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.
Highlights
Aberrant activation of the canonical Wnt signaling cascade plays a key role both during early and later phases of human colorectal cancer (CRC) development [1, 2]
To identify genes induced by L1 during colon cancer progression whose expression is elevated in intestinal stem cells, we compared patterns of upregulated gene expression that we obtained from L1-overexpressing Ls174T human CRC cells [10] to those obtained from Lgr5+-mouse intestinal stem cells [15]
Such comparisons revealed a list of common genes that are induced by L1 in human CRC cells that are expressed at increased levels in mouse intestinal stem cells (Table 1)
Summary
Aberrant activation of the canonical Wnt signaling cascade plays a key role both during early and later phases of human colorectal cancer (CRC) development [1, 2]. Wnt activation drives tumor progression by supporting the nuclear translocation of β-catenin where it forms a complex with DNA-binding proteins of the T-cell factor/ lymphoid enhancer factor (TCF/LEF) family and initiates transcription of multiple target genes [3]. L1 was found in populations of cells that reside at the invasive front of human CRC tissues that co-display strong nuclear β-catenin localization, indicative of Wnt pathway activation [8, 9]. Complementing these findings, the expression of L1 in human CRC cells that do not express L1 in vitro confers enhanced invasive activity and metastatic potential to the liver in vivo [10]. Our analyses of the signaling pathways that are involved in L1-mediated
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