Mutated in colorectal cancer protein modulates the NFκB 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 (NFκB) pathway. Therefore, we aimed to determine whether MCC modulates NFκB activation in colorectal cancer.


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.


CONCLUSIONS
These findings suggest that MCC modulates NFκB pathway signalling indirectly in colorectal cancer cells.
Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia.
Nicholas D
ND
Sigglekow
Laurent
L
Pangon
Tilman
T
Brummer
Mark
M
Molloy
Nicholas J
NJ
Hawkins
Robyn L
RL
Ward
Elizabeth A
EA
Musgrove
Maija R J
MR
Kohonen-Corish
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009218:Myosins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D021241:Spectrometry, Mass, Electrospray Ionization; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C498718:MYO10 protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C067857:MCC protein, human; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D053181:Caspase 8; D000251:Adenosine Triphosphatases; D009218:Myosins; C000614178:VCP protein, human; D000074405:Valosin Containing Protein