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GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling

Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclea...

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Autores principales: Wang, Liang, Wang, Jiayi, Yin, Xiaolin, Guan, Xin, Li, Ying, Xin, Chenqi, Liu, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054671/
https://www.ncbi.nlm.nih.gov/pubmed/35347223
http://dx.doi.org/10.1038/s41388-022-02255-4
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author Wang, Liang
Wang, Jiayi
Yin, Xiaolin
Guan, Xin
Li, Ying
Xin, Chenqi
Liu, Jing
author_facet Wang, Liang
Wang, Jiayi
Yin, Xiaolin
Guan, Xin
Li, Ying
Xin, Chenqi
Liu, Jing
author_sort Wang, Liang
collection PubMed
description Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-β-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa.
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spelling pubmed-90546712022-05-01 GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling Wang, Liang Wang, Jiayi Yin, Xiaolin Guan, Xin Li, Ying Xin, Chenqi Liu, Jing Oncogene Article Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-β-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa. Nature Publishing Group UK 2022-03-28 2022 /pmc/articles/PMC9054671/ /pubmed/35347223 http://dx.doi.org/10.1038/s41388-022-02255-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Liang
Wang, Jiayi
Yin, Xiaolin
Guan, Xin
Li, Ying
Xin, Chenqi
Liu, Jing
GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling
title GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling
title_full GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling
title_fullStr GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling
title_full_unstemmed GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling
title_short GIPC2 interacts with Fzd7 to promote prostate cancer metastasis by activating WNT signaling
title_sort gipc2 interacts with fzd7 to promote prostate cancer metastasis by activating wnt signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054671/
https://www.ncbi.nlm.nih.gov/pubmed/35347223
http://dx.doi.org/10.1038/s41388-022-02255-4
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