, prostate, ovary, nasopharynx, oral cavity, ESCC, head and neck. Conversely, overexpression of 14-3-3s has also been observed in many cancers, including pancreas, colorectal, head and neck, lung and ESCC. Furthermore, the correlation of 14-3-3s and prognosis varies in different malignancies. It is likely, therefore, that the role of 14-33s in human carcinogenesis is context-dependent. In the case of ESCC, more studies are needed to characterize the expression of 14-3-3s during the multi-stage disease development and its prognostic value. In this study, we investigated the expression pattern of 14-3-3s in biopsy and resected ESCC, and evaluated its relationship with clinicopathological features and survival. Consistently, one immortalized esophageal epithelial cell line NEC showed downregulation of 14-3-3s. Together with the association of 14-3-3s with ESCC precursor progression, our investigation indicates that 14-3-3s has the potential to be a biomarker defining a subset of high-risk subjects predisposed to developing ESCC. There have been conflicting reports concerning the role of 14-33s in tumor formation and development although it has generally been regarded as a tumor suppressor. By sequestering cdc2-cyclin B1 complex in the cytoplasm, 14-3-3s causes G2-M phase arrest which allows DNA damage repair and thus prevent genomic instability. Therefore, downregulation of 14-3-3s may play a key role in carcinogenesis in several human malignancies. On the other hand, overexpression of 14-3-3s has also been documented in some cancers and both over- and under-expression of 14-3-3s have been reported in the same type of cancer, such as ovarian cancer, ESCC. In prostate cancer, a significant downregulation of 14-3-3s was found during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer. However, islands of tumor cells with or without 14-3-3s expression coexisted sometimes in the same specimen and a paradoxical higher level of expression was observation.