Low disabled-2 expression promotes tumor progression and determines poor survival and high recurrence of esophageal squamous cell carcinoma
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Wen-Lun Wang1,7, Wei-Lun Chang1,2, Hsiao-Bai Yang3,4, Yu-Chi Wang5, I-Wei Chang6, Ching-Tai Lee7, Chi-Yang Chang7, Jaw-Town Lin7, Bor-Shyang Sheu1,2
1Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan
2Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
3Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
4Department of Pathology, Ton-Yen General Hospital, Hsin-Chu, Taiwan
5Department of Biological Science & Technology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
6Department of Pathology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
7Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
Bor-Shyang Sheu, email: [email protected]
Keywords: disabled-2, survival, recurrence, esophageal cancer
Received: September 02, 2015 Accepted: February 24, 2016 Published: March 29, 2016
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.
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