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The Value of Thioredoxin Family Proteins and Proliferation Markers in Dysplastic and Malignant Gallbladders in Patients with Primary Sclerosing Cholangitis

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Abstract

Background and aims

Patients with primary sclerosing cholangitis (PSC) have an increased risk for biliary and gallbladder malignancy and markers of early malignancy in PSC are lacking. The aims were to evaluate biomarkers to look for premalignancy/malignancy.

Methods

All available gallbladder specimens (n = 53) in patients with PSC at Karolinska University Hospital between 1985 and 2006 were reviewed. Immunohistochemical staining for p53, Ki-67, Cyclin D1 and the thioredoxin family redox proteins; Thioredoxin reductase 1 (TrxR1), isoform-TrxR1-v.2.3.5, Thioredoxin (Trx1) and Glutaredoxin1 (Grx1) was performed on tissues from patients with carcinoma (n = 6), dysplasia (n = 7) and non-cancerous gallbladder epithelium (n = 6).

Results

Dysplasia and carcinoma were found in 16/53 (30%) cases. Inflammation and fibrosis of the gallbladder wall were more common in tissue with gallbladder dysplasia/carcinoma than in benign tissue 12/25 (48%) versus 4/28 (12%) (p < 0.01) and in 13/21 (62%) versus 3/32 (9%) (p < 0.0001), respectively. Immunoreactivity for p53, Ki67, Cyclin D1 was detected in significantly more cases of dysplasia/carcinoma of the gallbladder than in non-cancerous epithelium. 2/19 (11%) of the samples were positive in non-cancerous epithelium versus 7/17 (41%) in dysplasia/carcinoma (p < 0.05) for TrxR1-v.2.3.5. Grx1 was down regulated; more specifically 15/19 (79%) positive cases in non-cancerous epithelium versus 7/17 (41%) in dysplasia/carcinoma.

Conclusion

PSC patients have a frequency of gallbladder dysplasia/carcinoma of 30% in operative specimens. The overexpression of TrxR1-v2,3,5 and down regulation of Grx1 in dysplastic gallbladder epithelium suggest that these proteins should be further evaluated as possible future immunohistochemical markers in the early diagnosis of biliary malignancy in PSC.

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Abbreviations

GR:

Glutathione reductase

Grx:

Glutaredoxin

GSH:

Glutathione

PSC:

Primary sclerosing cholangitis

PMN:

Polymorphonuclear

Trx:

Thioredoxin

TrxR:

Thioredoxin reductase

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Acknowledgments

This study was supported by grants from Wallenberg Foundation, Bengt Ihre’s Foundation, Swedish Cancer Society, Swedish Cancer and Allergy Society.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, 141 86, Stockholm, Sweden

    Karouk Said & Annika Bergquist

  2. Division of Pathology, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

    Hans Glaumann & Mikael Björnstedt

Authors
  1. Karouk Said
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  2. Hans Glaumann
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  3. Mikael Björnstedt
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  4. Annika Bergquist
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Correspondence to Karouk Said.

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Said, K., Glaumann, H., Björnstedt, M. et al. The Value of Thioredoxin Family Proteins and Proliferation Markers in Dysplastic and Malignant Gallbladders in Patients with Primary Sclerosing Cholangitis. Dig Dis Sci 57, 1163–1170 (2012). https://doi.org/10.1007/s10620-012-2089-4

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  • DOI: https://doi.org/10.1007/s10620-012-2089-4

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