title: Clusterin, a gene enriched in intestinal stem cells, is required for L1-mediated colon cancer metastasis.
abstract: Hyperactive Wnt signaling is a common feature in human colorectal cancer (CRC) cells. A central question is the identification and role of Wnt/β-catenin target genes in CRC and their relationship to genes enriched in colonic stem cells, since Lgr5+ intestinal stem cells were suggested to be the cell of CRC origin. Previously, we identified the neural immunoglobulin-like adhesion receptor L1 as a Wnt/β-catenin target gene localized in cells at the invasive front of CRC tissue and showed that L1 expression in CRC cells confers enhanced motility and liver metastasis. Here, we identified the clusterin (CLU) gene that is also enriched in Lgr5+ intestinal stem cells, as a gene induced during L1-mediated CRC metastasis. The increase in CLU levels by L1 in CRC cells resulted from transactivation of CLU by STAT-1. CLU overexpression in CRC cells enhanced their motility and the reduction in CLU levels in L1 overexpressing cells suppressed the ability of L1 to confer increased tumorigenesis and liver metastasis. Genes induced during L1-mediated CRC cell metastasis and enriched in intestinal stem cells might be important for both CRC progression and colonic epithelium homeostasis.
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Beny
authors.initials: B
authors.lastname: Shapiro
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Piera
authors.initials: P
authors.lastname: Tocci
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Haase
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Nancy
authors.initials: N
authors.lastname: Gavert
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Avri
authors.initials: A
authors.lastname: Ben-Ze'ev
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D051152:Clusterin / Q000235:genetics*; D003110:Colonic Neoplasms / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D045325:HCT116 Cells; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism*; D059467:Transcriptome
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D039842:Neural Cell Adhesion Molecule L1
keywords: L1; clusterin; colon cancer; metastasis