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Decreased Toll-interacting protein and peroxisome proliferator-activated receptor γ are associated with increased expression of Toll-like receptors in colon carcinogenesis
  1. Pedro Pimentel-Nunes1,2,
  2. Nádia Gonçalves1,
  3. Inês Boal-Carvalho1,
  4. Luís Afonso3,
  5. Paula Lopes3,
  6. Roberto Roncon-Albuquerque Jr1,
  7. João-Bruno Soares1,
  8. Elisabete Cardoso2,
  9. Rui Henrique3,
  10. Luís Moreira-Dias2,
  11. Mário Dinis-Ribeiro2,4,
  12. Adelino F Leite-Moreira1
  1. 1Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
  2. 2Gastroenterology Department, Portuguese Oncology Institute, Porto, Portugal
  3. 3Pathology Department, Portuguese Oncology Institute, Porto, Portugal
  4. 4CINTESIS/Department of Biostatistics and Medical Informatics, Porto Faculty of Medicine, Porto, Portugal
  1. Correspondence to Dr Pedro Pimentel-Nunes, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; pedronunesml{at}msn.com

Abstract

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.

Aim 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.

  • Adenoma
  • antibodies
  • antigenic epitopes
  • cancer
  • cancer genetics
  • CERB 2
  • colon
  • colorectal cancer
  • gastric cancer
  • gastroenterology
  • gastrointestinal disease
  • Helicobacter pylori
  • immunology
  • inflammation
  • molecular oncology
  • PPAR-γTLR2
  • TLR4
  • TLR5
  • TOLLIP

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Footnotes

  • Funding This study was supported by grants for medical investigation from the Portuguese Oncology Institute of Porto.

  • Competing interests None to declare.

  • Patient consent Obtained.

  • Ethics approval The study protocol respected the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the Portuguese Oncology Institute of Porto.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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