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New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals

Item Type:Article
Title:New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals
Creators Name:Qi, J. and Yu, Y. and Akilli Öztürk, Ö. and Holland, J.D. and Besser, D. and Fritzmann, J. and Wulf-Goldenberg, A. and Eckert, K. and Fichtner, I. and Birchmeier, W.
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/beta-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 beta-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/beta-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.
Keywords:Animal Disease Models, Basic-Leucine Zipper Transcription Factors, Cell Movement, Colorectal Neoplasms, Cultured Tumor Cells, Epithelial-Mesenchymal Transition, Experimental Liver Neoplasms, Liver Neoplasms, Neoplasm Metastasis, Nuclear Proteins, S cerevisiae CDC28 Protein Kinase, Wnt Signaling Pathway, Animals, Mice
Publisher:BMJ Publishing Group
Page Range:1690-1701
Date:October 2016
Official Publication:https://doi.org/10.1136/gutjnl-2014-307900
PubMed:View item in PubMed

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