Abstract
AimsThe asymptomatic nature of early-stage esophageal squamous cell carcinoma (ESCC) results in late presentation and consequent dismal prognosis This study characterized 14-3-3σ protein expression in the multi-stage development of ESCC and determined its correlation with clinical features and prognosis.Materials and MethodsWestern blot was used to examine 14-3-3σ protein expression in normal esophageal epithelium (NEE), low grade intraepithelial neoplasia (LGIN), high grade intraepithelial neoplasia (HGIN), ESCC of TNM I to IV stage and various esophageal epithelial cell lines with different biological behavior. Immunohistochemistry was used to estimate 14-3-3σ protein in 110 biopsy samples of NEE, LGIN or HGIN and in 168 ESCC samples all of whom had follow-up data. Support vector machine (SVM) was used to develop a classifier for prognosis.Results14-3-3σ decreased progressively from NEE to LGIN, to HGIN, and to ESCC. Chemoresistant sub-lines of EC9706/PTX and EC9706/CDDP showed high expression of 14-3-3σ protein compared with non-chemoresistant ESCC cell lines and immortalized NEC. Furthermore, the downregulation of 14-3-3σ correlated significantly with histological grade (P = 0.000) and worse prognosis (P = 0.004). Multivariate Cox regression analysis indicated that 14-3-3σ protein (P = 0.016) and T stage (P = 0.000) were independent prognostic factors for ESCC. The SVM ESCC classifier comprising sex, age, T stage, histological grade, lymph node metastasis, clinical stage and 14-3-3σ, distinguished significantly lower- and higher-risk ESCC patients (91.67% vs. 3.62%, P = 0.000).ConclusionsDownregulation of 14-3-3σ arises early in the development of ESCC and predicts poor survival, suggesting that 14-3-3σ may be a biomarker for early detection of high-risk subjects and diagnosis of ESCC. Our seven-feature SVM classifier for ESCC prognosis may help to inform clinical decisions and tailor individual therapy.
Highlights
Esophageal squamous cell carcinoma (ESCC) accounts for nearly 90% of all esophageal cancers and is the fourth leading cause of cancer death in China [1]
Western blots of precancerous lesions showed that 14-3-3s protein was attenuated in a stepwise manner from normal esophageal epithelium (NEE) to low grade intraepithelial neoplasia (LGIN), and to high grade intraepithelial neoplasia (HGIN), and reached its lowest level in HGIN (Figure 1A)
Downregulation or loss of 14-3-3s protein expression in ESCC at different clinical stages occurred in a pattern similar to the development from NEE to precursors and subsequently to ESCC
Summary
Esophageal squamous cell carcinoma (ESCC) accounts for nearly 90% of all esophageal cancers and is the fourth leading cause of cancer death in China [1]. Seven isoforms (a/b, c, e, s, f, t/h and g) [6,7], are implicated in diverse biological processes including protein trafficking, metabolism, cell cycle progression, cell differentiation, senescence, apoptosis, DNA repair and malignant transformation [8,9,10,11]. Of these seven mammalian isoforms, 14-3-3s is uniquely expressed in epithelial cells and is linked most directly to cancer [8,12]. 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
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