title: New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals.
abstract: We have previously identified a 115-gene signature that characterises the metastatic potential of human primary colon cancers. The signature included the canonical Wnt target gene BAMBI, which promoted experimental metastasis in mice. Here, we identified three new direct Wnt target genes from the signature, and studied their functions in epithelial-mesenchymal transition (EMT), cell migration and experimental metastasis.
  
  
  
  We examined experimental liver metastases following injection of selected tumour cells into spleens of NOD/SCID mice. Molecular and cellular techniques were used to identify direct transcription target genes of Wnt/β-catenin signals. Microarray analyses and experiments that interfered with cell migration through inhibitors were performed to characterise downstream signalling systems.
  
  
  
  Three new genes from the colorectal cancer (CRC) metastasis signature, BOP1, CKS2 and NFIL3, were identified as direct transcription targets of β-catenin/TCF4. Overexpression and knocking down of these genes in CRC cells promoted and inhibited, respectively, experimental metastasis in mice, EMT and cell motility in culture. Cell migration was repressed by interfering with distinct signalling systems through inhibitors of PI3K, JNK, p38 mitogen-activated protein kinase and/or mTOR. Gene expression profiling identified a series of migration-promoting genes, which were induced by BOP1, CKS2 and NFIL3, and could be repressed by inhibitors that are specific to these pathways.
  
  
  
  We identified new direct Wnt/β-catenin target genes, BOP1, CKS2 and NFIL3, which induced EMT, cell migration and experimental metastasis of CRC cells. These genes crosstalk with different downstream signalling systems, and activate migration-promoting genes. These pathways and downstream genes may serve as therapeutic targets in the treatment of CRC metastasis.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Qi
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Akilli Öztürk
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Jane D
authors.initials: JD
authors.lastname: Holland
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Besser
authors.affiliation: Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Carl Gustav Carus an der TU Dresden, Dresden, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Fritzmann
authors.affiliation: Experimental Pharmacology & Oncology (EPO), Berlin, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wulf-Goldenberg
authors.affiliation: Experimental Pharmacology & Oncology (EPO), Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Eckert
authors.affiliation: Experimental Pharmacology & Oncology (EPO), Berlin, Germany.
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D042846:CDC2-CDC28 Kinases; D017489:CDC28 Protein Kinase, S cerevisiae / Q000235:genetics*; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008114:Liver Neoplasms, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C488958:Bop1 protein, mouse; D018797:Cell Cycle Proteins; C497441:Nfil3 protein, mouse; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D042846:CDC2-CDC28 Kinases; D017489:CDC28 Protein Kinase, S cerevisiae; C474109:Cks2 protein, mouse
keywords: CELL BIOLOGY; CELL MIGRATION; CELL SIGNALLING; COLORECTAL CANCER; COLORECTAL METASTASES