title: Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection.
abstract: Heterogeneous biological characteristics of hepatocellular carcinoma may be attributed to the cellular origin of the tumor. Patients with hepatocellular carcinoma probably derived from hepatic progenitor cells had early tumor recurrence after surgical resection or liver transplantation, suggesting that these tumors have aggressive characteristics. Ezrin, a member of the ERM (ezrin-radixin-moesin) cytoskeleton-associated protein family, is highly expressed in several types of human cancers and correlations between its immunoreactivity and patient outcome have been shown. In this study, ezrin expression, as well as cytokeratin19 and cytokeratin 7 expression, which are regarded as progenitor cell/ductular markers were immunohistochemically assessed in cases of hepatocellular carcinoma. In normal livers, ezrin expression was not found in any cell types, whereas cytokeratin 7 and cytokeratin 19 were exclusively stained in bile duct cells. In contrast, in livers with chronic hepatitis or cirrhosis, positive ezrin expression was observed in ductular reactions with strong intensity and intermediate hepatobiliary cells with various intensity. Of 77 cases of hepatocellular carcinoma, 28 (36%) had positive ezrin expression, 32 (42%) had cytokeratin 7 expression, and 11 (14%) had cytokeratin 19 expression. Ezrin expression in hepatocellular carcinoma was significantly associated with cytokeratin 19 expression, but not with cytokeratin 7 expression. Patients with ezrin-positive hepatocellular carcinoma had a significantly higher prevalence of elevated serum alpha-fetoprotein. Patients with immunohistochemical ezrin-positive hepatocellular carcinoma demonstrated significantly shorter recurrence-free and overall survival compared to patients with ezrin-negative hepatocellular carcinoma. Multivariate analysis revealed positive ezrin expression and multiple tumors to be independently associated with early recurrence in patients with hepatocellular carcinoma after curative surgical resection. These results suggested that hepatocellular carcinoma with ezrin expression might be at least partly derived from hepatic progenitor cells. Measurement of ezrin expression might be used to identify patients with an increased risk of early recurrence.
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Okamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohtsuka
authors.forename: Fumio
authors.initials: F
authors.lastname: Kimura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshidome
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D019085:Fluorescent Antibody Technique, Direct; D006498:Hepatectomy; D006521:Hepatitis, Chronic / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007564:Japan / Q000453:epidemiology; D053539:Keratin-19 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D000509:alpha-Fetoproteins / Q000378:metabolism; D000099149:Ezrin
chemical_list: D014408:Biomarkers, Tumor; D003598:Cytoskeletal Proteins; D053539:Keratin-19; D053552:Keratin-7; D000509:alpha-Fetoproteins; D000099149:Ezrin; C097353:AFP protein, human