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Mutated in colorectal cancer protein modulates the NF?B pathway.


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 (NFkappaB) pathway. Therefore, we aimed to determine whether MCC modulates NFkappaB activation in colorectal cancer. MATERIALS AND METHODS: NFkappaB 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 NFkappaB-dependent transcription in tumour necrosis factor alpha (TNFalpha)- or lipopolysaccharide (LPS)-stimulated cells. Conversely, knockdown of MCC resulted in accumulation of the inhibitor of kappa B alpha (IkappaBalpha) protein, encoded by NFKBIA, a first response gene specifically and rapidly regulated by NFkappaB 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 NFkappaB pathway signalling indirectly in colorectal cancer cells.

Type Journal
Authors Sigglekow, N.D.; Pangon, L.; Brummer, T.; Molloy, M.; Hawkins, N.J.; Ward, R.L.; Musgrove, E.A.; Kohonen-Corish, M.
Published Date 2012-01-04
Published Volume 32
Published Issue 1
Published Pages 73-9
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version