低水平的Disabled-2表达促进肿瘤进展,并决定食管鳞状细胞癌的低生存率和高复发率。

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

作者信息

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

机构信息

Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan.

Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.

出版信息

Oncotarget. 2016 Nov 1;7(44):71169-71181. 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.

摘要

食管鳞状细胞癌(ESCC)患者生存率低且复发率高,但缺乏预后生物标志物。Disabled-2(DAB2)是一种关键的肿瘤抑制因子,但其在ESCC中的作用尚不确定。我们研究了ESCC中DAB2低表达是否会导致肿瘤进展和预后不良。我们的结果发现,DAB2低表达的ESCC患者肿瘤体积明显更大、肿瘤浸润深度更深、有淋巴结转移、生存率更差且复发率更高(P<0.05)。Cox回归模型显示,DAB2低表达是生存率差的独立因素(P<0.05),也是肿瘤复发的独立因素,其预测性能优于临床TNM分期(P<0.05)。通过DAB2敲低或过表达验证的DAB2低表达癌细胞具有更高的磷酸化ERK水平和迁移能力,而ERK抑制剂治疗可抑制这些能力。TGF-β诱导的上皮-间质转化(EMT)仅存在于DAB2高表达细胞中,且与DAB2高表达的ESCC患者预后较差相关(P<0.05)。总之,DAB2可抑制ERK信号传导,但与ESCC中TGF-β诱导的EMT相关。DAB2表达可能是识别生存率差和复发率高的患者的生物标志物。我们的数据表明,DAB2表达可对需要积极监测且可能从抗ERK或抗TGF-β治疗中获益的患者进行分层。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e2af/5342070/9c0f2924a7d8/oncotarget-07-71169-g001.jpg

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