Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
Revilla, Giovanna ![ORCID Identifier](/img/uab/orcid.ico)
(Institut d'Investigació Biomèdica Sant Pau)
Ruiz-Auladell, Lara (Institut d'Investigació Biomèdica Sant Pau)
Vallverdú, Núria Fucui (Institut d'Investigació Biomèdica Sant Pau)
Santamaría, Paula (Institut d'Investigació Biomèdica Sant Pau)
Moral Duarte, Antonio ![ORCID Identifier](/img/uab/orcid.ico)
(Institut d'Investigació Biomèdica Sant Pau)
Pérez, José Ignacio (Institut d'Investigació Biomèdica Sant Pau)
Li, Changda
(Universitat Autònoma de Barcelona)
Fuste, Victoria
(Institut d'Investigació Biomèdica Sant Pau)
Lerma Puertas, Enrique
(Institut d'Investigació Biomèdica Sant Pau)
Corcoy i Pla, Rosa
(Institut d'Investigació Biomèdica Sant Pau)
Pitoia, Fabián (Universidad de Buenos Aires)
Escolà-Gil, Joan Carles
(Institut d'Investigació Biomèdica Sant Pau)
Mato, Eugenia
(Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona
Date: |
2023 |
Abstract: |
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. |
Grants: |
Instituto de Salud Carlos III PI19/00136
|
Rights: |
Aquest 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. ![Creative Commons](/img/licenses/by.ico) |
Language: |
Anglès |
Document: |
Article ; recerca ; Versió publicada |
Subject: |
BRAF V600E ;
RAS/RAF/MAPK (MEK)/ERK pathway ;
Low-density lipoprotein (LDL) ;
Low-density lipoprotein receptor (LDLR) ;
Thyroid cancer (TC) |
Published in: |
International journal of molecular sciences, Vol. 24 (july 2023) , ISSN 1422-0067 |
DOI: 10.3390/ijms241311153
PMID: 37446330
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Record created 2024-04-24, last modified 2024-09-09