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  • A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis.

A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis.

Nature communications (2016-12-22)
Ines Jeric, Gabriele Maurer, Anna Lina Cavallo, Josipa Raguz, Enrico Desideri, Bartosz Tarkowski, Matthias Parrini, Irmgard Fischer, Kurt Zatloukal, Manuela Baccarini
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-ROKα/ROCK-II Antibody, clone A9W4, rabbit monoclonal, culture supernatant, clone A9W4, from rabbit
Sigma-Aldrich
1,3-Diiodo-5,5-dimethylhydantoin, ≥96%
Sigma-Aldrich
PP2, ≥98% (HPLC)
Sigma-Aldrich
MISSION® esiRNA, targeting human RAF1