Keratins in colorectal epithelial function and disease

Abstract

Summary Keratins are the largest subgroup of intermediate filament proteins, which are an important constituent of the cellular cytoskeleton. The principally expressed keratins (K) of the intestinal epithelium are K8, K18 and K19. The specific keratin profile of a particular epithelium provides it with strength and integrity. In the colon, keratins have been shown to regulate electrolyte transport, likely by targeting ion transporters to their correct location in the colonocytes. Keratins are highly dynamic and are subject to post‐translational modifications including phosphorylation, acetylation and glycosylation. These affect the filament dynamics and hence solubility of keratins and may contribute to protection against degradation. Keratin null mice (K8−/−) develop colitis, and abnormal keratin mutations have been shown to be associated with inflammatory bowel disease (IBD). Abnormal expression of K7 and K20 has been noted in colitis‐associated dysplasia and cancers. In sporadic colorectal cancers (CRCs) may be useful in predicting tumour prognosis; a low K20 expression is noted in CRCs with high microsatellite instability; and keratins have been noted as dysregulated in peri‐adenomatous fields. Caspase‐cleaved fragment of K18 (M30) in the serum of patients with CRC has been used as a marker of cancer load and to assess response to therapy. These data suggest an emerging importance of keratins in maintaining normal function of the gastrointestinal epithelium as well as being a marker of various colorectal diseases. This review will primarily focus on the biology of these proteins, physiological functions and alterations in IBD and CRCs.

Serum M 30 Levels Reflects Ulcerative Colitis Activity

“…15 T-cell apoptosis is an important mechanism in the development of the peripheral immune tolerance. The results of our study demonstrate the hypothesis reported by Majumdar et al 10 showing that apoptosis increases in patients with ulcerative colitis. As a consequence of the induction of antiapoptotic factors such as Bcl-xL and Bcl-2, a resistance against apoptosis in active T cells evolves through IL-6.…”

“…14 Conversely, it was reported in laboratory studies that mucosal T cells were showing a higher resistance against apoptosis in active ulcerative colitis. 10 In our study, serum M 30 levels were significantly higher in patients with ulcerative colitis compared with the healthy controls. Production of IL-6 increases in the inflamed tissue, as observed in active ulcerative colitis, showing an antiapoptotic signal feature.…”

“…M-30 serum levels escalate in epithelial cell apoptosis, being an indirect indicator of apoptosis. 10 In this study, we aimed to evaluate the relation between M 30 serum levels and ulcerative colitis activity. 9 Epithelial cells of the gastrointestinal system include CK-18, and it is a necessary protein for the colonic epithelial cells to maintain their normal functions.…”

Identification of proteins with the CDw75 epitope in human colorectal cancer

“…Regarding CRC cell lines, the unique K8 and K18 bands were also coincident with one of the CDw75-positive bands. These proteins are the main keratin pair in simple epithelia, such as the colorectal epithelium, where K8 and K18 are crucial for tissue homeostasis (47). In addition, there are numerous evidence for abnormalities of K8/K18 expression in CRC (48)(49)(50)(51)(52).…”

Novel mouse model recapitulates genome and transcriptome alterations in human colorectal carcinomas

“…KRT8, KRT18, KRT19, and KRT20 are considered markers of normal human intestinal epithelial cells (Moll et al, 2008). Krt7, Krt8, and Krt20 were significantly downregulated at the LT stage, which, reportedly are also found to be significantly downregulated in human colon CRCs and associated with EMT transitions and ultimately poor survival rates (Knosel et al, 2006;Bayrak et al, 2011;Gurzu and Jung 2012;Majumdar et al, 2012;Fortier et al, 2013). Krt7, Krt8, and Krt20 were significantly downregulated at the LT stage, which, reportedly are also found to be significantly downregulated in human colon CRCs and associated with EMT transitions and ultimately poor survival rates (Knosel et al, 2006;Bayrak et al, 2011;Gurzu and Jung 2012;Majumdar et al, 2012;Fortier et al, 2013).…”