Oncotarget

Research Papers:

DDA1 promotes stage IIB–IIC colon cancer progression by activating NFκB/CSN2/GSK-3β signaling

Senlin Zhao, Huamei Tang, Dongwang Yan, Junwei Fan, Hongcheng Sun, Yugang Wen, Fudong Yu, Feifei Cui, Dongyuan Zhang, Yingming Xue, Chenchen Liu, Ben Yue, Jian Chen, Jingtao Wang, Xiao Wang, Meng Zhang, Yang Yu, Weiliang Jiang, Xisheng Liu, Yushuai Mi, Zongguang Zhou, Xuebin Qin and Zhihai Peng _

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Oncotarget. 2016; 7:19794-19812. https://doi.org/10.18632/oncotarget.7847

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Abstract

Senlin Zhao1,*, Huamei Tang2,*, Dongwang Yan1,*, Junwei Fan1,*, Hongcheng Sun1, Yugang Wen1, Fudong Yu1, Feifei Cui1, Dongyuan Zhang1, Yingming Xue1, Chenchen Liu1, Ben Yue1, Jian Chen1, Jingtao Wang1, Xiao Wang1, Meng Zhang3, Yang Yu1, Weiliang Jiang4, Xisheng Liu1, Yushuai Mi1, Zongguang Zhou5, Xuebin Qin6, Zhihai Peng1

1Department of General Surgery, Shanghai First People’s Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China

2Department of Pathology, Shanghai First People’s Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China

3Department of Pathology, Fudan University Affiliated Shanghai Cancer Center, Shanghai, China

4Department of Gastroenterology, Shanghai First People’s Hospital, Affiliated to Shanghai Jiaotong University, Shanghai, China

5Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China

6Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA, USA

*These authors contributed equally to this work

Correspondence to:

Zhihai Peng, e-mail: [email protected]

Xuebin Qin, e-mail: [email protected]

Zongguang Zhou, e-mail: [email protected]

Keywords: DDA1, colon cancer, tumor recurrence, prognosis, NFκB

Received: September 01, 2015     Accepted: February 06, 2016     Published: March 02, 2016

ABSTRACT

Conventional high-recurrence risk factors are not sufficient to predict post-operative risk of tumor recurrence or sensitivity to 5-fluorouracil (5-FU)-based chemotherapy for stage II colon cancer. DDA1, an evolutionarily conserved gene located at 19p13.11, may be involved in the activation of nuclear factor kappaB (NFκB). This study aimed to investigate whether DDA1 contributes to tumorigenesis and progression of stage II colon cancer via activation of the NFκB pathway. We found that positive expression of DDA1 alone or in combination with p65 nuclear translocation correlated with increased risk of tumor recurrence in patients with stage IIB–IIC colon cancer. DDA1 overexpression in colon cancer lines promoted cell proliferation, facilitated cell cycle progression, inhibited 5-FU-induced apoptosis, enhanced invasion, and induced the epithelial-mesenchymal transition. Suppression of DDA1 inhibited tumor progression, and reduced tumor growth in vivo. We also demonstrated that DDA1-mediated tumor progression is associated with the activation of the NFκB/COP9 signalosome 2(CSN2)/glycogen synthase kinase3β (GSK3β) pathway. These results indicate that DDA1 promotes colon cancer progression through activation of NFκB/CSN2/GSK3β signaling. DDA1, together with NFκB activation status, may serve as a sensitive biomarker for tumor recurrence risk and prognosis in patients with stage IIB–IIC colon cancers.


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