title: BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling.
abstract: Colorectal cancer remains the fourth most common cause of cancer-related mortality worldwide. Here we investigate the role of nuclear factor-κB (NF-κB) co-factor B-cell CLL/lymphoma 3 (BCL-3) in promoting colorectal tumour cell survival.
  
  
  
  Immunohistochemistry was carried out on 47 tumour samples and normal tissue from resection margins. The role of BCL-3/NF-κB complexes on cell growth was studied in vivo and in vitro using an siRNA approach and exogenous BCL-3 expression in colorectal adenoma and carcinoma cells. The question whether BCL-3 activated the AKT/protein kinase B (PKB) pathway in colorectal tumour cells was addressed by western blotting and confocal microscopy, and the ability of 5-aminosalicylic acid (5-ASA) to suppress BCL-3 expression was also investigated.
  
  
  
  We report increased BCL-3 expression in human colorectal cancers and demonstrate that BCL-3 expression promotes tumour cell survival in vitro and tumour growth in mouse xenografts in vivo, dependent on interaction with NF-κB p50 or p52 homodimers. We show that BCL-3 promotes cell survival under conditions relevant to the tumour microenvironment, protecting both colorectal adenoma and carcinoma cells from apoptosis via activation of the AKT survival pathway: AKT activation is mediated via both PI3K and mammalian target of rapamycin (mTOR) pathways, leading to phosphorylation of downstream targets GSK-3β and FoxO1/3a. Treatment with 5-ASA suppressed BCL-3 expression in colorectal cancer cells.
  
  
  
  Our study helps to unravel the mechanism by which BCL-3 is linked to poor prognosis in colorectal cancer; we suggest that targeting BCL-3 activity represents an exciting therapeutic opportunity potentially increasing the sensitivity of tumour cells to conventional therapy.
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Urban
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Collard
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Eagle
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Southern
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Greenhough
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Hamdollah-Zadeh
authors.affiliation: Centre for Digestive Diseases, National Centre for Bowel Research and Surgical Intervention, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, UK.
authors.forename: Anil
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Centre for Digestive Diseases, National Centre for Bowel Research and Surgical Intervention, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, UK.
authors.forename: Richard
authors.identifier: 0000-0001-8567-3543
authors.initials: R
authors.lastname: Poulsom
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Christos
authors.initials: C
authors.lastname: Paraskeva
authors.affiliation: Centre for Digestive Diseases, National Centre for Bowel Research and Surgical Intervention, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Williams
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis; D000081242:B-Cell Lymphoma 3 Protein; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003106:Colon / Q000737:chemistry; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D019804:Mesalamine / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012007:Rectum / Q000737:chemistry; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000081242:B-Cell Lymphoma 3 Protein; D019804:Mesalamine; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; C494929:PTEN protein, human
keywords: APOPTOSIS; CANCER PREVENTION; COLORECTAL CANCER; INFLAMMATION; NUCLEAR FACTOR KAPPA B