Low disabled-2 expression promotes tumor progression and determines poor survival and high recurrence of esophageal squamous cell carcinoma.

Wen-Lun Wang,Yu-Chi Wang,Chi-Yang Chang,Wei-Lun Chang,I-Wei Chang,Jaw-Town Lin,Ching-Tai Lee,Bor-Shyang Sheu,Hsiao-Bai Yang

doi:10.18632/oncotarget.8460

Abstract

Patients with esophageal squamous cell carcinomas (ESCCs) have poor survival and high recurrence rate, but lack a prognostic biomarker. Disabled-2 (DAB2) is a crucial tumor suppressor, but its roles in ESCCs are uncertain. We investigated whether low DAB2 expression in ESCCs could lead into tumor progression and poor prognosis. Our results found patients with low-DAB2 expression ESCCs had significantly larger tumor size, deeper tumor invasion depth, lymph node metastasis, worse survival, and higher recurrence rate (P<0.05). The Cox-regression model revealed low-DAB2 expression was an independent factor of poor survival (P<0.05), and also of tumor recurrence with the predictive performance superior to clinical TNM stage (P<0.05). Low-DAB2 cancer cells, validated by DAB2 knockdown or over-expression, had higher phosphorylated ERK and migration abilities, which could be suppressed by ERK inhibitor treatment. TGF-β-induced epithelial-to-mesenchymal transition (EMT) only existed in the high-DAB2 cells, and related to worse prognosis of high-DAB2 ESCCs (P<0.05). In conclusion, DAB2 can suppress the ERK signaling, but correlate to have TGF-β-induced EMT in ESCCs. DAB2 expression could be a biomarker to identify patients with worse survival and high recurrence. Our data suggest DAB2 expression can stratify patients in need of aggressive surveillance and with possible benefit from anti-ERK or anti-TGF-β therapies.

Highlights

Esophageal cancer is a highly lethal disease, causing more than 400,000 deaths per year in the world [1]
This study provides the first integrated investigation of DAB2 in esophageal squamous cell carcinoma (ESCC) at both cellular and clinical levels
A low-DAB2 expression can be an independent biomarker of worse survival and high recurrence for ESCC, even with better predictive performance than clinical TNM stages

Summary

Introduction

Esophageal cancer is a highly lethal disease, causing more than 400,000 deaths per year in the world [1]. We continue to lack prognostic biomarkers to identify the risky patients with tumor recurrence and poor survival. A decreased DAB2 expression has been shown in many types of tumors, including head & neck [20], lung [25], ovarian [26], prostate [27], breast [28], and esophageal cancers [29]. A recent study revealed the DAB2 expression level can predict metastasis and poor prognosis in human squamous cell carcinomas of the head & neck [20]. This study is highly original to illustrate low DAB2 expression level can be a prognostic biomarker for the recurrence and survival of patients with ESCC. The study disclosed DAB2 can suppress the ERK signaling, but may correlate to have TGF-β-induced epithelial-to-mesenchymal transition (EMT) in ESCC. The study suggests DAB2 expression may stratify patients who require aggressive surveillance, and point out the cases with potential benefit from anti-ERK or antiTGF-β therapies for ESCC

Methods

Results

Conclusion