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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.
AuthorsBeny Shapiro, Piera Tocci, Gal Haase, Nancy Gavert, Avri Ben-Ze'ev
JournalOncotarget (Oncotarget) Vol. 6 Issue 33 Pg. 34389-401 (Oct 27 2015) ISSN: 1949-2553 [Electronic] United States
PMID26399194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CLU protein, human
  • Clusterin
  • Neural Cell Adhesion Molecule L1
Topics
  • Animals
  • Chromatin Immunoprecipitation
  • Clusterin (genetics)
  • Colonic Neoplasms (pathology)
  • Fluorescent Antibody Technique
  • HCT116 Cells
  • Heterografts
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neural Cell Adhesion Molecule L1 (metabolism)
  • Real-Time Polymerase Chain Reaction
  • Stem Cells (metabolism)
  • Transcriptome

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