Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Abstract

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)β-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, TGFβ, and MMP2 expression in monocytes through the hypoxia-inducible factor. Lastly, both PSPC1 and TGFβ 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 TGFβ activation signaling further promotes tumor metastasis and supports cancer aggressiveness in patients with OSA.

SMAD4 Expression in Monocytes as a Potential Biomarker for Atherosclerosis Risk in Patients with Obstructive Sleep Apnea

“…Moreover, we found that IH could be underlying SMAD4 upregulation in OSA patients, since in vitro exposure to IH is capable of inducing SMAD4 upregulation in healthy monocytes, contributing to its release to the extracellular space in a HIF-1α dependent manner. These results are in line with previous studies reporting an upregulation of the TGF-β/Smad4 pathway upon IH conditions both in in vitro and animal models [23,35,56]. Taken together, this data suggests monocytes as the potential source of sSMAD4 in the plasma.…”

“…In this context, a plethora of studies showed that TGFβ1/Smad signaling pathway played a central role in cardiovascular and cerebrovascular diseases, including atherosclerosis [16,17,[44][45][46][47]. Interestingly, it is reported that the TGF-β pathway is upregulated in OSA patients, and its activity is related to the hypoxemia severity [23,24,[48][49][50][51]. Although TGF-β has been classically defined as an anti-inflammatory cytokine, its role in inflammation has been recently reviewed [27,52].…”

“…On the other hand, the TGF-β pathway could also limit atherosclerosis progression by modulating the inflammatory response and preventing lipid accumulation in the vessel wall [22]. Interestingly, OSA patients frequently present an increase in TGF-β levels [15,23,24] suggesting that the pathways dependent on its activation could play a role in the high rates of atherosclerotic patients among OSA subjects.…”

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

“…It is now widely accepted that hypoxia enhances the malignant properties of tumors, and can strongly influence tumor growth, differentiation and migration [ 69 , 70 ]. Several studies have identified specific patterns of miRNA dysregulation in human cancers, including melanoma [ 61 , 71 , 72 ].…”

Asociación de apnea obstructiva del sueño y cáncer. Un nuevo modelo para el enfoque de la comorbilidad

“…Así, se ha descrito que los pacientes apneicos jóvenes y no obesos experimentan una mayor activación de la cadena de señalización intracelular TGF-β-SMAD, que constituye una de las principales vías reguladoras de la progresión de células cancerígenas 13 . Este efecto parece deberse a la mayor inducción, mediada por la hipoxia intermitente, de la expresión de PSPC1 (paraspeckle component 1), un integrante de la cromatina del núcleo celular que regula la transición epitelio-mesénquima y la adquisición de características similares a las CSC (cancer stem cells), elementos clave para el desarrollo de metástasis 14 . Este fenómeno también resulta relevante en enfermos con un cáncer ya establecido.…”