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Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer

Colorectal cancer’s (CRC) ability to invade local tissues and lymph nodes and generate distant metastases is the key for TNM classification. Aspartate-β-hydroxylase (ASPH), a transmembrane protein that catalyzes Notch receptors and ligand activation, is involved in tumor invasion. Because Notch is i...

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Autores principales: Benelli, Roberto, Costa, Delfina, Mastracci, Luca, Grillo, Federica, Olsen, Mark Jon, Barboro, Paola, Poggi, Alessandro, Ferrari, Nicoletta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226058/
https://www.ncbi.nlm.nih.gov/pubmed/32295249
http://dx.doi.org/10.3390/cancers12040971
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author Benelli, Roberto
Costa, Delfina
Mastracci, Luca
Grillo, Federica
Olsen, Mark Jon
Barboro, Paola
Poggi, Alessandro
Ferrari, Nicoletta
author_facet Benelli, Roberto
Costa, Delfina
Mastracci, Luca
Grillo, Federica
Olsen, Mark Jon
Barboro, Paola
Poggi, Alessandro
Ferrari, Nicoletta
author_sort Benelli, Roberto
collection PubMed
description Colorectal cancer’s (CRC) ability to invade local tissues and lymph nodes and generate distant metastases is the key for TNM classification. Aspartate-β-hydroxylase (ASPH), a transmembrane protein that catalyzes Notch receptors and ligand activation, is involved in tumor invasion. Because Notch is involved in gut homeostasis, it could be a target for CRC therapy. ASPH mRNA and protein expression, promoter methylation and gene copy numbers were evaluated using the TCGA and CPTAC human CRC datasets. Using digital pathology, ASPH was scored in the luminal area (LM), center tumor (CT) and invasive margin (IM) of 100 human CRCs. The effect of ASPH targeting on invasiveness and viability was tested by siRNA knockdown and small molecule inhibitors (SMI). Bioinformatics analysis showed increased expression of ASPH mRNA and protein in CRC, paired with a decreased methylation profile. ASPH genetic gain or amplification was frequent (56%), while deletion was rare (0.03%). Digital pathology analysis showed that ASPH exerted its pathological activity in the invasive margin of the tumor, affecting invasive front morphology, tumor budding and patients’ overall survival. In vitro, ASPH targeting by siRNA or SMI reduced cell invasion and growth and caused Notch-1 downregulation. This study demonstrates that ASPH targeting by specific inhibitors could improve CRC treatment strategies.
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spelling pubmed-72260582020-05-18 Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer Benelli, Roberto Costa, Delfina Mastracci, Luca Grillo, Federica Olsen, Mark Jon Barboro, Paola Poggi, Alessandro Ferrari, Nicoletta Cancers (Basel) Brief Report Colorectal cancer’s (CRC) ability to invade local tissues and lymph nodes and generate distant metastases is the key for TNM classification. Aspartate-β-hydroxylase (ASPH), a transmembrane protein that catalyzes Notch receptors and ligand activation, is involved in tumor invasion. Because Notch is involved in gut homeostasis, it could be a target for CRC therapy. ASPH mRNA and protein expression, promoter methylation and gene copy numbers were evaluated using the TCGA and CPTAC human CRC datasets. Using digital pathology, ASPH was scored in the luminal area (LM), center tumor (CT) and invasive margin (IM) of 100 human CRCs. The effect of ASPH targeting on invasiveness and viability was tested by siRNA knockdown and small molecule inhibitors (SMI). Bioinformatics analysis showed increased expression of ASPH mRNA and protein in CRC, paired with a decreased methylation profile. ASPH genetic gain or amplification was frequent (56%), while deletion was rare (0.03%). Digital pathology analysis showed that ASPH exerted its pathological activity in the invasive margin of the tumor, affecting invasive front morphology, tumor budding and patients’ overall survival. In vitro, ASPH targeting by siRNA or SMI reduced cell invasion and growth and caused Notch-1 downregulation. This study demonstrates that ASPH targeting by specific inhibitors could improve CRC treatment strategies. MDPI 2020-04-14 /pmc/articles/PMC7226058/ /pubmed/32295249 http://dx.doi.org/10.3390/cancers12040971 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Benelli, Roberto
Costa, Delfina
Mastracci, Luca
Grillo, Federica
Olsen, Mark Jon
Barboro, Paola
Poggi, Alessandro
Ferrari, Nicoletta
Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer
title Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer
title_full Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer
title_fullStr Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer
title_full_unstemmed Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer
title_short Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer
title_sort aspartate-β-hydroxylase: a promising target to limit the local invasiveness of colorectal cancer
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226058/
https://www.ncbi.nlm.nih.gov/pubmed/32295249
http://dx.doi.org/10.3390/cancers12040971
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