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CTLA-4 is a direct target of Wnt/beta-catenin signaling and is expressed in human melanoma tumors.

ABSTRACT: Our goal was to identify genes regulated by Wnt/beta-catenin signaling in melanoma cells, as this pathway has been implicated in melanocyte development and in melanoma biology. We therefore undertook transcriptional profiling of UACC 1273 human melanoma cells following treatment with recombinant Wnt-3a and found that cytotoxic T-lymphocyte antigen-4 (CTLA-4) was the most highly induced gene. We observed CTLA-4 expression in human epidermal melanocytes and in patient-derived primary melanoma tumors and found that Wnt/beta-catenin signaling elevates CTLA-4 expression in two cultured melanoma cell lines. CTLA-4 is likely a direct target of Wnt/beta-catenin signaling, as the beta-catenin responsiveness of a 1.7 kb region of the CTLA-4 promoter requires a T-cell factor-1/lymphoid enhancing factor-1 consensus site present at -114 to -119 bp from the transcriptional start site. These findings are the initial demonstration that CTLA-4 is a direct target of Wnt/beta-catenin signaling and the first report of its expression in primary melanoma tumors and melanocytes. Given the described role of CTLA-4 in inhibiting the immune response, these findings may shed light on the role of Wnt/beta catenin signaling in melanoma and on the mechanism of action of human anti-CTLA-4 antibody, currently in phase III clinical trials for the treatment of melanoma.

SUBMITTER: Shah KV

PROVIDER: S-EPMC3135173 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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CTLA-4 is a direct target of Wnt/beta-catenin signaling and is expressed in human melanoma tumors.

Shah Kavita V KV Chien Andy J AJ Yee Cassian C Moon Randall T RT

The Journal of investigative dermatology 20080619 12

Our goal was to identify genes regulated by Wnt/beta-catenin signaling in melanoma cells, as this pathway has been implicated in melanocyte development and in melanoma biology. We therefore undertook transcriptional profiling of UACC 1273 human melanoma cells following treatment with recombinant Wnt-3a and found that cytotoxic T-lymphocyte antigen-4 (CTLA-4) was the most highly induced gene. We observed CTLA-4 expression in human epidermal melanocytes and in patient-derived primary melanoma tumo ...[more]

PMID: 18563180

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Project description:Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of putative stem cell origin that predominantly occurs in children and young adults. Although most patients with localized ES can be cured with intensive therapy, the clinical course is variable and up to one third of patients relapse following initial remission. Unfortunately, little is yet known about the biologic features that distinguish low-risk from high-risk disease or the mechanisms of ES disease progression. Recent reports have suggested that putative cancer stem cells exist in ES and may contribute to an aggressive phenotype. The cell surface receptor leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a somatic stem cell marker that functions as an oncogene in several human cancers, most notably colorectal carcinoma. LGR5 is a receptor for the R-spondin (RSPO) family of ligands and RSPO-mediated activation of LGR5 potentiates Wnt/β-catenin signaling, contributing to stem cell proliferation and self-renewal. Given its presumed stem cell origin, we investigated whether LGR5 contributes to ES pathogenesis. We found that LGR5 is expressed by ES and that its expression is relatively increased in cells and tumors that display a more aggressive phenotype. In particular, LGR5 expression was increased in putative cancer stem cells. We also found that neural crest-derived stem cells express LGR5, raising the possibility that expression of LGR5 may be a feature of ES cells of origin. LGR5-high ES cells showed nuclear localization of β-catenin and robust activation of TCF reporter activity when exposed to Wnt ligand and this was potentiated by RSPO. However, modulation of LGR5 or exposure to RSPO had no impact on proliferation confirming that Wnt/β-catenin signaling in ES cells does not recapitulate signaling in epithelial cells. Together these studies show that the RSPO-LGR5-Wnt-β-catenin axis is present and active in ES and may contribute to tumor pathogenesis.

Project description:BackgroundDeregulation of Wnt/β-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein β-catenin. β-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop-helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by β-catenin in colorectal cancer cell lines, we analyzed β-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to β-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database.ResultsTreatment of DLD1 and SW480 cells with β-catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published β-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed β-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway - the steroid biosynthesis pathway - was regulated in all three cell lines.ConclusionsBased on the large number of potential β-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed β-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/β-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential β-catenin target genes are useful starting points for further studies.

Dataset Information

CTLA-4 is a direct target of Wnt/beta-catenin signaling and is expressed in human melanoma tumors.

Publications

CTLA-4 is a direct target of Wnt/beta-catenin signaling and is expressed in human melanoma tumors.

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