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

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dc.contributor.authorKhalyfa, Abdelnaby
dc.contributor.authorTrzepizur, Wojciech
dc.contributor.authorGileles-Hillel, Alex
dc.contributor.authorQiao, Zhuanhong
dc.contributor.authorSanz Rubio, David
dc.contributor.authorMarin, José M.
dc.contributor.authorMartinez-Garcia, Miguel A.
dc.contributor.authorCampos-Rodríguez, Francisco
dc.contributor.authorAlmendros, Isaac
dc.contributor.authorFarré, Ramon
dc.contributor.authorSánchez de la Torre, Manuel
dc.contributor.authorGarcía-Río, Francisco
dc.contributor.authorGozal, David
dc.date.accessioned2022-11-11T12:29:03Z
dc.date.available2022-11-11T12:29:03Z
dc.date.issued2021
dc.description.abstractObstructive 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-tosevere 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 CRL1424 cells.ca_ES
dc.identifier.doihttps://doi.org/10.3390/cancers13194781
dc.identifier.idgrec031775
dc.identifier.issn2072-6694
dc.identifier.urihttp://hdl.handle.net/10459.1/84187
dc.language.isoengca_ES
dc.publisherMDPIca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.3390/cancers13194781ca_ES
dc.relation.ispartofCancers, 2021, núm. 13, 4781ca_ES
dc.rightscc-by (c) Abdelnaby Khalyfa et.al., 2021ca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectSleep apneaca_ES
dc.subjectPositive airway pressureca_ES
dc.subjectCPAPca_ES
dc.subjectExosomesca_ES
dc.subjectMelanomaca_ES
dc.subjectMiRNAsca_ES
dc.subjectAMPKca_ES
dc.subjectCRL-1424ca_ES
dc.subjectCRL-1619ca_ES
dc.subjectCRL-1675ca_ES
dc.subjectIntermittent hypoxiaca_ES
dc.titleHeterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxiaca_ES
dc.typeinfo:eu-repo/semantics/articleca_ES
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_ES
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