TY - JOUR
T1 - Mutated in colorectal cancer protein modulates the NFκB pathway
AU - Sigglekow, Nicholas D.
AU - Pangon, Laurent
AU - Brummer, Tilman
AU - Molloy, Mark
AU - Hawkins, Nicholas J.
AU - Ward, Robyn L.
AU - Musgrove, Elizabeth A.
AU - Kohonen-Corish, Maija R J
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84855709768&partnerID=8YFLogxK
M3 - Article
C2 - 22213290
AN - SCOPUS:84855709768
SN - 0250-7005
VL - 32
SP - 73
EP - 79
JO - Anticancer Research
JF - Anticancer Research
IS - 1
ER -