Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: N. R., Shruthi, Behera, Minakshi M., Naik, Sanoj Kumar, Das, Sunil Kumar, Gopan, Sooraj, Ghosh, Amit, Sahu, Rabi Narayan, Patra, Susama, Purkait, Suvendu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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
_version_ 1784811645181100032
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
work_keys_str_mv AT nrshruthi elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT beheraminakshim elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT naiksanojkumar elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT dassunilkumar elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT gopansooraj elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT ghoshamit elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT sahurabinarayan elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT patrasusama elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma
AT purkaitsuvendu elevatedexpressionofcholesteroltransporterlrp1iscruciallyimplicatedinthepathobiologyofglioblastoma