Background & Aims
Overexpression of FoxM1 correlates with poor prognosis in hepatocellular carcinoma
(HCC). Moreover, the Ras-signaling pathway is found to be ubiquitously activated in
HCC through epigenetic silencing of the Ras-regulators. We investigated the roles
of FoxM1 in Ras-driven HCC, and on HCC cells with stem-like features.
Methods
We employed a transgenic mouse model that expresses the oncogenic Ras in the liver.
That strain was crossed with a strain that harbor floxed alleles of FoxM1 and the MxCre gene that allows conditional deletion of FoxM1. FoxM1 alleles were deleted after development of HCC, and the effects on the tumors were
analyzed. Also, FoxM1 siRNA was used in human HCC cell lines to determine its role
in the survival of the HCC cells with stem cell features.
Results
Ras-driven tumors overexpress FoxM1. Deletion of FoxM1 inhibits HCC progression. There
was increased accumulation of reactive oxygen species (ROS) in the FoxM1 deleted HCC
cells. Moreover, FoxM1 deletion caused a disproportionate loss of the CD44+ and EpCAM+
HCC cells in the tumors. We show that FoxM1 directly activates expression of CD44
in human HCC cells. Moreover, the human HCC cells with stem cell features are addicted
to FoxM1 for ROS-regulation and survival.
Conclusion
Our results provide genetic evidence for an essential role of FoxM1 in the progression
of Ras-driven HCC. In addition, FoxM1 is required for the expression of CD44 in HCC
cells. Moreover, FoxM1 plays a critical role in the survival of the HCC cells with
stem cell features by regulating ROS.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: March 27, 2015
Accepted:
March 19,
2015
Received in revised form:
March 13,
2015
Received:
October 20,
2014
Identification
Copyright
Published by Elsevier Inc.
