Mutated in colorectal cancer protein modulates the NF?B pathway
01.01.2012
Sigglekow ND, Pangon L, Brummer T, Molloy M, Hawkins NJ, Ward RL, Musgrove EA, Kohonen-Corish MR.
Anticancer Res 2012;32(1):73-9.
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 (NF?B) pathway. Therefore, we aimed to determine whether MCC modulates NF?B activation in colorectal cancer. Materials and Methods: NF?B 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 NF?B-dependent transcription in tumour necrosis factor alpha (TNF?)- or lipopolysaccharide (LPS)-stimulated cells. Conversely, knockdown of MCC resulted in accumulation of the inhibitor of kappa B alpha (I?B?) protein, encoded by NF?BIA, a first response gene specifically and rapidly regulated by NF?B 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 NF?B pathway signalling indirectly in colorectal cancer cells.
