Heterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxia.

Fecha de publicación: 24/09/2021 Fecha Ahead of Print: 24/09/2021

Autores de IIS La Fe

Miguel Ángel Martínez García

Autor

Participantes ajenos a IIS La Fe

Khalyfa A
Trzepizur W
Gileles-Hillel A
Qiao Z
Sanz-Rubio D
Marin JM
Campos-Rodriguez F
Almendros I
Farre R
Sanchez-de-la-Torre M
García-Río F
Gozal D

Grupos

Neumología

Leader

Miguel Ángel Martínez García

Abstract

Obstructive sleep apnea (OSA) is associated with increased cutaneous melanoma incidence and adverse outcomes. Exosomes are secreted by most cells, and play a role in OSA-associated tumor progression and metastasis. We aimed to study the effects of plasma exosomes from OSA patients before and after adherent treatment with continuous positive airway pressure (CPAP) on melanoma cells lines, and also to identify exosomal miRNAs from melanoma cells exposed to intermittent hypoxia (IH) or normoxia. Plasma-derived exosomes were isolated from moderate-to-severe OSA patients before (V1) and after (V2) adherent CPAP treatment for one year. Exosomes were co-incubated with three3 different melanoma cell lines (CRL 1424; CRL 1619; CRL 1675) that are characterized by genotypes involving different mutations in BRAF, STK11, CDKN2A, and PTEN genes to assess the effect of exosomes on cell proliferation and migration, as well as on pAMK activity in the presence or absence of a chemical activator. Subsequently, CRL-1424 and CRL-1675 cells were exposed to intermittent hypoxia (IH) and normoxia, and exosomal miRNAs were identified followed by GO and KEG pathways and gene networks. The exosomes from these IH-exposed melanoma cells were also administered to THP1 macrophages to examine changes in M1 and M2 polarity markers. Plasma exosomes from V1 increased CRL-1424 melanoma cell proliferation and migration compared to V2, but not the other two cell lines. Exposure to CRL-1424 exosomes reduced pAMPK/tAMPK in V1 compared to V2, and treatment with AMPK activator reversed the effects. Unique exosomal miRNAs profiles were identified for CRL-1424 and CRL-1675 in IH compared to normoxia, with six miRNAs being regulated and several KEGG pathways were identified. Two M1 markers (CXCL10 and IL6) were significantly increased in monocytes when treated with exosomes from IH-exposed CRL-1424 and CRL-1625 cells. Our findings suggest that exosomes from untreated OSA patients increase CRL-1424 melanoma malignant properties, an effect that is not observed in two other melanoma cell lines. Exosomal cargo from CRL-1424 cells showed a unique miRNA signature compared to CRL-1675 cells after IH exposures, suggesting that melanoma cells are differentially susceptible to IH, even if they retain similar effects on immune cell polarity. It is postulated that mutations in STK-11 gene encoding for the serine/threonine kinase family that acts as a tumor suppressor may underlie susceptibility to IH-induced metabolic dysfunction, as illustrated by CRL-1424 cells.

Datos de la publicación

ISSN/ISSNe:: 2072-6694, 2072-6694
Tipo:: Article
Páginas:: -
DOI:: 10.3390/cancers13194781
PubMed:: 34638272
Factor de Impacto:: 1,349 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Khalyfa A:: Department of Child Health and the Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO 65201, USA
Trzepizur W:: Department of Respiratory and Sleep Medicine, INSERM Unit 1063, Angers University Hospital, 49000 Angers, France
Gileles-Hillel A:: Pediatric Pulmonology and Sleep Unit, Hadassah Medical Center, Jerusalem 9987500, Israel

Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9987500, Israel
Qiao Z:: Department of Child Health and the Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO 65201, USA
Sanz-Rubio D:: Translational Research Unit, Hospital Universitario Miguel Servet, IISAragon, Department of Medicine, University of Zaragoza, 50002 Zaragoza, Spain
Marin JM:: Translational Research Unit, Hospital Universitario Miguel Servet, IISAragon, Department of Medicine, University of Zaragoza, 50002 Zaragoza, Spain

CIBER de Enfermedades Respiratorias, ISCIII, 28012 Madrid, Spain
Martinez-Garcia MA:: CIBER de Enfermedades Respiratorias, ISCIII, 28012 Madrid, Spain

Pneumology Department, University and Polytechnic la Fe Hospital, 46026 Valencia, Spain
Campos-Rodriguez F:: CIBER de Enfermedades Respiratorias, ISCIII, 28012 Madrid, Spain

Respiratory Department, Hospital Universitario de Valme, 41014 Sevilla, Spain
Almendros I:: CIBER de Enfermedades Respiratorias, ISCIII, 28012 Madrid, Spain

Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciencies de la Salut, Universitat de Barcelona-Institut Investigacions Biomediques August Pi Sunyer, 08036 Barcelona, Spain
Farre R:: CIBER de Enfermedades Respiratorias, ISCIII, 28012 Madrid, Spain

Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciencies de la Salut, Universitat de Barcelona-Institut Investigacions Biomediques August Pi Sunyer, 08036 Barcelona, Spain
Sanchez-de-la-Torre M:: CIBER de Enfermedades Respiratorias, ISCIII, 28012 Madrid, Spain

Group of Precision Medicine in Chronic Diseases, Hospital Arnau de Vilanova-Santa Maria, IRBLleida, Department of Nursing and Physiotherapy, Faculty of Nursing and Physiotherapy, University of Lleida, 25198 Lleida, Spain
García-Río F:: CIBER de Enfermedades Respiratorias, ISCIII, 28012 Madrid, Spain

Respiratory Department, Hospital Universitario La Paz-IdiPAZ, Universidad Autónoma de Madrid, 28046 Madrid, Spain
Gozal D:: Department of Child Health and the Child Health Research Institute, University of Missouri School of Medicine, Columbia, MO 65201, USA