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Original article
New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals
  1. Jingjing Qi1,
  2. Yong Yu1,
  3. Özlem Akilli Öztürk1,
  4. Jane D Holland1,
  5. Daniel Besser1,
  6. Johannes Fritzmann2,
  7. Annika Wulf-Goldenberg3,
  8. Klaus Eckert3,
  9. Iduna Fichtner3,
  10. Walter Birchmeier1
  1. 1Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany
  2. 2Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Carl Gustav Carus an der TU Dresden, Dresden, Germany
  3. 3Experimental Pharmacology & Oncology (EPO), Berlin, Germany
  1. Correspondence to Professor Walter Birchmeier, Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany; wbirch{at}mdc-berlin.de

Abstract

Objectives 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.

Design 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.

Results 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.

Conclusions 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.

  • COLORECTAL METASTASES
  • CELL BIOLOGY
  • CELL MIGRATION
  • CELL SIGNALLING
  • COLORECTAL CANCER

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