Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased β-catenin-mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes Axin2 and CCND1 In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/β-catenin signaling. In addition, we showed that nuclear β-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/β-catenin pathway demonstrated antitumor efficacy in various GIST models, both in vitro and in vivo Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered KitV558Δ/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/β-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. Mol Cancer Ther; 16(9); 1954-66. ©2017 AACR.
Details
Original language | English |
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Pages (from-to) | 1954-1966 |
Number of pages | 13 |
Journal | Molecular cancer therapeutics |
Volume | 16 |
Issue number | 9 |
Publication status | Published - Sept 2017 |
Peer-reviewed | Yes |
External IDs
PubMedCentral | PMC5587376 |
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Scopus | 85029208898 |
ORCID | /0000-0002-5329-3164/work/147141103 |
Keywords
Sustainable Development Goals
Keywords
- Animals, Antineoplastic Agents/pharmacology, Cell Line, Tumor, Disease Models, Animal, Gastrointestinal Stromal Tumors/drug therapy, Humans, Imatinib Mesylate/pharmacology, Intercellular Signaling Peptides and Proteins/metabolism, Mice, Mice, Transgenic, Molecular Targeted Therapy, Neoplasm Grading, Neoplasm Staging, Ubiquitin-Protein Ligases/metabolism, Wnt Signaling Pathway/drug effects, Wnt3A Protein/metabolism, Xenograft Model Antitumor Assays, beta Catenin/metabolism