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.

RAF1 expression is correlated with HAF, a parameter of liver computed tomographic perfusion, and may predict the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients

“…However, there exists only one striking study which unexpectedly discovered a RAF1 expression reduction in human HCC samples. In this study, RAF1 downregulation increased the proliferation of HCC in xenografts and in culture [21]. Our conclusion seems to point that highly expressed RAF1 is associated with sorafenib resistance.…”

Analysis of miRNA expression profiles in the liver ofClockΔ19mutant mice

“…Our results showed that miR-340-3p, miR-669d, miR-374 and miR-338-5p could directly target circadian genes (miR-340-3p targeting Clock , Per1 , Cry2 ; miR-669d targeting Per2 ; miR-374 targeting Per3 ; miR-338-5p targeting Nr1d1 ), further supporting this idea. The other main pathway was pathway in cancer, and the genes in this pathway can impact tumor cell proliferation (PPARG, RAF1), regulate hepatic glucose and lipid metabolism (FOXO1), and decrease the viability and invasiveness of HCC cells (RALA) (Ezzeldin et al, 2014; O-Sullivan et al, 2015; Jeric et al, 2016; Li et al, 2017; Savic et al, 2016). This suggests that at the molecular level, CLOCK-regulated miRNAs may be involved in cancer initiation or progression by directly controlling cell proliferation, cell invasion, or metabolism-related genes in the mouse liver.…”

BRAF, A gatekeeper controlling endothelial permeability

“…while ECs together with keratinocytes, mouse embryonic fibroblasts or macrophages were unaffected by deletion of RAF1 [15]. Whether BRAF ablation in hepatocellular carcinoma has similar effects is currently unknown and warrants further investigation.…”

“…observed in lung ECs. Further evidence of tissue specificity for RAF1 comes from the liver, where RAF1 ablation in hepatocellular carcinoma promoted proliferation and carcinogenesis, while ECs together with keratinocytes, mouse embryonic fibroblasts or macrophages were unaffected by deletion of RAF1 . Whether BRAF ablation in hepatocellular carcinoma has similar effects is currently unknown and warrants further investigation.…”