Extracellular vesicles derived-microRNAs predicting enzalutamide-resistance in 3D spheroid prostate Cancer model

被引:0
|
作者
Tavares, Ines [1 ,2 ]
Morais, Mariana [1 ,2 ]
Dias, Francisca [1 ]
Ferreira, Mariana [1 ,2 ]
Martins, Gabriela [3 ]
Fernandes, Rui [4 ,5 ]
Bidarra, Silvia Joana [6 ,7 ]
Medeiros, Rui [1 ,2 ,8 ,9 ,10 ]
Teixeira, Ana Luisa [1 ]
机构
[1] Portuguese Oncol Inst Porto IPO Porto, Res Ctr IPO Porto CI IPOP, RISECI IPOP Hlth Res Network, Porto Comprehens Canc Ctr Raquel Seruca Porto CCC,, Porto, Portugal
[2] Univ Porto, Abel Salazar Inst Biomed Sci, ICBAS, Porto, Portugal
[3] Portuguese Oncol Inst Porto IPO Porto, Dept Immunol, Porto, Portugal
[4] Univ Porto, HEMS Histol & Electron Microscopy, Inst Invest & Inovacao Saude I3S, Porto, Portugal
[5] Univ Porto, IBMC Inst Biol Mol & Celular, Porto, Portugal
[6] Univ Porto, Inst Invest & Inovacao Saude I3S, Bioengn 3D Microenvironm Grp, Porto, Portugal
[7] Univ Porto, INEB Inst Engn Biomed, Porto, Portugal
[8] Fernando Pessoa Univ UFP, Fac Hlth Sci, Biomed Reasearch Ctr CEBIMED, Porto, Portugal
[9] Portuguese League Canc LPCC NRNorte, Res Dept, Porto, Portugal
[10] Univ Porto, Fac Med Univ Porto FMUP, Porto, Portugal
关键词
Prostate cancer; Resistance acquisition; Extracellular vesicles derived-miRNAs; Predictive biomarkers; 2ND-GENERATION ANTIANDROGEN; EXPRESSION; DISEASES; MIR-221; GROWTH;
D O I
10.1016/j.ijbiomac.2024.137993
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Enzalutamide (ENZ) has emerged as a major treatment advance in castration-resistant prostate cancer (CRPC) patients; however the development of resistance remains a key challenge. The extracellular vesicles (VEs)derived miRNAs play crucial roles tumor microenvironment cell communication, thereby influencing resistance mechanisms. Considering the urgent need for molecular biomarkers to monitor ENZ response and predict resistance, we intend to identify an EV-derived miRNA profile associated with ENZ resistance using an innovative 3D-spheroid in vitro model. Through the generation of this model, we provide a comprehensive platform for elucidating the molecular alterations involved in the process. An in vitro model of ENZ resistance was established through continuous exposure of LNCaP to increasing ENZ concentrations. A screening of 799 miRNAs from resistant and normal LNCaP cells were quantified. A bioinformatic analysis was performed using miRTarbase and Cytoscape and top 5 overexpressed miRNAs were selected, that will be analyzed in extracellular vesicles derived from ENZ resistance 3D spheroid models. We identified 12 up- and 13 downregulated miRNAs in LNCaP 30 mu M ENZ cells compare to LNCaP & sdot;In silico analysis led to the construction of a 76 proteins cluster and functional enrichment revealed terms like PI3K/AKT, TFG-beta and FOXO. hsa-miR-22-3p was significantly decreased at 5 and 20 mu M ENZ concentration intracellularly, but significantly increased at 20 mu M ENZ in EVs. hsa-miR-221-3p and miR-222-3p were upregulated in all concentrations both intracellularly and in EVs. The developed 3D-spheroid model effectively replicated the ENZ resistance to ENZ in an AR-independent manner, underscoring the importance of EVs-derived miRNAs in this adaptive process.
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页数:15
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