Emerging roles of extracellular vesicle-associated non-coding RNAs in hypoxia: Insights from cancer, myocardial infarction and ischemic stroke

Abstract

Hypoxia is a central pathophysiological component in cancer, myocardial infarction and ischemic stroke, which represent the most common medical conditions resulting in long-term disability and death. Recent evidence suggests common signaling pathways in these diverse settings mediated by non-coding RNAs (ncRNAs), which are packaged in extracellular vesicles (EVs) protecting ncRNAs from degradation. EVs are a heterogeneous group of lipid bilayer-covered vesicles released from virtually all cells, which have important roles in intercellular communication. Recent studies pointed out that ncRNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are selectively sorted into EVs, modulating specific aspects of cancer development, namely cell proliferation, migration, invasion, angiogenesis, immune tolerance or drug resistance, under conditions of hypoxia in recipient cells. In myocardial infarction and stroke, ncRNAs shuttled via EVs have been shown to control tissue survival and remodeling post-hypoxia by regulating cell injury, inflammatory responses, angiogenesis, neurogenesis or neuronal plasticity. This review discusses recent evidence on EV-associated ncRNAs in hypoxic cancer, myocardial infarction and stroke, discussing their cellular origin, biological function and disease significance. The emerging concept of lncRNA-circular RNA/ miRNA/ mRNA networks is outlined, upon which ncRNAs synergistically respond to hypoxia in order to modify disease responses. Particular notion is given to ncRNAs participating in at least two of the three conditions, which revealed a large degree of overlaps across pathophysiological conditions. Possible roles of EV-ncRNAs as therapeutic products or theranostic markers are defined.

Figure 1

Brief overview of mechanisms of cellular communication by EVs. miRNAs are formed in the nucleus as pre-miRNAs that are processed to pre-miRNAs and mature miRNAs that are released into the cytosol. ncRNAs containing different RNA motifs are loaded into microvesicles and multivesicular bodies (MVBs) via different RNA-binding proteins. ILVs are formed within MVBs which are released into the extracellular space as exosomes. Recipient cells can take up EV-associated ncRNAs by direct fusion or endocytosis, both of which may be controlled by integrin receptor signaling.

Figure 2

The involvement of EV-ncRNAs derived from the hypoxic tumor in the regulation of the tumor microenvironment. Hypoxic cancer cells can affect recipient cells by transferring ncRNAs via EVs, which, in turn, are taken up by recipient cells and modulate various biological processes including cell proliferation, immune tolerance, angiogenesis and drug resistance, thus facilitating tumor growth and progression.

Figure 3

The involvement of ncRNAs shuttled via EVs in myocardial infarction. Different donor cells can impact recipient cells by transmitting ncRNAs via EVs, which can be taken up by recipient cells and alter various biological responses including cell survival, autophagy, inflammation and angiogenesis, thus regulating myocardial infarction progression and recovery. ADSC, adipose tissue-derived mesenchymal stromal cell; CMC, cardiomyocyte; CPC, cardiomyocyte precursor cell; DC, dendritic cell; EC, endothelial cell; SMC, smooth muscle cell.

Figure 4

The involvement of ncRNAs shuttled via EVs in ischemic stroke. In the central and peripheral nervous system, different donor cells including neurons, microglia, astrocytes and MSCs can regulate recipient cells by transferring various EV-ncRNAs, modulating biological behaviors including neuronal survival, autophagy, inflammation, angiogenesis, neurogenesis and neuronal plasticity, thus modifying ischemic stroke progression and recovery. USC, umbilical cord-derived mesenchymal stromal cell; EC, endothelial cell