Decreased Toll-interacting protein and peroxisome proliferator-activated receptor γ are associated with increased expression of Toll-like receptors in colon carcinogenesis.
BACKGROUND
Animal data suggest that Toll-like receptors (TLR) may play an important role in colon carcinogenesis. Studies in humans to support that hypothesis are scarce.


OBJECTIVE
To evaluate the expression of TLR2, TLR4 and TLR5, and the expression of several other related molecules, in different human colonic lesions.


METHODS
Colon biopsy samples from normal mucosa, normal mucosa adjacent to lesion, adenoma or sporadic carcinoma were obtained from 35 consecutive patients undergoing colonoscopy. Quantification of TLR2, TLR4, TLR5, Toll-interacting protein (TOLLIP), peroxisome proliferator-activated receptor γ (PPAR-γ), nuclear factor κB, tumour necrosis factor (TNF) α, cyclooxygenase (COX) 1 and 2 mRNA was performed by real-time reverse transcription PCR. TLR2, TLR4 and TLR5 protein expression was quantified by immunohistochemistry.


RESULTS
When compared with normal mucosa (1.0 arbitrary unit (AU)), adjacent normal mucosa presented higher expression of COX-2 (1.86±0.3 AU, p=0.01) and TNFα (1.44±0.18 AU, p=0.04) and lower TOLLIP expression (0.75±0.05 AU, p=0.004). Adenomas and carcinomas presented higher expression of COX-2 (1.63±0.27 and 1.38±0.14 AU, p=0.03 and p=0.05, respectively) and lower expression of TOLLIP (0.44±0.04 AU, p<0.001), with diffuse and higher TLR protein expression (p<0.001). Carcinomas also expressed higher TLR2 (2.31±0.32 AU, p=0.006) and lower PPAR-γ (0.56±0.12 AU, p=0.003). There was a trend towards decreased TOLLIP (p<0.001) and PPAR-γ (p=0.05) from normal mucosa to adenoma/carcinoma.


CONCLUSIONS
Persistently positive TLR expression and lower expression of TLR inhibitors was associated with higher TLR protein levels throughout the spectrum of lesions of colon carcinogenesis. Increasing activation of these receptors by bacteria may play a crucial role in colon carcinogenesis and tumour progression.
Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal. pedronunesml@msn.com
Pedro
P
Pimentel-Nunes
Nádia
N
Gonçalves
Inês
I
Boal-Carvalho
Luís
L
Afonso
Paula
P
Lopes
Roberto
R
Roncon-Albuquerque
João-Bruno
JB
Soares
Elisabete
E
Cardoso
Rui
R
Henrique
Luís
L
Moreira-Dias
Mário
M
Dinis-Ribeiro
Adelino F
AF
Leite-Moreira
D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism*; D003430:Cross-Sectional Studies; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D047495:PPAR gamma; C410602:TOLLIP protein, human; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2