Inflammation decreases keratin level in ulcerative colitis; inadequate restoration associates with increased risk of colitis-associated cancer

Abstract

BackgroundKeratins are intermediate filament (IF) proteins, which form part of the epithelial cytoskeleton and which have been implicated pathology of inflammatory bowel diseases (IBD).MethodsIn this study biopsies were obtained from IBD patients grouped by disease duration and subtype into eight categories based on cancer risk and inflammatory status: quiescent recent onset (<5 years) UC (ROUC); UC with primary sclerosing cholangitis; quiescent long-standing pancolitis (20–40 years) (LSPC); active colitis and non-inflamed proximal colonic mucosa; pancolitis with dysplasia-both dysplastic lesions (DT) and distal rectal mucosa (DR); control group without pathology. Alterations in IF protein composition across the groups were determined by quantitative proteomics. Key protein changes were validated by western immunoblotting and immunohistochemical analysis.ResultAcute inflammation resulted in reduced K8, K18, K19 and VIM (all p<0.05) compared to controls and non inflamed mucosa; reduced levels of if– associated proteins were also seen in DT and DR. Increased levels of keratins in LSPC was noted relative to controls or ROUC (K8, K18, K19 and VIM, p<0.05). Multiple K8 forms were noted on immunoblotting, with K8 phosphorylation reduced in progressive disease along with an increase in VIM:K8 ratio. K8 levels and phosphorylation are reduced in acute inflammation but appear restored or elevated in subjects with clinical and endoscopic remission (LSPC) but not apparent in subjects with elevated risk of cancer.ConclusionsThese data suggest that keratin regulation in remission may influence subsequent cancer risk.

Keratins Are Altered in Intestinal Disease-Related Stress Responses

“…Even if a 1.5–2.5-fold increase in specific keratins is seen in most colonic stress-conditions tested here, a slight decrease in K8, K18 and K19 can be observed in the acute DSS-models. A recent human study reports similar decreased K8, K18 and K19 levels in ulcerative colitis patients [ 35 ], and such downregulation could be explained by a local destruction of the single-layered colonic epithelium that can occur after acute DSS-treatment or in active human inflammatory disease.…”

“…IFs and keratins are similarly upregulated and modified in stress situations [ 9 , 22 ] and during recovery from stress, e.g., as seen in liver [ 23 , 24 , 25 , 26 , 27 ], pancreas [ 28 , 29 ], kidney [ 30 ], lung [ 31 ], and skin [ 32 , 33 , 34 ]. Contrary to increased hepatic K8 and K18 levels in human liver disease [ 23 ], colonic K8, K18 and K19 levels have recently been reported to decrease in human colon during inflammatory stress, as observed in ulcerative colitis [ 35 ]. Furthermore, K7, K8 and K20 are increased in human colitis-associated dysplasia and colorectal cancer compared to healthy controls [ 36 , 37 , 38 , 39 ].…”

Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Northern Han Chinese

“…Furthermore, the risk allele “G” of rs7525764 and “T” of rs2055491 for UC co-occur with the “A” allele of rs17106184 in the same haplotype. The “A” allele of rs17106184 may be able to escalate the inflammatory response, which plays a role in the pathogenesis of UC [ 33 ]. Considering that inflammation is involved in the common pathogenesis of chronic disease, including T2DM, hypertension, and UC [ 34 ], it can be inferred that the “A” allele of rs17106184 is associated with the pathogenesis of T2DM via inflammation pathway.…”

Application of Proteomics to Inflammatory Bowel Disease Research: Current Status and Future Perspectives

“…K8 and K18 play a role in TNF- α -induced apoptosis [170, 171]. A recent study by our group (Corfe et al) exploited the subcellular fractionation technique to identify differential expression of intermediate filaments (IF) in UC patients at differing risk for colorectal cancer [172]. Colonic biopsies were collected endoscopically from the following patients: recent-onset colitis in remission ( n = 8), longstanding pancolitis in remission ( n = 10), and UC with PSC ( n = 6).…”