Mutated in colorectal cancer protein modulates the NFκB pathway

Anticancer Res. 2012 Jan;32(1):73-9.

Abstract

Background: The tumour suppressor gene 'mutated in colorectal cancer' (MCC) is silenced through promoter methylation in colorectal cancer and has been implicated as a regulator of the nuclear factor kappa B (NFκB) pathway. Therefore, we aimed to determine whether MCC modulates NFκB activation in colorectal cancer.

Materials and methods: NFκB activation was assessed using luciferase reporter assays in colorectal cancer cells in vitro. MCC methylation was analysed in primary tumour specimens from patients with inflammatory bowel disease.

Results: Re-expression of MCC reduced NFκB-dependent transcription in tumour necrosis factor alpha (TNFα)- or lipopolysaccharide (LPS)-stimulated cells. Conversely, knockdown of MCC resulted in accumulation of the inhibitor of kappa B alpha (IκBα) protein, encoded by NFKBIA, a first response gene specifically and rapidly regulated by NFκB pathway activation. The MCC gene is methylated in up to 6/16 of inflammatory bowel disease-associated tissue specimens, and myosin-10 and valosin-containing protein were identified as MCC-interacting proteins.

Conclusion: These findings suggest that MCC modulates NFκB pathway signalling indirectly in colorectal cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis
  • Caspase 8 / metabolism
  • Cell Cycle Proteins / metabolism
  • Colorectal Neoplasms / complications
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • DNA Methylation*
  • Enzyme Activation
  • Female
  • Humans
  • I-kappa B Proteins / metabolism
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / metabolism*
  • Inflammatory Bowel Diseases / pathology
  • Lipopolysaccharides / pharmacology
  • Luciferases / metabolism
  • Male
  • Middle Aged
  • Myosins / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic / genetics
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Spectrometry, Mass, Electrospray Ionization
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Valosin Containing Protein

Substances

  • Cell Cycle Proteins
  • I-kappa B Proteins
  • Lipopolysaccharides
  • MYO10 protein, human
  • NF-kappa B
  • NFKBIA protein, human
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • MCC protein, human
  • NF-KappaB Inhibitor alpha
  • Luciferases
  • Caspase 8
  • Adenosine Triphosphatases
  • Myosins
  • VCP protein, human
  • Valosin Containing Protein