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.
Highlights
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, but its molecular heterogeneity hampers the design of targeted therapies
Patient data show reduced RAF1 expression in human HCCs; based on this, we have investigated the role of RAF1 in HCC using two different mouse models: (1) HCC xenografts and (2) hepatocarcinogenesis induced by the alkylating agent diethylnitrosamine (DEN) and promoted by Phenobarbital (Pb), which mimics human disease in terms of gene expression profiles and critically depends on inflammation[11,12,13,14]
A tremendous increase in tumour mass was observed in HCC xenografts in nude mice when RAF1 was knocked down in vivo by adding doxycycline to the drinking water (Fig. 1c)
Summary
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, but its molecular heterogeneity hampers the design of targeted therapies. Raf[1] ablation causes liver apoptosis[9,10], suggesting an essential function in this organ and a potential role in liver cancer development Contrary to this expectation, patient data show reduced RAF1 expression in human HCCs; based on this, we have investigated the role of RAF1 in HCC using two different mouse models: (1) HCC xenografts and (2) hepatocarcinogenesis induced by the alkylating agent diethylnitrosamine (DEN) and promoted by Phenobarbital (Pb), which mimics human disease in terms of gene expression profiles and critically depends on inflammation[11,12,13,14]. Both models have revealed a tumour suppressor function of RAF1 in HCC, consistent with the reduced RAF1 expression in HCC patients
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