title: Deregulation of FoxM1b leads to tumour metastasis.
abstract: The forkhead box M1b (FoxM1b) transcription factor is over-expressed in human cancers, and its expression often correlates with poor prognosis. Previously, using conditional knockout strains, we showed that FoxM1b is essential for hepatocellular carcinoma (HCC) development. However, over-expression of FoxM1b had only marginal effects on HCC progression. Here we investigated the effect of FoxM1b expression in the absence of its inhibitor Arf. We show that transgenic expression of FoxM1b in an Arf-null background drives hepatic fibrosis and metastasis of HCC. We identify novel mechanisms of FoxM1b that are involved in epithelial-mesenchymal transition, cell motility, invasion and a pre-metastatic niche formation. FoxM1b activates the Akt-Snail1 pathway and stimulates expression of Stathmin, lysyl oxidase, lysyl oxidase like-2 and several other genes involved in metastasis. Furthermore, we show that an Arf-derived peptide, which inhibits FoxM1b, impedes metastasis of the FoxM1b-expressing HCC cells. The observations indicate that FoxM1b is a potent activator of tumour metastasis and that the Arf-mediated inhibition of FoxM1b is a critical mechanism for suppression of tumour metastasis.
authors.affiliation: Department of Biochemistry and Molecular Genetics, UIC-Cancer Center, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Galina
authors.initials: G
authors.lastname: Gusarova
authors.forename: Zebin
authors.initials: Z
authors.lastname: Wang
authors.forename: Janai R
authors.initials: JR
authors.lastname: Carr
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Ki-Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.forename: Yoon-Dong
authors.initials: YD
authors.lastname: Park
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Angela L
authors.initials: AL
authors.lastname: Tyner
authors.forename: Lester F
authors.initials: LF
authors.lastname: Lau
authors.forename: Robert H
authors.initials: RH
authors.lastname: Costa
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D058750:Epithelial-Mesenchymal Transition; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D050777:Stathmin / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D050777:Stathmin; D014157:Transcription Factors; D008249:Protein-Lysine 6-Oxidase; D051057:Proto-Oncogene Proteins c-akt; D020727:ADP-Ribosylation Factors