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.