title: Growth suppression of the hepatocellular carcinoma cell line Hepa1-6 by an activatable interferon regulatory factor-1 in mice.
abstract: Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis and few therapeutic options. The aim of the study was to evaluate the potential of IFN regulatory factor-1 (IRF-1) for cytokine gene therapy of HCC using an IRF-1/human estrogen receptor fusion protein (IRF-1hER), which is reversibly activatable by beta-estradiol (E2). IRF-1hER stably expressing murine Hepa1-6 HCC cells (HepaIRF-1hER) were characterized by lowMHC 1, highCD54, and lack of MHC II, CD80, and CD86 expression. Activation of HepaIRF-1hER cells induced a highMHC I, lowMHC II, and highCD54 phenotype. Furthermore, they were characterized by IFN-beta secretion, decreased anchorage-independent growth in a soft agar assay, and diminished cell growth. Tumor growth in E2-treated syngeneic C57L/J mice, but not in E2-untreated mice, was suppressed. These E2-treated mice were protected against rechallenge with HepaIRF-1hER and wild-type Hepa1-6 tumors even in the absence of E2, suggesting induction of tumor specific immunity. In fact, significant CTL activity against Hepa1-6 tumors and the endogenously expressed HCC-specific self antigen alpha-fetoprotein was observed. Antitumoral effects, however, were only partially dependent on both CD4+ and CD8+ T cells. IRF-1 treatment of mice bearing HepaIRF-1hER tumors resulted in growth arrest of tumors, and a significant survival benefit was observed in comparison to E2-untreated mice. In conclusion, our data demonstrate that IRF-1 suppresses HCC growth through both a direct antitumor growth effect and enhanced immune cell recognition of the tumor and is a promising candidate for gene therapy of HCC.
authors: Department of Gene Regulation and Differentiation, Gesellschaft für Biotechnologische Forschung, Freiburg, Germany.
authors: A
authors: A
authors: Kröger
authors: D
authors: D
authors: Ortmann
authors: T U
authors: TU
authors: Krohne
authors: L
authors: L
authors: Mohr
authors: H E
authors: HE
authors: Blum
authors: H
authors: H
authors: Hauser
authors: M
authors: M
authors: Geissler
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D000509:alpha-Fetoproteins; D004958:Estradiol; D016899:Interferon-beta