Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Simple Summary Patients with obstructive sleep apnea (OSA) exhibit an intermittent hypoxia-dependent paraspeckle protein-1 (PSPC1) increase, which is eventually delivered to the plasma through its cleavage from OSA monocytes by matrix metalloprotease-2, promoting tumor growth factor (TGF beta) expression and increasing epithelial-to-mesenchymal transition in a tumor functional model using a melanoma cell line. These results connect the phenomena of sleep apnea with increased plasma PSPC1 levels, which has a functional effect on the TGF beta pathway and accelerates tumor progression. As some evidence suggests that hypoxia might be an inducer of nuclear paraspeckle formation, we explore whether intermittent hypoxia (IH)-mediated paraspeckle protein-1 (PSPC1) overexpression might contribute to the activation of tumor growth factor (TGF)beta-SMAD pathway in patients with obstructive sleep apnea (OSA). This activation would promote changes in intracellular signaling that would explain the increased cancer aggressiveness reported in these patients. Here, we show that patients with OSA exhibit elevated PSPC1 levels both in plasma and in monocytes. Our data suggest that PSPC1 is ultimately delivered to the plasma through its cleavage from OSA monocytes by matrix metalloproteinase-2 (MMP2). In addition, IH promotes PSPC1, TGF beta, and MMP2 expression in monocytes through the hypoxia-inducible factor. Lastly, both PSPC1 and TGF beta induce increased expression of genes that drive the epithelial-to-mesenchymal transition. Our study details the mechanism by which hypoxemia upmodulates the extracellular release of PSPC1 by means of MMP2, such that plasma PSPC1 together with TGF beta activation signaling further promotes tumor metastasis and supports cancer aggressiveness in patients with OSA.