title: miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF-κB signaling in gastric carcinogenesis.
abstract: BACKGROUND
  NF-κB signaling pathway plays an important role in gastric carcinogenesis. The basic expression and functional role of NFKB1 and RELA (components of canonical NF-κB pathway) in gastric cancer (GC) have not been well elucidated. In this study, the role of NFKB1 and RELA in gastric tumorigenesis will be investigated and their regulation by microRNAs (miRNAs) will be deeply explored.
  
  
  METHODS
  The mRNA and protein expression of NFKB1 and RELA were investigated by qRT-PCR and Western blot in GC cell lines and primary tumors. The functional roles of NFKB1 and RELA in GC were demonstrated by MTT proliferation assay, monolayer colony formation, cell invasion and migration, cell cycle analysis and in vivo study through siRNA mediated knockdown. Identification of NFKB1 as a direct target of tumor suppressor miRNA miR-508-3p was achieved by expression regulation assays together with dual luciferase activity experiments.
  
  
  RESULTS
  NFKB1 and RELA were up-regulated in GC cell lines and primary tumors compared with normal gastric epithelium cells and their upregulation correlation with poor survival in GC. siRNA mediated knockdown of NFKB1 or RELA exhibited anti-oncogenic effect both in vitro and in vivo. NFKB1 was further revealed to be a direct target of miR-508-3p in gastric tumorigenesis and their expression showed negative correlation in primary GC samples. miR-508-3p was down-regulated in GC cells compared with normal gastric epithelium samples and its ectopic expression in GC cell lines also exerts tumor suppressor function. NFKB1 re-expression was found to partly abolish the tumor-suppressive effect of miR-508-3p in GC.
  
  
  CONCLUSIONS
  All these findings supports that canonical NF-κB signaling pathway is activated in GC at least by the inactivation of miR-508-3p and this might have therapeutic potential in GC treatment.
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. huangtingting0531@gmail.com.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. huangtingting0531@gmail.com.|Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. huangtingting0531@gmail.com.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. huangtingting0531@gmail.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. weikang@cuhk.edu.hk.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. weikang@cuhk.edu.hk.|Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. weikang@cuhk.edu.hk.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. weikang@cuhk.edu.hk.
authors.forename: Wei
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, PR China. billzhangnju@foxmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. wufeng@link.cuhk.edu.hk.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. wufeng@link.cuhk.edu.hk.|Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. wufeng@link.cuhk.edu.hk.
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.affiliation: Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. celia.yj.dong@gmail.com.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. celia.yj.dong@gmail.com.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. jtong@cuhk.edu.hk.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. jtong@cuhk.edu.hk.|Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. jtong@cuhk.edu.hk.
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. weiqinyang1021@cuhk.edu.hk.|School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China. weiqinyang1021@cuhk.edu.hk.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. zyhjoe@gmail.com.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. zyhjoe@gmail.com.|Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. zyhjoe@gmail.com.
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. yblhzl@hotmail.com.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. yblhzl@hotmail.com.|Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. yblhzl@hotmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. alfredcheng@cuhk.edu.hk.|School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, PR China. alfredcheng@cuhk.edu.hk.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.affiliation: Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. junyu@cuhk.edu.hk.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. junyu@cuhk.edu.hk.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, PR China. junyu@cuhk.edu.hk.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. kfto@cuhk.edu.hk.|Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. kfto@cuhk.edu.hk.|Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, PR China. kfto@cuhk.edu.hk.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. kfto@cuhk.edu.hk.
authors.forename: Ka Fai
authors.initials: KF
authors.lastname: To
mesh_terms: D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D016016:Proportional Hazards Models; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C571981:MIRN508 microRNA, human; D035683:MicroRNAs; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D051996:Transcription Factor RelA