title: Low disabled-2 expression promotes tumor progression and determines poor survival and high recurrence of esophageal squamous cell carcinoma.
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.
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan.|Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: Wen-Lun
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan.|Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Chang
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.|Department of Pathology, Ton-Yen General Hospital, Hsin-Chu, Taiwan.
authors.forename: Hsiao-Bai
authors.initials: HB
authors.lastname: Yang
authors.affiliation: Department of Biological Science & Technology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Pathology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: I-Wei
authors.initials: IW
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: Chi-Yang
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
authors.forename: Jaw-Town
authors.initials: JT
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan.|Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Bor-Shyang
authors.initials: BS
authors.lastname: Sheu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000401:mortality*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D004938:Esophageal Neoplasms / Q000401:mortality*; D000077277:Esophageal Squamous Cell Carcinoma; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D009364:Neoplasm Recurrence, Local / Q000209:etiology; D016016:Proportional Hazards Models; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: disabled-2; esophageal cancer; recurrence; survival