Expression analysis in colitis-associated carcinoma: a role for osteopontin?

There is an increased risk for ulcerative colitis (UC) and Crohn’s colitis (CD) patients to develop colitis-associated carcinoma (CAC). This disorder is usually included in the diagnosis and treatment for the sporadic colorectal carcinoma (CRC), although its progression being molecularly different. Inflammation plays an important role in the CAC tumorigenesis; however, most of what is known about CAC is deduced from animal studies since reports using human samples are scarce. Furthermore, the aim of this study was to aggregate knowledge about the inflammatory and immune pathways that participate in the CAC progression. Surgical colon samples were collected from 60 patients belonging to 6 experimental groups: Control, ulcerative colitis (UC), Crohn’s disease-colitis (CD), UC- or CD-related CAC and CRC. RNA was extracted from paraffin-embedded samples and gene expression analysis was performed using the nCounter technique. A set of 624 genes related to immunology and epithelial barrier function was analysed. Data analysis was performed in the nSolver and Ingenuity Pathway Analysis (IPA) software. In the canonical pathway analysis, the CAC conditions showed considerably less activation of inflammatory and adaptive immunity pathways when compared with IBD, but activation of a number of signalling pathways related to NfkappaB signalling, which is known to play a role in the tumorigenesis of CAC. The most differentially expressed gene in both CD-CAC vs. CD and UC-CAC vs. UC was SPP1, with an increase of 18- and 8-fold, respectively. This gene was also represented in the upstream regulator analysis as an upstream regulator predicted to be activated in CAC vs. IBD. SPP1 codifies the osteopontin protein, a cytokine that participates in a variety of biological processes, including tumorigenesis. Genes related to osteopontin activation such as STAT3, SMAD3 and AKT show a trend of activation whereas genes involved in the negative regulation of osteopontin such as, TNF-signalling related genes, IFR1 and STAT1 present a trend of inhibition, supporting the hypothesis that its activation is important to CAC pathogenesis. Several different signalling pathways are involved in the progression of CAC. Osteopontin, whose involvement in CAC progression has not been elucidated, might play an important role in its tumorigenesis and should be further investigated.