Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells

We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) ex...

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Autores: Revilla, Giovanna|||0000-0003-2971-5651, Ruiz-Auladell, Lara, Fucui Vallverdú, Núria, Santamaría, Paula, Moral, Antonio|||0000-0001-5551-0145, Pérez, José Ignacio, Li, Changda|||0000-0002-2847-3737, Fuste, Victoria|||0000-0001-5065-3737, Lerma Puertas, Enrique|||0000-0001-7908-2747, Corcoy i Pla, Rosa|||0000-0001-5055-6814, Pitoia, Fabián, Escolà-Gil, Joan Carles|||0000-0001-9021-2485, Mato, Eugènia|||0000-0001-8121-9335
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:291488
Acceso en línea:https://ddd.uab.cat/record/291488
https://dx.doi.org/urn:doi:10.3390/ijms241311153
Access Level:acceso abierto
Palabra clave:BRAF V600E
RAS/RAF/MAPK (MEK)/ERK pathway
Low-density lipoprotein (LDL)
Low-density lipoprotein receptor (LDLR)
Thyroid cancer (TC)
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spelling Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor CellsRevilla, Giovanna|||0000-0003-2971-5651Ruiz-Auladell, LaraFucui Vallverdú, NúriaSantamaría, PaulaMoral, Antonio|||0000-0001-5551-0145Pérez, José IgnacioLi, Changda|||0000-0002-2847-3737Fuste, Victoria|||0000-0001-5065-3737Lerma Puertas, Enrique|||0000-0001-7908-2747Corcoy i Pla, Rosa|||0000-0001-5055-6814Pitoia, FabiánEscolà-Gil, Joan Carles|||0000-0001-9021-2485Mato, Eugènia|||0000-0001-8121-9335BRAF V600ERAS/RAF/MAPK (MEK)/ERK pathwayLow-density lipoprotein (LDL)Low-density lipoprotein receptor (LDLR)Thyroid cancer (TC)We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E.Universitat Autònoma de Barcelona 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/291488https://dx.doi.org/urn:doi:10.3390/ijms241311153reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI19/00136open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2914882026-06-06T12:50:31Z
dc.title.none.fl_str_mv Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
title Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
spellingShingle Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
Revilla, Giovanna|||0000-0003-2971-5651
BRAF V600E
RAS/RAF/MAPK (MEK)/ERK pathway
Low-density lipoprotein (LDL)
Low-density lipoprotein receptor (LDLR)
Thyroid cancer (TC)
title_short Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
title_full Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
title_fullStr Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
title_full_unstemmed Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
title_sort Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
dc.creator.none.fl_str_mv Revilla, Giovanna|||0000-0003-2971-5651
Ruiz-Auladell, Lara
Fucui Vallverdú, Núria
Santamaría, Paula
Moral, Antonio|||0000-0001-5551-0145
Pérez, José Ignacio
Li, Changda|||0000-0002-2847-3737
Fuste, Victoria|||0000-0001-5065-3737
Lerma Puertas, Enrique|||0000-0001-7908-2747
Corcoy i Pla, Rosa|||0000-0001-5055-6814
Pitoia, Fabián
Escolà-Gil, Joan Carles|||0000-0001-9021-2485
Mato, Eugènia|||0000-0001-8121-9335
author Revilla, Giovanna|||0000-0003-2971-5651
author_facet Revilla, Giovanna|||0000-0003-2971-5651
Ruiz-Auladell, Lara
Fucui Vallverdú, Núria
Santamaría, Paula
Moral, Antonio|||0000-0001-5551-0145
Pérez, José Ignacio
Li, Changda|||0000-0002-2847-3737
Fuste, Victoria|||0000-0001-5065-3737
Lerma Puertas, Enrique|||0000-0001-7908-2747
Corcoy i Pla, Rosa|||0000-0001-5055-6814
Pitoia, Fabián
Escolà-Gil, Joan Carles|||0000-0001-9021-2485
Mato, Eugènia|||0000-0001-8121-9335
author_role author
author2 Ruiz-Auladell, Lara
Fucui Vallverdú, Núria
Santamaría, Paula
Moral, Antonio|||0000-0001-5551-0145
Pérez, José Ignacio
Li, Changda|||0000-0002-2847-3737
Fuste, Victoria|||0000-0001-5065-3737
Lerma Puertas, Enrique|||0000-0001-7908-2747
Corcoy i Pla, Rosa|||0000-0001-5055-6814
Pitoia, Fabián
Escolà-Gil, Joan Carles|||0000-0001-9021-2485
Mato, Eugènia|||0000-0001-8121-9335
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv BRAF V600E
RAS/RAF/MAPK (MEK)/ERK pathway
Low-density lipoprotein (LDL)
Low-density lipoprotein receptor (LDLR)
Thyroid cancer (TC)
topic BRAF V600E
RAS/RAF/MAPK (MEK)/ERK pathway
Low-density lipoprotein (LDL)
Low-density lipoprotein receptor (LDLR)
Thyroid cancer (TC)
description We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E.
publishDate 2023
dc.date.none.fl_str_mv 2
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/291488
https://dx.doi.org/urn:doi:10.3390/ijms241311153
url https://ddd.uab.cat/record/291488
https://dx.doi.org/urn:doi:10.3390/ijms241311153
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI19/00136
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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