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The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression

Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been dem...

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Autores principales: Choi, Jang-Hyun, Jang, Tae-Young, Jeon, So-El, Kim, Jee-Heun, Lee, Choong-Jae, Yun, Hyeon-Ji, Jung, Ji-Youn, Park, So-Yeon, Nam, Jeong-Seok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704261/
https://www.ncbi.nlm.nih.gov/pubmed/34948208
http://dx.doi.org/10.3390/ijms222413413
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author Choi, Jang-Hyun
Jang, Tae-Young
Jeon, So-El
Kim, Jee-Heun
Lee, Choong-Jae
Yun, Hyeon-Ji
Jung, Ji-Youn
Park, So-Yeon
Nam, Jeong-Seok
author_facet Choi, Jang-Hyun
Jang, Tae-Young
Jeon, So-El
Kim, Jee-Heun
Lee, Choong-Jae
Yun, Hyeon-Ji
Jung, Ji-Youn
Park, So-Yeon
Nam, Jeong-Seok
author_sort Choi, Jang-Hyun
collection PubMed
description Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis.
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spelling pubmed-87042612021-12-25 The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression Choi, Jang-Hyun Jang, Tae-Young Jeon, So-El Kim, Jee-Heun Lee, Choong-Jae Yun, Hyeon-Ji Jung, Ji-Youn Park, So-Yeon Nam, Jeong-Seok Int J Mol Sci Article Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis. MDPI 2021-12-14 /pmc/articles/PMC8704261/ /pubmed/34948208 http://dx.doi.org/10.3390/ijms222413413 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Choi, Jang-Hyun
Jang, Tae-Young
Jeon, So-El
Kim, Jee-Heun
Lee, Choong-Jae
Yun, Hyeon-Ji
Jung, Ji-Youn
Park, So-Yeon
Nam, Jeong-Seok
The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression
title The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression
title_full The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression
title_fullStr The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression
title_full_unstemmed The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression
title_short The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression
title_sort small-molecule wnt inhibitor icg-001 efficiently inhibits colorectal cancer stemness and metastasis by suppressing meis1 expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704261/
https://www.ncbi.nlm.nih.gov/pubmed/34948208
http://dx.doi.org/10.3390/ijms222413413
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