title: Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607, United States.
authors.forename: Dragana
authors.initials: D
authors.lastname: Kopanja
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607, United States.
authors.forename: Akshay
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Kiefer
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607, United States.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607, United States.
authors.forename: Neha
authors.initials: N
authors.lastname: Chandan
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607, United States; Department of Medicine, University of California, San Francisco, CA, United States.
authors.forename: Janai R
authors.initials: JR
authors.lastname: Carr
authors.affiliation: Transgenic Production Facility, University of Illinois, College of Medicine, 909 S. Wolcott Ave, Chicago, IL 60612, United States.
authors.forename: Roberta
authors.initials: R
authors.lastname: Franks
authors.affiliation: Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Republic of Korea.
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.affiliation: Department of Pathology, University of Illinois, College of Medicine, 840 S. Wood St, Chicago, IL 60612, United States.
authors.forename: Grace
authors.initials: G
authors.lastname: Guzman
authors.affiliation: Department of Medicine, University of Illinois, College of Medicine, 909 S. Wolcott Ave, Chicago, IL 60612, United States.
authors.forename: Ajay
authors.initials: A
authors.lastname: Maker
authors.affiliation: Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607, United States; Jesse Brown VA Medical Center, 820 S. Damen Ave., Chicago, IL 60612, United States. Electronic address: pradip@uic.edu.
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011379:Prognosis; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018631:ras Proteins
keywords: FoxM1; Liver cancer cells with stem cell features; Ras-driven liver cancer
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