title: Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells.
abstract: The roles of fibroblast growth factor-2 (FGF-2) in the hepatocellular carcinoma (HCC) development are still controversial. In this study, we investigated the expression of FGF-2 in chronic hepatitis (CH) type C patients with or without HCC and the immunoregulation of FGF-2 in NK sensitivity of HCC cells. The FGF-2 expressions were detected in the liver tissues of patients, but not in normal liver. The serum FGF-2 levels of the patients with CH, liver cirrhosis (LC) or HCC were significantly higher than those of healthy volunteers. The serum FGF-2 levels of patients decreased with the progression of chronic liver disease. HCC occurrence of LC patients with high levels of serum FGF-2 was significantly lower than that with low levels of serum FGF-2. Proinflammatory cytokines, such as IL-1β and IL-6, induced FGF-2 expressions in HCC cells and normal hepatocytes. FGF-2 stimulation resulted in increasing the expression of the membrane-bound major histocompatibility complex class I-related chain A (MICA), an NK activating molecule, and decreasing that of human leukocyte antigen (HLA) class I, an NK inhibitory molecule, on HCC cells. This did not occur with normal hepatocytes. Adding anti-FGF receptor-2 neutralizing antibody resulted in inhibiting the change of MICA and HLA class I expressions on FGF-2 stimulated HCC cells. FGF-2 stimulation on HCC cells resulted in increasing NK sensitivity against HCC cells. These findings indicate that FGF-2 produced by HCC cells or normal hepatocytes of chronic liver disease may play critical roles in eliminating HCC cells by innate immunity.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hinako
authors.initials: H
authors.lastname: Tsunematsu
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kohga
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aketa
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D006680:HLA Antigens / Q000096:biosynthesis; D019698:Hepatitis C, Chronic / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000096:biosynthesis; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016222:Fibroblast Growth Factor 2; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2