Expression of COX-2, NF-kappaB-p65, NF-kappaB-p50 and IKKalpha in malignant and adjacent normal human colorectal tissue.
BACKGROUND
Cyclooxygenase-2 (COX-2) is selectively over-expressed in colorectal tumours. The mechanism of COX-2 induction in these tumours is not fully understood, although evidence suggests a possible link between nuclear factor (NF)-kappaB and COX-2. We hypothesised an association between COX-2 expression and NF-kappaB-p65, NF-kappaB-p50 and IkappaB-kinase-alpha (IKKalpha) in both epithelial and stromal cells in human colorectal cancer.


METHODS
Using immunohistochemistry, we measured COX-2, NF-kappaB-p65, NF-kappaB-p65 nuclear localisation sequence (NLS), NF-kappaB-p50, NF-kappaB-p50 NLS and IKKalpha protein expression in matched colorectal biopsy samples comprising both non-tumour and adjacent tumour tissue from 32 patients with colorectal cancer.


RESULTS
We have shown that stromal cells of malignant and surrounding normal colorectal tissue express COX-2. In all cell types of malignant tissue, and in vascular endothelial cells (VECs) of neighbouring normal tissue, COX-2 expression was strongly associated with NF-kappaB-p65 expression (Pearson's correlation, P=0.019 for macrophages, P=0.001 for VECs, P=0.002 for fibroblasts (malignant tissue), and P=0.011 for VECs (non-malignant tissue)) but not NF-kappaB-p50 or IKKalpha.


CONCLUSIONS
These data suggest that in these cells COX-2 induction may be mediated through activation of the canonical NF-kappaB pathway. Finally, the lack of association between COX-2, NF-kappaB-p65 or IKKalpha in stromal cells with the clinical severity of colorectal cancer as determined by Duke's stage, suggests that COX-2, NF-kappaB-p65 and IKKalpha expression are possibly early post-initiation events, which could be involved in tumour progression.
Charalambous
M P
MP
Leeds Institute of Molecular Medicine, Wellcome Trust, St James's University Hospital, Leeds, UK.
Lightfoot
T
T
Speirs
V
V
Horgan
K
K
Gooderham
N J
NJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis*; D051996:Transcription Factor RelA / Q000096:biosynthesis*
D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase