title: Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia.
abstract: Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa.
  
  
  
  Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry.
  
  
  
  In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients.
  
  
  
  In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer.
authors.affiliation: Digestive Disease Center K, Bispebjerg Hospital, Copenhagen, DK-2400, Denmark. badar@me.com.|Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark. badar@me.com.
authors.forename: Badar
authors.initials: B
authors.lastname: Mahmood
authors.affiliation: Digestive Disease Center K, Bispebjerg Hospital, Copenhagen, DK-2400, Denmark.|Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Morten Matthiesen Bach
authors.initials: MM
authors.lastname: Damm
authors.affiliation: Digestive Disease Center K, Bispebjerg Hospital, Copenhagen, DK-2400, Denmark.
authors.forename: Thorbjørn Søren Rønn
authors.initials: TS
authors.lastname: Jensen
authors.affiliation: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Marie Balslev
authors.initials: MB
authors.lastname: Backe
authors.affiliation: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Mattias Salling
authors.initials: MS
authors.lastname: Dahllöf
authors.affiliation: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Steen Seier
authors.initials: SS
authors.lastname: Poulsen
authors.affiliation: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Bindslev
authors.affiliation: Digestive Disease Center K, Bispebjerg Hospital, Copenhagen, DK-2400, Denmark.|Zealand Pharma, Glostrup, DK-2600, Denmark.
authors.forename: Mark Berner
authors.initials: MB
authors.lastname: Hansen
mesh_terms: D000368:Aged; D001706:Biopsy; D003106:Colon / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*
chemical_list: D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP
keywords: Cyclic nucleotide phosphodiesterases and colorectal cancer; Endoscopic biopsy; Human