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Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma
Glioblastoma (GBM) is the most common primary malignant brain tumor with a grave prognosis. The present study evaluated the expression of Cholesterol transporter [importer -Lipoprotein Receptor-related Protein-1 (LRP-1) and exporter -ATP-binding cassette transporters-1 (ABCA-1)] in GBM and their imp...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576951/ https://www.ncbi.nlm.nih.gov/pubmed/36267880 http://dx.doi.org/10.3389/fneur.2022.1003730 |
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author | N. R., Shruthi Behera, Minakshi M. Naik, Sanoj Kumar Das, Sunil Kumar Gopan, Sooraj Ghosh, Amit Sahu, Rabi Narayan Patra, Susama Purkait, Suvendu |
author_facet | N. R., Shruthi Behera, Minakshi M. Naik, Sanoj Kumar Das, Sunil Kumar Gopan, Sooraj Ghosh, Amit Sahu, Rabi Narayan Patra, Susama Purkait, Suvendu |
author_sort | N. R., Shruthi |
collection | PubMed |
description | Glioblastoma (GBM) is the most common primary malignant brain tumor with a grave prognosis. The present study evaluated the expression of Cholesterol transporter [importer -Lipoprotein Receptor-related Protein-1 (LRP-1) and exporter -ATP-binding cassette transporters-1 (ABCA-1)] in GBM and their implications in tumor-biology, clinical outcome and therapeutic potentials. The mRNA and protein expression was assessed by qRT-PCR and immunohistochemistry, respectively, in 85 GBMs. For comparison, 25 lower-grade astrocytomas (IDH-mutant, grade-2/3) [LGA] 16 cases of high-grade astrocytomas (IDH-mutant, grade-4) [HGA] were also evaluated. In-vitro analysis was performed on U87MG and LN229 glioma cell line. The expression of LRP-1 (mRNA and protein) was significantly higher in GBM than LGA, HGA and normal brain (NB) [p-values 0.007, 0.003 and <0.001 for mRNA; 0.024, <0.001 and <0.001 for immunohistochemistry]. Majority of the GBMs (82.4%) showed strong immunoreactivity for LRP-1, and all tumor cases were positive while the normal brain was negative. LRP-1 immunoreactivity positively correlated with the MIB-1 labeling index (p-value-0.013). LRP-1 knockdown in-vitro was associated with decreased cell survival, proliferation, migration, invasion, and increased apoptosis. Similar effect was also demonstrated by Receptor Associated Protein (RAP), a LRP-1 inhibitory drug. The silencing of LRP-1 was also associated with decreased cholesterol level. The ABCA-1 expression was higher in GBM than LGA and NB (p-value 0.011 and <0.001), however there was no significant association with other parameters. LRP-1 showed a positive correlation with ABCA-1 and associated with decreased expression with LRP-1 knock-down in-vitro. The expression of LRP-1 and ABCA-1 didn't correlate with overall survival in GBMs. Hence, LRP-1 is crucial for the tumor cells' survival and aggressive biological behavior which is maintain through the regulation of high intracellular cholesterol import. Its expression is significantly higher in GBMs and also implicated in the regulation of ABCA-1 expression. Considering its immune-positivity only in the neoplastic cell and strong positivity in GBM it may be a useful adjunct to the diagnosis. For the first time, the present study emphasized its role as a potential therapeutic target in the form of RAP which is presently being used in other neurological diseases under clinical trials. |
format | Online Article Text |
id | pubmed-9576951 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95769512022-10-19 Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma N. R., Shruthi Behera, Minakshi M. Naik, Sanoj Kumar Das, Sunil Kumar Gopan, Sooraj Ghosh, Amit Sahu, Rabi Narayan Patra, Susama Purkait, Suvendu Front Neurol Neurology Glioblastoma (GBM) is the most common primary malignant brain tumor with a grave prognosis. The present study evaluated the expression of Cholesterol transporter [importer -Lipoprotein Receptor-related Protein-1 (LRP-1) and exporter -ATP-binding cassette transporters-1 (ABCA-1)] in GBM and their implications in tumor-biology, clinical outcome and therapeutic potentials. The mRNA and protein expression was assessed by qRT-PCR and immunohistochemistry, respectively, in 85 GBMs. For comparison, 25 lower-grade astrocytomas (IDH-mutant, grade-2/3) [LGA] 16 cases of high-grade astrocytomas (IDH-mutant, grade-4) [HGA] were also evaluated. In-vitro analysis was performed on U87MG and LN229 glioma cell line. The expression of LRP-1 (mRNA and protein) was significantly higher in GBM than LGA, HGA and normal brain (NB) [p-values 0.007, 0.003 and <0.001 for mRNA; 0.024, <0.001 and <0.001 for immunohistochemistry]. Majority of the GBMs (82.4%) showed strong immunoreactivity for LRP-1, and all tumor cases were positive while the normal brain was negative. LRP-1 immunoreactivity positively correlated with the MIB-1 labeling index (p-value-0.013). LRP-1 knockdown in-vitro was associated with decreased cell survival, proliferation, migration, invasion, and increased apoptosis. Similar effect was also demonstrated by Receptor Associated Protein (RAP), a LRP-1 inhibitory drug. The silencing of LRP-1 was also associated with decreased cholesterol level. The ABCA-1 expression was higher in GBM than LGA and NB (p-value 0.011 and <0.001), however there was no significant association with other parameters. LRP-1 showed a positive correlation with ABCA-1 and associated with decreased expression with LRP-1 knock-down in-vitro. The expression of LRP-1 and ABCA-1 didn't correlate with overall survival in GBMs. Hence, LRP-1 is crucial for the tumor cells' survival and aggressive biological behavior which is maintain through the regulation of high intracellular cholesterol import. Its expression is significantly higher in GBMs and also implicated in the regulation of ABCA-1 expression. Considering its immune-positivity only in the neoplastic cell and strong positivity in GBM it may be a useful adjunct to the diagnosis. For the first time, the present study emphasized its role as a potential therapeutic target in the form of RAP which is presently being used in other neurological diseases under clinical trials. Frontiers Media S.A. 2022-10-04 /pmc/articles/PMC9576951/ /pubmed/36267880 http://dx.doi.org/10.3389/fneur.2022.1003730 Text en Copyright © 2022 N. R., Behera, Naik, Das, Gopan, Ghosh, Sahu, Patra and Purkait. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neurology N. R., Shruthi Behera, Minakshi M. Naik, Sanoj Kumar Das, Sunil Kumar Gopan, Sooraj Ghosh, Amit Sahu, Rabi Narayan Patra, Susama Purkait, Suvendu Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma |
title | Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma |
title_full | Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma |
title_fullStr | Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma |
title_full_unstemmed | Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma |
title_short | Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma |
title_sort | elevated expression of cholesterol transporter lrp-1 is crucially implicated in the pathobiology of glioblastoma |
topic | Neurology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9576951/ https://www.ncbi.nlm.nih.gov/pubmed/36267880 http://dx.doi.org/10.3389/fneur.2022.1003730 |
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