Open Access Research article

Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis C: an immunohistochemical and PCR study of human liver biopsies

Maha Guimei15, Nahed Baddour15*, Dalal ElKaffash235, Laila Abdou15 and Yousry Taher45

Author Affiliations

1 Departments of Pathology, Champillion street, Alexandria, Egypt

2 Clinical Pathology, Champillion street, Alexandria, Egypt

3 Alexandria Center for Women’s Health, Champillion street, Alexandria, Egypt

4 Internal Medicine (Hepatobiliary unit), Champillion street, Alexandria, Egypt

5 Faculty of Medicine, University of Alexandria, Azarita, PO Box 31211, Alexandria, Egypt

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BMC Research Notes 2012, 5:390  doi:10.1186/1756-0500-5-390

Published: 29 July 2012

Abstract

Background

The possible role of secretory products of fibrous tissue in the development of hepatocellular carcinoma (HCC) complicating chronic hepatitis C was investigated. Our hypothesis was that gremlin, secreted by fibroblasts, inhibited bone morphogenic protein (BMP), which mediates stem cell maturation into adult functioning hepatocytes, and thus, arrest stem cell maturation and promoted their proliferation in an immature state possibly culminating into development of HCCs.

Results

Protein expression of cytokeratin 19 (CK19) and fibroblast growth factor 2 (FGF-2), and mRNA expression of gremlin and BMP-7 were studied in 35 cases of chronic hepatitis, cirrhosis and HCC complicating chronic hepatitis C. CK19 expression was higher in cases of cirrhosis (0.004), which correlated with the grade (r = 0.64, p = 0.009) and stage (r = 0.71, p = 0.001). All HCCs were negative for CK19. Stem cell niche activation (as indicated as a ductular reaction) was highest in cases of cirrhosis (p = 0.001) and correlated with CK19 expression (r = 0.42, p = 0.012), the grade(r = 0.56, p = 0.024) and stage (0.66, p = 0.006). FGF-2 expression was highest in HCCs and correlated with the grade (r = 0.6, p = 0.013), stage (0.72, p = 0.002), CK19 expression (r = 0.71, p = 002) and ductular reaction (0.68, p = 0.004) in hepatitis cases. Higher numbers of cirrhosis cases and HCCs (p = 0.009) showed gremlin expression, which correlated with the stage (r = 0.7, p = 0.002). Gremlin expression correlated with that of CK19 (r = 0.699, p = 0.003) and FGF2 (r = 0.75, p = 0.001) in hepatitis cases.

Conclusions

Fibrosis promotes carcinogenesis by fibroblast-secreted gremlin that blocks BMP function and promotes stem cell activation and proliferation as well as possibly HCC development.

Keywords:
Gremlin; Bone morphogenetic protein 7; Hepatocellular carcinoma; Hepatic progenitor cells