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SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness

SIMPLE SUMMARY: The Wnt-β-catenin signaling regulates liver homeostasis and repair in adulthood, while its abnormal regulation is involved in the development of several chronic diseases and tumors. SerpinB3 has been shown to induce β-catenin, and both molecules are overexpressed in tumors, particula...

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Autores principales: Quarta, Santina, Cappon, Andrea, Turato, Cristian, Ruvoletto, Mariagrazia, Cannito, Stefania, Villano, Gianmarco, Biasiolo, Alessandra, Maggi, Maristella, Protopapa, Francesca, Bertazza, Loris, Fasolato, Silvano, Parola, Maurizio, Pontisso, Patrizia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295789/
https://www.ncbi.nlm.nih.gov/pubmed/37372056
http://dx.doi.org/10.3390/biology12060771
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author Quarta, Santina
Cappon, Andrea
Turato, Cristian
Ruvoletto, Mariagrazia
Cannito, Stefania
Villano, Gianmarco
Biasiolo, Alessandra
Maggi, Maristella
Protopapa, Francesca
Bertazza, Loris
Fasolato, Silvano
Parola, Maurizio
Pontisso, Patrizia
author_facet Quarta, Santina
Cappon, Andrea
Turato, Cristian
Ruvoletto, Mariagrazia
Cannito, Stefania
Villano, Gianmarco
Biasiolo, Alessandra
Maggi, Maristella
Protopapa, Francesca
Bertazza, Loris
Fasolato, Silvano
Parola, Maurizio
Pontisso, Patrizia
author_sort Quarta, Santina
collection PubMed
description SIMPLE SUMMARY: The Wnt-β-catenin signaling regulates liver homeostasis and repair in adulthood, while its abnormal regulation is involved in the development of several chronic diseases and tumors. SerpinB3 has been shown to induce β-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of our study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and monocytic cells, the main type of inflammatory cells in the tumor microenvironment. We have demonstrated that SerpinB3 modulates the Wnt cascade upregulating the Wnt co-receptors, low-density lipoprotein receptor-related protein 5 (LRP-5) and LRP-6, as well as LRP-1, implicated in cell survival and invasiveness. These data were confirmed in experimental carcinogenesis. In conclusion, the upregulation of LRP family members by SerpinB3 determines Wnt signaling activation and increased cell survival and invasiveness. ABSTRACT: Abnormal activation of the Wnt-β-catenin signaling cascade is involved in tumor growth and dissemination. SerpinB3 has been shown to induce β-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of this study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and in monocytic cells, the main type of inflammatory cells in the tumor microenvironment. The Wnt cascade, Wnt co-receptors, and low-density lipoprotein receptor-related protein (LRP) members were analyzed in different cell lines and human monocytes in the presence or absence of SerpinB3. The Wnt-β-catenin axis was also evaluated in liver tumors induced in mice with different extents of SeprinB3 expression. In monocytic cells, SerpinB3 induced a significant upregulation of Wnt-1/7, nuclear β-catenin, and c-Myc, which are associated with increased cell lifespan and proliferation. In liver tumors in mice, the expression of β-catenin was significantly correlated with the presence of SerpinB3. In hepatoma cells, Wnt co-receptors LRP-5/6 and LRP-1, implicated in cell survival and invasiveness, were upregulated by SerpinB3. The LRP pan-inhibitor RAP not only induced a decrease in LRP expression, but also a dose–dependent reduction in SerpinB3-induced invasiveness. In conclusion, SerpinB3 determines the activation of the Wnt canonical pathway and cell invasiveness through the upregulation of LRP family members.
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spelling pubmed-102957892023-06-28 SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness Quarta, Santina Cappon, Andrea Turato, Cristian Ruvoletto, Mariagrazia Cannito, Stefania Villano, Gianmarco Biasiolo, Alessandra Maggi, Maristella Protopapa, Francesca Bertazza, Loris Fasolato, Silvano Parola, Maurizio Pontisso, Patrizia Biology (Basel) Article SIMPLE SUMMARY: The Wnt-β-catenin signaling regulates liver homeostasis and repair in adulthood, while its abnormal regulation is involved in the development of several chronic diseases and tumors. SerpinB3 has been shown to induce β-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of our study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and monocytic cells, the main type of inflammatory cells in the tumor microenvironment. We have demonstrated that SerpinB3 modulates the Wnt cascade upregulating the Wnt co-receptors, low-density lipoprotein receptor-related protein 5 (LRP-5) and LRP-6, as well as LRP-1, implicated in cell survival and invasiveness. These data were confirmed in experimental carcinogenesis. In conclusion, the upregulation of LRP family members by SerpinB3 determines Wnt signaling activation and increased cell survival and invasiveness. ABSTRACT: Abnormal activation of the Wnt-β-catenin signaling cascade is involved in tumor growth and dissemination. SerpinB3 has been shown to induce β-catenin, and both molecules are overexpressed in tumors, particularly in those with poor prognoses. The aim of this study was to evaluate the ability of SerpinB3 to modulate the Wnt pathway in liver cancer and in monocytic cells, the main type of inflammatory cells in the tumor microenvironment. The Wnt cascade, Wnt co-receptors, and low-density lipoprotein receptor-related protein (LRP) members were analyzed in different cell lines and human monocytes in the presence or absence of SerpinB3. The Wnt-β-catenin axis was also evaluated in liver tumors induced in mice with different extents of SeprinB3 expression. In monocytic cells, SerpinB3 induced a significant upregulation of Wnt-1/7, nuclear β-catenin, and c-Myc, which are associated with increased cell lifespan and proliferation. In liver tumors in mice, the expression of β-catenin was significantly correlated with the presence of SerpinB3. In hepatoma cells, Wnt co-receptors LRP-5/6 and LRP-1, implicated in cell survival and invasiveness, were upregulated by SerpinB3. The LRP pan-inhibitor RAP not only induced a decrease in LRP expression, but also a dose–dependent reduction in SerpinB3-induced invasiveness. In conclusion, SerpinB3 determines the activation of the Wnt canonical pathway and cell invasiveness through the upregulation of LRP family members. MDPI 2023-05-26 /pmc/articles/PMC10295789/ /pubmed/37372056 http://dx.doi.org/10.3390/biology12060771 Text en © 2023 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
Quarta, Santina
Cappon, Andrea
Turato, Cristian
Ruvoletto, Mariagrazia
Cannito, Stefania
Villano, Gianmarco
Biasiolo, Alessandra
Maggi, Maristella
Protopapa, Francesca
Bertazza, Loris
Fasolato, Silvano
Parola, Maurizio
Pontisso, Patrizia
SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness
title SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness
title_full SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness
title_fullStr SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness
title_full_unstemmed SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness
title_short SerpinB3 Upregulates Low-Density Lipoprotein Receptor-Related Protein (LRP) Family Members, Leading to Wnt Signaling Activation and Increased Cell Survival and Invasiveness
title_sort serpinb3 upregulates low-density lipoprotein receptor-related protein (lrp) family members, leading to wnt signaling activation and increased cell survival and invasiveness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295789/
https://www.ncbi.nlm.nih.gov/pubmed/37372056
http://dx.doi.org/10.3390/biology12060771
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