title: A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis.
abstract: Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, but its molecular heterogeneity hampers the design of targeted therapies. Currently, the only therapeutic option for advanced HCC is Sorafenib, an inhibitor whose targets include RAF. Unexpectedly, RAF1 expression is reduced in human HCC samples. Modelling RAF1 downregulation by RNAi increases the proliferation of human HCC lines in xenografts and in culture; furthermore, RAF1 ablation promotes chemical hepatocarcinogenesis and the proliferation of cultured (pre)malignant mouse hepatocytes. The phenotypes depend on increased YAP1 expression and STAT3 activation, observed in cultured RAF1-deficient cells, in HCC xenografts, and in autochthonous liver tumours. Thus RAF1, although essential for the development of skin and lung tumours, is a negative regulator of hepatocarcinogenesis. This unexpected finding highlights the contribution of the cellular/tissue environment in determining the function of a protein, and underscores the importance of understanding the molecular context of a disease to inform therapy design.
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Jeric
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Maurer
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Anna Lina
authors.initials: AL
authors.lastname: Cavallo
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Josipa
authors.initials: J
authors.lastname: Raguz
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Enrico
authors.initials: E
authors.lastname: Desideri
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Tarkowski
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Parrini
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Fischer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz A-8036, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.affiliation: Department of Microbiology, Immune biology, and Genetics, Center for Molecular Biology, University of Vienna-Max F. Perutz Laboratories, Doktor-Bohr-Gasse 9, Vienna 1030, Austria.
authors.forename: Manuela
authors.identifier: 0000-0002-3033-391X
authors.initials: M
authors.lastname: Baccarini
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004052:Diethylnitrosamine; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D025521:Tumor Suppressor Proteins; D004052:Diethylnitrosamine; D019908:Proto-Oncogene Proteins c-raf; C000627598:Raf1 protein, human