A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

Ines Jeric, Gabriele Maurer, Anna Lina Cavallo,w, Josipa Raguz, Enrico Desideri, Bartosz Tarkowski, Matthias Parrini, Irmgard Fischer.

NATURE COMMUNICATIONS Published 21 Dec 2016

Speaker: Yi-Zhen Wu (吳宜臻)                                    Time: 13:00~14:00, Feb, 22 2016

Commentator: Dr. Chia-Jui Yen (顏家瑞醫師)            Place: Room 601

Abstract:

        Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women worldwide. HCC is the second among the top ten leading causes of death in cancer. To treat HCC, Sorafenib, an inhibitor whose targets include RAF1 is the only standard clinical drug against advanced HCC. However, in the mouse, RAF1 deletion causes liver apoptosis, which indicating that RAF1 may promote liver cancer development. In addition to this deservation, patient data also show reduced RAF1 expression in human HCC. According to these previous findings, here authors investigated the role of RAF1 in HCC by two different mouse models, one is HCC xenografts and the other is hepatocarcinogenesis induced by the diethylnitrosamine (DEN) and promoted by Phenobarbital (Pb), which mimics human disease. Authors found that RAF1 deletion promotes chemical hepatocarcinogenesis and the proliferation of cultured premalignant mouse hepatocytes. In previous studies showed that the Hippo pathway and its target YAP1 are key regulators of hepatocyte differentiation in hepatocarcinogenesis. Lack of RAF1 resulted in the increased expression of YAP1 and GP130 and in STAT3 phosphorylation/activation in all tested models. Both models have revealed a tumour suppressor function of RAF1 in HCC, which is consistent with the reduced RAF1 expression in HCC patients. The finding was entirely unexpected as the existing literature unanimously points to pro-tumourigenic functions of RAF1.

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