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Esophageal squamous cell carcinoma (ESCC) is an invasive gastrointestinal malignancy and in urgent need of new effective therapies. Gambogic acid (GA) exhibits anti-cancer effects in many cancer cells, but it remains to be determined whether GA has the same effect on ESCC. Here, we reported that GA treatment caused an inhibition in ESCC cell proliferation, migration and invasion. Meanwhile, GA induced dose-dependent apoptosis of ESCC cells, repressed the expression of Bcl2 and up-regulated the levels of Bax protein, cleaved-PARP1 and cleaved-caspase 3/9. Further investigation showed that GA down-regulated the levels of PI3K, p-AKT and p-mTOR, while promoted PTEN expression in ESCC cells. Taken together, we provided the first demonstration that GA exerts anti-tumor effects on ESCC cells presumably through regulating PTEN-PI3K-AKT-mTORpathway, suggestive of a therapeutic potential for ESCC.

Objectives The NEK2 (never in mitosis gene A-related kinase 2), a serine/threonine kinase involved in chromosome instability and tumorigenesis. Hence, this study aimed to explore the molecular function of NEK2 in esophageal squamous cell carcinoma (ESCC). Methods By available transcriptome datasets (GSE53625 cohort, GSE38129 cohort, and GSE21293 cohort), we analyzed the differentially expressed genes in invading and non-invading ESCC. Subsequently, we evaluated the association between NEK2 expression level and clinical outcomes through Kaplan–Meier analysis method. The quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) analyses were performed to determine the expression levels of NEK2 mRNA and protein, respectively. We knocked down the NEK2 expression in ESCC cells (ECA109 and TE1), and evaluated the NEK2 biology function associated with ESCC cell proliferation, migration, invasion, and colony formation abilities. Finally, the downstream pathway of NEK2 was analyzed through Gene Set Enrichment Analysis (GSEA) and validated the regulatory mechanism of NEK2 on the potential pathway through WB. Results We found that NEK2 was highly expressed in ESCC cells compared with human esophageal epithelial cells (HEEC) (P < 0.0001), and high NEK2 expression was remarkably associated with poor survival (P = 0.019). Knockdown of NEK2 showed the significant inhibitory effect for tumorigenesis, and suppressed the ESCC cells proliferation, migration, invasion, and formation of colonies abilities. Additionally, GSEA revealed that Wnt/β-catenin pathway was a downstream pathway of NEK2. WB results further validated the regulatory mechanism of NEK2 for Wnt/β-catenin signaling. Conclusions Our results indicated that NEK2 promotes ESCC cell proliferation, migration and invasion by activating the Wnt/β-catenin pathway. NEK2 could be a promising target for ESCC.

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