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.

Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs

“…miR-21 has been shown to be upregulated in patients with Crohn's disease and ulcerative colitis (41). Moreover, miR-21 and miR-181b expression levels are increased in colorectal cancer, and expression levels have been linked to a poor prognosis in an American cohort (42).…”

Biomarkers of Inflammatory Bowel Disease

“…PDCD4/miR-21 was often un-balance in precancerous changes or intraepithelial neoplasias of mucosa in IBD. miR-21 increases but PDCD4 decreases may indicate they could be biomarkers of IBD canceration [133]. miRNAs increases significantly in mucosa of IBD by micro-array analysis and real-time polymerase chain reaction [134].…”

Implication of miRNAs for inflammatory bowel disease treatment: Systematic review

“…Ludwig et al [73] showed up-regulated level of miR-21 in IBD-associated dysplastic lesions compared to active IBD patients, which was inversely correlated with the expression of PDCD4, a newly characterized tumor suppressor gene. Olaru et al [74,75] found expressions of miR-224 and miR-31 increased successively at each stage of IBD progression from non-inflamed to inflamed non-neoplastic, dysplastic and finally cancerous mucosae.…”