A cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis

被引：29

作者：

Jeric, Ines ^{[1
]}

Maurer, Gabriele ^{[1
]}

Cavallo, Anna Lina ^{[1
,4
]}

Raguz, Josipa ^{[1
]}

Desideri, Enrico ^{[1
]}

Tarkowski, Bartosz ^{[1
,5
]}

Parrini, Matthias ^{[1
,3
]}

Fischer, Irmgard ^{[1
]}

Zatloukal, Kurt ^{[2
]}

Baccarini, Manuela ^{[1
]}

机构：

[1] Univ Vienna, Ctr Mol Biol, Dept Microbiol Immune Biol & Genet, Max F Perutz Labs, Doktor Bohr Gasse 9, A-1030 Vienna, Austria

[2] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[3] Univ Vet Med, Inst Anim Breeding & Genet, A-1210 Vienna, Austria

[4] AstraZeneca R&D Discovery Sci RAD, SE-43183 Molndal, Sweden

[5] Int Inst Mol & Cell Biol, Lab Mol & Cell Neurobiol, PL-02109 Warsaw, Poland

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

奥地利科学基金会;

关键词：

HEPATOCELLULAR-CARCINOMA; KAPPA-B; C-RAF; STAT3; INFLAMMATION; PROGRESSION; CANCER; YAP; TRANSCRIPTION; RESISTANCE;

D O I：

10.1038/ncomms13781

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

共 56 条

[1] YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response [J].