title: PDCD4/miR-21 dysregulation in inflammatory bowel disease-associated carcinogenesis.
abstract: Inflammatory bowel diseases (IBDs; both ulcerative colitis [UC] and Crohn's colitis [CC]) are well-established predisposing pathological conditions for colorectal cancer (CRC) development. In IBDs, both the endoscopy and the histology assessment of CRC precursors (i.e., dysplasia, also defined as intraepithelial neoplasia) are associated with low interobserver consistency, and no reliable dysplasia-specific biomarker is available. The programmed cell death 4 (PDCD4) tumor suppressor gene is involved in sporadic colorectal oncogenesis, but scanty information is available on its involvement in IBD-associated colorectal oncogenesis. One hundred twenty tissue samples representative of active and inactive IBD and of flat dysplasia were obtained from 30 cases of UC and 30 of CC who undergone colectomy. Twenty additional biopsy samples obtained from patients with irritable bowel syndrome acted as normal controls. PDCD4 expression was assessed by immunohistochemistry; the expression of miR-21 (a major PDCD4 regulator) was investigated by quantitative real-time PCR and in situ hybridization in different series of a hundred samples. Tissue specimens from both controls and inactive IBD consistently featured strong PDCD4 nuclear immunostain; conversely, lower PDCD4 nuclear expression was featured by both active IBD and IBD-associated dysplastic lesions. Significant PDCD4 down-regulation distinguished IBD-associated dysplasia (p < 0.001) versus active IBD. In both active IBD and dysplasia, PDCD4 down-regulation was significantly associated with miR-21 up-regulation. PDCD4 nuclear down-regulation (which parallels miR-21 up-regulation) is involved in the molecular pathway of IBD-associated carcinogenesis. PDCD4 nuclear expression may be usefully applied as ancillary maker in the histological assessment of IBD-associated dysplastic lesions.
authors.affiliation: Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Ludwig
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Claudia
authors.initials: C
authors.lastname: Mescoli
authors.forename: Marco
authors.initials: M
authors.lastname: Pizzi
authors.forename: Mariangela
authors.initials: M
authors.lastname: Balistreri
authors.forename: Laura
authors.initials: L
authors.lastname: Albertoni
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pucciarelli
authors.forename: Marco
authors.initials: M
authors.lastname: Scarpa
authors.forename: Giacomo Carlo
authors.initials: GC
authors.lastname: Sturniolo
authors.forename: Imerio
authors.initials: I
authors.lastname: Angriman
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011230:Precancerous Conditions; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins