Highlights
- •Downregulation of the FBXW7 tumor suppressor gene was identified as a universal feature of human intrahepatic cholangiocarcinoma (iCCA).
- •Hydrodynamic transfection of inactivated Fbxw7 synergized with an activated form of AKT to induce rapid iCCA in mice.
- •Cholangiocarcinogenesis was prevented by c-Myc suppression, while being delayed by either Yap or Notch 2 depletion in these mice.
- •Inhibition of c-MYC might represent an innovative therapeutic strategy for the treatment of human iCCA with low FBXW7.
Background & Aims
The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized
as a tumor suppressor in many cancer types due to its ability to promote the degradation
of numerous oncogenic target proteins. Herein, we aimed to elucidate its role in intrahepatic
cholangiocarcinoma (iCCA).
Methods
Herein, we first confirmed that FBXW7 gene expression was reduced in human iCCA specimens. To identify the molecular mechanisms
by which FBXW7 dysfunction promotes cholangiocarcinogenesis, we generated a mouse
model by hydrodynamic tail vein injection of Fbxw7ΔF, a dominant negative form of Fbxw7, either alone or in association with an activated/myristylated
form of AKT (myr-AKT). We then confirmed the role of c-MYC in human iCCA cell lines and its relationship
to FBXW7 expression in human iCCA specimens.
Results
FBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. While
forced overexpression of Fbxw7ΔF alone did not induce any appreciable abnormality in the mouse liver, co-expression
with AKT triggered cholangiocarcinogenesis and mice had to be euthanized by 15 weeks
post-injection. At the molecular level, a strong induction of Fbxw7 canonical targets,
including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-MYC was
consistently confirmed as a FBXW7 target in human CCA cell lines. Most importantly,
selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 only delayed tumorigenesis in the
same model. In human iCCA specimens, an inverse correlation between the expression
levels of FBXW7 and c-MYC transcriptional activity was observed.
Conclusions
Downregulation of FBXW7 is ubiquitous in human iCCA and cooperates with AKT to induce
cholangiocarcinogenesis in mice via c-Myc-dependent mechanisms. Targeting c-MYC might
represent an innovative therapy against iCCA exhibiting low FBXW7 expression.
Lay summary
There is mounting evidence that FBXW7 functions as a tumor suppressor in many cancer
types, including intrahepatic cholangiocarcinoma, through its ability to promote the
degradation of numerous oncoproteins. Herein, we have shown that the low expression
of FBXW7 is ubiquitous in human cholangiocarcinoma specimens. This low expression
is correlated with increased c-MYC activity, leading to tumorigenesis. Our findings
suggest that targeting c-MYC might be an effective treatment for intrahepatic cholangiocarcinoma.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 10, 2019
Accepted:
May 31,
2019
Received in revised form:
May 8,
2019
Received:
December 28,
2018
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
