title: Knockdown of NIK and IKKβ-Binding Protein (NIBP) Reduces Colorectal Cancer Metastasis through Down-Regulation of the Canonical NF-κΒ Signaling Pathway and Suppression of MAPK Signaling Mediated through ERK and JNK.
abstract: BACKGROUND
  Despite the identification of many signaling pathways involved in colorectal cancer (CRC) tumorigenesis, metastatic CRC still remains one of the major causes of cancer related death. NIK and IKKβ-binding protein (NIBP) is one of the key regulators of the NF-κB signaling pathway, which has been implicated in CRC metastasis. The aim of this study was to investigate the possible role of NIBP in CRC metastasis through its regulation of NF-κΒ and extracellular regulated kinase/c-Janus kinase (ERK/JNK) signaling pathways.
  
  
  METHODS
  In this study NIBP, phosphorylated (p)-p65, p-ERK1/2, and p-JNK1/2 expression was examined in 130 CRC, and 25 adenoma tissue samples were studied by immunohistochemistry. NIBP shRNA knockdown was performed in HCT116 cells, and NF-κB and ERK/JNK pathway activity was measured after TNF-α stimulation in vitro and in vivo.
  
  
  RESULTS
  We found that NIBP, p-p65, p-ERK1/2, and p-JNK1/2 expression was higher in late stages of CRC compared to early stages or adenomas. Expression of p-p65, p-IκBα, p-IκBβ, p-ERK1/2, and p-JNK1/2 was inhibited in TNF-α stimulated HCT116 cells following NIBP knockdown. Nevertheless, p-ERK1/2 expression in un-transfected and NIBP knockdown HCT116 cells remained the same in the absence of TNF-α stimulation. Furthermore, cell motility and invasion were reduced in HCT116 cells following NIBP knockdown even after TNF-α treatment. Finally, primary tumor weight and liver metastasis were reduced in nude mice with orthotopically transplanted NIBP knockdown of HCT116 cells.
  
  
  CONCLUSIONS
  In conclusion, we demonstrated that NIBP knockdown reduces colorectal cancer metastasis through down-regulation of canonical NF-κΒ signaling and suppression of ERK and JNK signaling.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
authors.forename: Mengbin
authors.initials: M
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
authors.forename: Jinxiu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
authors.forename: Shiquan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
authors.forename: Jiean
authors.initials: J
authors.lastname: Huang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D051996:Transcription Factor RelA / Q000235:genetics; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; C498143:RELA protein, human; C503887:TRAPPC9 protein, human; D051996:Transcription Factor RelA; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4