Abstract
BackgroundEsophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor.MethodsIn this study, we applied western blot, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, RNA-Seq analysis, luciferase reporter assay, Chip-qPCR, bioinformatics analysis, and a series of functional assays to show the potential role of LEF1 in regulating esophageal CSCs.ResultsWe found that the overexpression of LEF1 was associated with aberrant clinicopathological characteristics and the poor prognosis of ESCC patients. In addition, the elevated expression of LEF1 and OV6 was significantly associated with aberrant clinicopathological features, and poor patient prognosis. Moreover, the overexpression of LEF1 was observed in esophageal CSCs purified by the magnetic sorting of adherent and spheroidal ESCC cells. The increased level of LEF1 in CSCs facilitated the expression of CSC markers, stem cell-like properties, resistance to chemotherapy, and tumorigenicity and increased the percentage of CSCs in ESCC samples. Conversely, the knockdown of LEF1 significantly diminished the self-renewal properties of ESCC. We showed that LEF1 played an important mechanical role in activating the TGF-β signaling pathway by directly binding to the ID1 gene promoter. A positive association between LEF1 and ID1 expression was also observed in clinical ESCC samples.ConclusionOur results indicate that the overexpression of LEF1 promotes a CSC-like phenotype in and the tumorigenicity of ESCC by activating the TGF-β signaling pathway. The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression.
Highlights
Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy
We investigated the relationship between Lymphoid enhancer-binding factor 1 (LEF1) expression and the clinicopathological features of ESCC patients
Representative staining intensity of LEF1 and anti-OV6 antibody (OV6) represent different expression levels. b Overall survival rate for patients with low LEF1 expression and patients with high LEF1 expression, P < 0.01. c The overall survival rates of 95 patients with ESCC were compared with different groups by Kaplan–Meier analysis, P = 0.0002. d The percentage of patients with high LEF1 staining was higher in the OV6-high group. e Correlation between expression levels of OCT4 and LEF1 in ESCC measured by spearman’s rank correlation analysis, Spearman r = 0.214, P = 0.037 we showed that the expression of LEF1 mRNA and protein levels were significantly increased in the magnetically sorted OV6+ subpopulation of adherent ECA109 and TE1 cells (Fig. 2a)
Summary
Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor. Despite advances in diagnosis and therapy, the prognosis of patients with ESCC remains poor even after surgery [3]. Cancer stem cells (CSCs) are known to exist in different types of cancers and contribute to aggressive tumor behavior [5]. We demonstrated that OV6 expression was closely associated with the clinical outcome and prognosis of ESCC patients and contributed to tumorigenesis and chemotherapy resistance [11]. The mechanisms involved in the expansion and function of CSCs are not well understood
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