Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer

Abstract

Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer.

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

“…Such genes were selected among the genes annotated in the "Pancreatic Secretion Pathway" (map04972), available in the KEGG database (22). The 70 genes selected were classified into six groups according to the activity of the encoded protein or their role in the pathogenesis of pancreatitis: (i) genes encoding proteins potentially involved in premature intrapancreatic activation of trypsin (CFTR, PRSS1, PRSS2, SPINK1, CTRC, CTSB, KRT8 and CASR) (23)(24)(25)(26)(27)(28)(29)(30); (ii) CF modifier genes the risk increases for patients with residual pancreatic function (about 10% of cases). However, also excluding all such causes, about one-third of recurrent/ chronic pancreatitis remains idiopathic, and this number is higher in children, who seldom report the classical risk factors observed in adults (8).…”

Keratins let liver live: Mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies

“…Interestingly, the frequency of K8 G61C in a European control group was variable and ranges from 0.8% (4/486) in the Czech Republic to 1.5% (23/1532) in Germany to 3.5% (7/200) in England. 16 K8 G61C is completely silent in mice (and humans) unless challenged with hepatotoxic stress (Table 1). Hence, K8/K18 mutations can be considered "sleeper" biologically-silent variants unless they meet an appropriate stress stimulus.…”

“…16 Both variants are likely to be pathogenic since transfection of K8 Y53H into cultured cells results in unstable keratin filaments 12 while the G433S variant decreases K8 S431 phosphorylation in response to extracellular-regulated-kinase-1/2. 13 K8 variants also associate with fibrosis progression during chronic HCV infection in a well-characterized German cohort.…”

“…Liver keratins serve as stress markers by increasing their expression up to 3-fold, akin to heat shock protein (hsp)-70 which they bind to, 3 and by undergoing posttranslational modifications such as phosphorylation, caspase-mediated fragmentation, ubiquitination and cross-linking. 7,17 Dynamic increased/decreased keratin 12 Tao et al, 63 Schneider et al 65 Europe** 37/2255 (1.6%) 88/6061 (1.5%) Ͼ0.5 1.1 (0.8-1.7) Strnad et al, 14 Treiber et al, 16 Halangk et al, 59 , Schoniger-Hekele et al, 60 Strnad et al, 62 Owens et al, 64 Buning et al, 66 Cavestro et al 67 site-specific phosphorylation serve as reliable markers for human liver disease progression/regression, 18 and for epithelial cell injury in general. 7 The keratin-related genetic animal models 3,7,19,20 and ex vivo cell culture studies 20,21 demonstrated the importance of keratins in protecting hepatocytes from oxidative and other hepatotoxic injuries that promote apoptosis, and also highlighted several important keratin functions (Fig.…”

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

“…For example, the early finding of an association of K8 variants with human chronic pancreatitis 33 is likely due to small patient sample size since two other much larger studies did not identify an association. 34,35 Virus-dependent roles for keratinspossible mechanisms of action One potential compensatory mechanism that may account for pancreas-specific functional redundancy for keratin absence is the marked up-regulation of Reg-II in K8-null pancreata. 9 Reg-II is a stress-inducible protein that is normally upregulated 1-4 days after caerulein and CDD-induced pancreatitis and is likely involved in the amelioration Keratins in coxsackievirus-induce pancreatitis Dovepress submit your manuscript | www.dovepress.com Dovepress of pancreatitis.…”