HB-EGF is a paracrine growth stimulator for early tumor prestages in inflammation-associated hepatocarcinogenesis

• Published in: Journal of hepatology 2008-12, Vol.49 (6), p.955-964
• Main Authors: Sagmeister, Sandra, Drucker, Claudia, Losert, Annemarie, Grusch, Michael, Daryabeigi, Anahita, Parzefall, Wolfram, Rohr-Udilova, Nataliya, Bichler, Christoph, Smedsrød, Bård, Kandioler, Daniela, Grünberger, Thomas, Wrba, Fritz, Schulte-Hermann, Rolf, Grasl-Kraupp, Bettina
• Format: Article
• Language: English
• Subjects: Adenoma, Liver Cell - immunology; Adenoma, Liver Cell - pathology; Adenoma, Liver Cell - physiopathology; Animals; Biological and medical sciences; Cancer prestages; Cell Division; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - immunology; Genes, erbB-1 - genetics; HB-EGF; Heparin-binding EGF-like Growth Factor; Hepatitis - immunology; Hepatitis - pathology; Hepatocytes - pathology; Humans; Inflammation; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Liver cancer; Liver Neoplasms - immunology; Liver Neoplasms - pathology; Liver Neoplasms - physiopathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mesenchyme; Mesoderm - cytology; Mitosis; Neoplasm Staging; Paracrine Communication - immunology; Rats; Rats, Wistar; Tumor Cells, Cultured; Tumors
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2008.06.031

Background/Aims We studied the impact of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on inflammation-driven hepatocarcinogenesis. Methods HB-EGF expression was determined by qRT-PCR and immunodetection in hepatocellular adenoma and carcinoma and in mesenchymal (MC) and parenchymal liver cells obtained from different models of inflammation. The functions of HB-EGF in early hepatocarcinogenesis were assessed in co-cultures of unaltered and initiated/premalignant hepatocytes. Results In human and rat (pre)malignant liver lesions, HB-EGF levels were comparable to that of the surrounding tissue. In inflamed livers HB-EGF was expressed predominantly in MC and was further increased by pro-inflammatory lipopolysaccharide (LPS) or linoleic acid hydroperoxide (LOOH). In culture, DNA-replication occurred rather in initiated/premalignant than unaltered hepatocytes and was further elevated by LOOH- or LPS-stimulated MC-supernatants. The supernatant effects were abrogated by pre-incubation with HB-EGF-neutralizing antisera. HB-EGF itself induced DNA-replication and mitosis preferentially in the initiated/premalignant cells. When transducing hepatocytes with a dominant-negative ErbB1-construct, HB-EGF-induced DNA-replications were blocked completely in unaltered hepatocytes but incompletely in initiated/premalignant cells, which suggests elevated ErbB-mediated signal transduction in first stages of hepatocarcinogenesis. Conclusions Pro-inflammatory stimuli induce the release of HB-EGF from MC, which stimulates DNA-replication in initiated/premalignant hepatocytes. Similar mechanisms may contribute to carcinogenesis in human inflammatory liver diseases.