Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells
Por:
Revilla, G, Ruiz-Auladell, L, Vallverdu, NF, Santamaria, P, Moral, A, Perez, JI, Li, CD, Fuste, V, Lerma, E, Corcoy, R, Pitoia, F, Escola-Gil, JC, Mato, E
Publicada:
6 jul 2023
Ahead of Print:
6 jul 2023
Resumen:
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 & PLUSMN; 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.
Filiaciones:
Revilla, G:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
Univ Autonoma Barcelona UAB, Dept Biochem & Mol Biol, Barcelona 08025, Spain
Ruiz-Auladell, L:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
Vallverdu, NF:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
Santamaria, P:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
Hosp Santa Creu & Sant Pau, Dept Endocrinol & Nutr, Barcelona 08041, Spain
Moral, A:
Hosp Santa Creu & Sant Pau, Dept Gen Surg, Barcelona 08041, Spain
Univ Autonoma Barcelona UAB, Dept Med, Barcelona 08193, Spain
Perez, JI:
Hosp Santa Creu & Sant Pau, Dept Gen Surg, Barcelona 08041, Spain
Li, CD:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
Univ Autonoma Barcelona UAB, Dept Biochem & Mol Biol, Barcelona 08025, Spain
Fuste, V:
Hosp Santa Creu & Sant Pau, Dept Pathol Anat, Barcelona 08041, Spain
Lerma, E:
Hosp Santa Creu & Sant Pau, Dept Pathol Anat, Barcelona 08041, Spain
Corcoy, R:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
Hosp Santa Creu & Sant Pau, Dept Endocrinol & Nutr, Barcelona 08041, Spain
Univ Autonoma Barcelona UAB, Dept Med, Barcelona 08193, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Pitoia, F:
Univ Buenos Aires, Hosp Clin, Div Endocrinol, C1120 AAF, Buenos Aires, Argentina
Escola-Gil, JC:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
Univ Autonoma Barcelona UAB, Dept Biochem & Mol Biol, Barcelona 08025, Spain
CIBER Diabet & Enfermedades Metab Asociadas CIBERD, Madrid 28029, Spain
Mato, E:
Inst Invest Biomed IIB St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
gold, All Open Access, Gold
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