title: Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis C: an immunohistochemical and PCR study of human liver biopsies.
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.
authors: Departments of Pathology, Alexandria, Egypt.
authors: Maha
authors: M
authors: Guimei
authors: Nahed
authors: N
authors: Baddour
authors: Dalal
authors: D
authors: Elkaffash
authors: Laila
authors: L
authors: Abdou
authors: Yousry
authors: Y
authors: Taher
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053539:Keratin-19; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2