RT Journal Article
SR Electronic
T1 New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1690
OP 1701
DO 10.1136/gutjnl-2014-307900
VO 65
IS 10
A1 Jingjing Qi
A1 Yong Yu
A1 Özlem Akilli Öztürk
A1 Jane D Holland
A1 Daniel Besser
A1 Johannes Fritzmann
A1 Annika Wulf-Goldenberg
A1 Klaus Eckert
A1 Iduna Fichtner
A1 Walter Birchmeier
YR 2016
UL http://gut.bmj.com/content/65/10/1690.abstract
AB 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.