Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features

Dragana Kopanja, Akshay Pandey, Megan Kiefer, Zebin Wang, Neha Chandan, Janai R. Carr, Roberta Franks, Dae Yeul Yu, Grace Guzman, Ajay Maker, Pradip Raychaudhuri

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)429-436
Number of pages8
JournalJournal of Hepatology
Volume63
Issue number2
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • FoxM1
  • Liver cancer cells with stem cell features
  • Ras-driven liver cancer

ASJC Scopus subject areas

  • Hepatology

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    Kopanja, D., Pandey, A., Kiefer, M., Wang, Z., Chandan, N., Carr, J. R., Franks, R., Yu, D. Y., Guzman, G., Maker, A., & Raychaudhuri, P. (2015). Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. Journal of Hepatology, 63(2), 429-436. https://doi.org/10.1016/j.jhep.2015.03.023