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Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation

Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic activity. Mutations of HPSE2 were identified in patients diagnosed with urofacial syndrome (UFS), a rare genetic disorder that exh...

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Autores principales: Kayal, Yasmin, Barash, Uri, Naroditsky, Inna, Ilan, Neta, Vlodavsky, Israel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368643/
https://www.ncbi.nlm.nih.gov/pubmed/37491420
http://dx.doi.org/10.1038/s41419-023-05990-y
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author Kayal, Yasmin
Barash, Uri
Naroditsky, Inna
Ilan, Neta
Vlodavsky, Israel
author_facet Kayal, Yasmin
Barash, Uri
Naroditsky, Inna
Ilan, Neta
Vlodavsky, Israel
author_sort Kayal, Yasmin
collection PubMed
description Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic activity. Mutations of HPSE2 were identified in patients diagnosed with urofacial syndrome (UFS), a rare genetic disorder that exhibits abnormal facial expression and bladder voiding dysfunction, leading to renal damage and eventually renal failure. In order to reveal the role of HPSE2 in tissue homeostasis, we established a conditional Hpa2-KO mouse. Interestingly, the lack of Hpa2 was associated with a marked decrease in the expression of key pancreatic transcription factors such as PTF1, GATA6, and Mist1. This was associated with a two-fold decrease in pancreas weight, increased pancreatic inflammation, and profound morphological alterations of the pancreas. These include massive accumulation of fat cells, possibly a result of acinar-to-adipocyte transdifferentiation (AAT), as well as acinar-to-ductal metaplasia (ADM), both considered to be pro-tumorigenic. Furthermore, exposing Hpa2-KO but not wild-type mice to a carcinogen (AOM) and pancreatic inflammation (cerulein) resulted in the formation of pancreatic intraepithelial neoplasia (PanIN), lesions that are considered to be precursors of invasive ductal adenocarcinoma of the pancreas (PDAC). These results strongly support the notion that Hpa2 functions as a tumor suppressor. Moreover, Hpa2 is shown here for the first time to play a critical role in the exocrine aspect of the pancreas.
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spelling pubmed-103686432023-07-27 Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation Kayal, Yasmin Barash, Uri Naroditsky, Inna Ilan, Neta Vlodavsky, Israel Cell Death Dis Article Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic activity. Mutations of HPSE2 were identified in patients diagnosed with urofacial syndrome (UFS), a rare genetic disorder that exhibits abnormal facial expression and bladder voiding dysfunction, leading to renal damage and eventually renal failure. In order to reveal the role of HPSE2 in tissue homeostasis, we established a conditional Hpa2-KO mouse. Interestingly, the lack of Hpa2 was associated with a marked decrease in the expression of key pancreatic transcription factors such as PTF1, GATA6, and Mist1. This was associated with a two-fold decrease in pancreas weight, increased pancreatic inflammation, and profound morphological alterations of the pancreas. These include massive accumulation of fat cells, possibly a result of acinar-to-adipocyte transdifferentiation (AAT), as well as acinar-to-ductal metaplasia (ADM), both considered to be pro-tumorigenic. Furthermore, exposing Hpa2-KO but not wild-type mice to a carcinogen (AOM) and pancreatic inflammation (cerulein) resulted in the formation of pancreatic intraepithelial neoplasia (PanIN), lesions that are considered to be precursors of invasive ductal adenocarcinoma of the pancreas (PDAC). These results strongly support the notion that Hpa2 functions as a tumor suppressor. Moreover, Hpa2 is shown here for the first time to play a critical role in the exocrine aspect of the pancreas. Nature Publishing Group UK 2023-07-25 /pmc/articles/PMC10368643/ /pubmed/37491420 http://dx.doi.org/10.1038/s41419-023-05990-y Text en © The Author(s) 2023 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
Kayal, Yasmin
Barash, Uri
Naroditsky, Inna
Ilan, Neta
Vlodavsky, Israel
Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation
title Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation
title_full Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation
title_fullStr Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation
title_full_unstemmed Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation
title_short Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation
title_sort heparanase 2 (hpa2)- a new player essential for pancreatic acinar cell differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368643/
https://www.ncbi.nlm.nih.gov/pubmed/37491420
http://dx.doi.org/10.1038/s41419-023-05990-y
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