title: DDA1 promotes stage IIB-IIC colon cancer progression by activating NFκB/CSN2/GSK-3β signaling.
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.
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Senlin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Huamei
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Dongwang
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hongcheng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Fudong
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Cui
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Dongyuan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Yue
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Fudan University Affiliated Shanghai Cancer Center, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Affiliated to Shanghai Jiaotong University, Shanghai, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yushuai
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Zongguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Xuebin
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Shanghai First People's Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Peng
mesh_terms: D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D000075686:COP9 Signalosome Complex / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D011184:Postoperative Period; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: C541165:DDA1 protein, human; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D000071679:Glycogen Synthase Kinase 3 beta; D000075686:COP9 Signalosome Complex; D005472:Fluorouracil
keywords: DDA1; NFκB; colon cancer; prognosis; tumor recurrence