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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7226058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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