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Hypoxia-Induced circRNAs in Human Diseases: History
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Contributor: Zhaowu Ma , Lingzhi Wang ,
, Mingliang You

Hypoxia is the driving force that is responsible for the characteristic metabolic switch from the oxidation of fatty acids in a healthy heart to the utilization of glucose in a failing myocardium. It also promotes the reactivation of fetal gene programs, thereby inducing the cardiac hypertrophy response, changing the composition of the extracellular matrix, and affecting mitochondrial biogenesis, as well as myocardial contractility. Hypoxia-related circRNAs may add to the complexities involved in the regulation of hypoxia-mediated effects, and unraveling the roles played by these circRNAs may provide new directions for the treatment of diverse diseases.

  • circular RNAs
  • hypoxic microenvironment
  • human diseases

1. circRNAs Function as Novel Regulators in Hypoxia

1.1. Basic Features and Functions of circRNAs

The first circRNA to be discovered was a viroid linked by host cell enzymes [1][2]. Subsequently, others were detected in eukaryotic cells using electron microscopy. More recently, the importance of circRNAs in terms of their characteristics and functions have come to the forefront [3]. Owing to their tissue- or developmental stage-specific expressions, circRNAs are promising biomarkers for many human diseases. It was showed that circRNAs can be classified into four types, namely exon-internal circRNA (EIciRNA) [4], exonic circRNAs (ecircRNAs) [5], intronic circRNAs (ciRNAs) [6], and circRNAs produced from tRNAs (tricRNAs) [7].
circRNAs have been found to regulate gene expression and are characterized by several features, including: (i) their highly conserved nature irrespective of the evolutionary distance among species. For instance, approximately 15,000 circRNAs are expressed from mouse and human orthologous loci, representing 40% and 15% of the total circRNAs in mice and humans, respectively; (ii) their high abundance, with expression levels 10 times higher than those of the corresponding linear mRNAs. These molecules are found in fruit flies, mice, plants, archaea, and humans. The balance between circRNA production, nuclear output, and turnover efficiency results in the steady-state abundance of circRNAs [1]; (iii) their tissue- and developmental stage-specific expression profiles [3], (iv) and lastly, their greater stability than linear RNAs, on account of lacking free terminals that confer RNase R resistance and having a covalent closed-loop structure [8].
Several biological functions of circRNAs have been identified, including: (i) the recruitment of various epigenetic factors to coordinate signal transduction and gene transcription [9]; (ii) interactions with target gene promoters and transcription factors or cofactors to regulate gene transcription [10]; (iii) the regulation of the competitive interactions of mRNAs and pre-mRNAs with splicing factors, transfer RNA binding proteins, or miRNAs [11][12]; (iv) the regulation of a protein or RNA modifications to influence their activation and stability [13][14]; (v) and finally, encoding functional peptides that play key roles in various biological processes [15]. Therefore, circRNA-mediated gene regulation is a complex biological process that participates in a diverse array of diseases, thereby providing avenues for the development of prospective therapeutic interventions.

1.2. circRNAs Are New Players for Hypoxic Response

HIF is a transcription factor that senses and adapts to changes in the intracellular oxygen level. It is a heterodimer consisting of an alpha and a beta subunit (the expression of the alpha subunit is oxygen-dependent, whereas the beta subunit is constitutively expressed). Currently, three known alpha subunits (HIF-1α, HIF-2α, and HIF 3α) and a beta subunit (HIF-1β) are known [16][17]. HIFs play relatively more important roles under hypoxic conditions than under normal or high-oxygen conditions [18][19][20][21]. In normoxia, HIF-1α is degraded, and the reports by Ratcliffe and Kaelin showed that prolyl hydroxylases (PHDs) and von Hippel-Lindau (VHL), a tumor suppressor, play important roles in this process. PHD regulates the oxygen-dependent hydroxylation of HIF-1α at two proline residues, namely Pro564 and Pro402. These hydroxylated prolines are recognized by the VHL E3 ubiquitin ligase, and HIF-1α is subsequently ubiquitinated, followed by rapid degradation by the proteasome [18][22]. In hypoxic conditions, PHDs lack access to their co-substrate oxygen and are consequently inhibited. This results in the accumulation of HIF-1α, which subsequently enters the nucleus. In the nucleus, HIF-1α binds to HIF-1β (aryl hydrocarbon receptor nuclear translocator) and activates the associated genes. HIF plays important roles in various physiological and pathological processes, including those associated with immunity, inflammation [22], diabetes [18], atherosclerosis [16], and intestinal disease [19]. To date, a phase III of the HIF-2α inhibitor MK-6482 is underway on advanced clear cell renal cell carcinoma (NCT04195750), suggesting that targeting HIF-2α could be a promising strategy in a clinical setting. Recently, circRNAs have been established as regulators in hypoxia and have been shown to play multifunctional roles in multiple cellular processes. It was focused on the emerging roles of circRNAs in the hypoxic microenvironment.

1.3. Emerging Roles of circRNAs in Pathological Responses to Hypoxia

It has been conclusively proven that circRNAs are related to the pathogenesis of various diseases affecting the cardiovascular, pulmonary, nervous, and gynecological systems. Under hypoxia, these molecules play fundamental roles in disease progression via unique mechanisms [23][24].
The physiological and pathological processes of many cardiac diseases are affected by hypoxia. Hypoxia is the driving force that is responsible for the characteristic metabolic switch from the oxidation of fatty acids in a healthy heart to the utilization of glucose in a failing myocardium. It also promotes the reactivation of fetal gene programs, thereby inducing the cardiac hypertrophy response, changing the composition of the extracellular matrix, and affecting mitochondrial biogenesis, as well as myocardial contractility. Hypoxia-related circRNAs may add to the complexities involved in the regulation of hypoxia-mediated effects, and unraveling the roles played by these circRNAs may provide new directions for the treatment of cardiovascular diseases [25]. The first is to reveal the biological function of a circRNA in the heart was published in 2016 [26]. Subsequently, Li et al. discovered that circNCX1 was related to cardiomyocyte apoptosis induced by oxidative stress. This effect is mediated by the sponging of miR-133a-3p by circNCX1, which decreases the inhibitory activity of the proapoptotic gene encoding the cell death-inducing protein and promotes myocardial ischemia–reperfusion (I/R) injury and apoptosis [27]. Cdr1as (or CiRS-7) has been shown to be significantly upregulated in cardiomyocytes undergoing either hypoxia treatment or myocardial infarction, where it regulates the expression of SP1 and PARP by sponging miR-7a to promote cardiomyocyte apoptosis [28]. Similarly, circ-Ttc3 is upregulated in hypoxic-ischemic cardiomyocytes. A knockdown of circ-Ttc3 promotes hypoxia-induced apoptosis and ATP consumption. These findings indicate that the circ-Ttc3/miR-15b/Arl2 axis can protect the heart during myocardial infarction [29]. Du et al. demonstrated the high-level expression of circ-Foxo3 in the heart, which is related to cellular senescence, and the knockdown of circ-Foxo3 inhibited senescence in fibroblasts. Mechanistically, circFoxo3 harbors binding sites for various proteins and interacts with E2F1 (E2F transcription factor 1), FAK (focal adhesion kinase 1), anti-stress transcription factor ID1 (DNA-binding protein inhibitor ID-1), and HIF-1α to promote cell senescence. Additionally, the ectopic expression of circ-Foxo3 induces senescence [30]. Another is demonstrated that hsa-circ-000595 expression is significantly upregulated in hypoxic aortic smooth muscle cells and promotes apoptosis in the same by adsorbing miR-19a [31]. Thus, circRNAs exert negative or protective influences on the progression of cardiac remodeling by various mechanisms. An in-depth understanding of the circRNA-induced mechanisms may, therefore, provide novel ideas for the treatment of heart diseases.

2. Functions of circRNAs in Hypoxic Microenvironments

2.1. Hypoxic circRNAs in Cancer Progression

Recently is has been indicated that circRNAs regulate cancer progression by regulating various hypoxia-related molecules. For instance, Wei et al. reported that circ-CDYL is upregulated in HCC and is a competing endogenous RNA for miR-328-3p and miR-892a via its interactions with mRNA encoding hypoxia-inducible factor 1-α inhibitor (HIF1AN) and hepatoma-derived growth factor (HDGF). The subsequent activation of the PI3K-AKT serine/threonine kinase mTOR kinase complex 1/β-catenin and NOTCH2 pathways promotes the expression of the effector proteins, baculoviral IAP repeat containing 5 (BIRC5 or SURVIVIN), and MYC proto-oncogene. Therefore, the overexpression of circ-CDYL results in the self-renewal and malignant proliferation of liver cells [32]. Another was demonstrated that the overexpression of cytoplasmic circPIP5K1A promotes the proliferation and metastasis of NSCLC, since it adsorbs miR-600, which interacts with the 3′-untranslated region (UTR) of HIF-1α [33]. A similar one showed that circ-HIPK3 is upregulated in CC cells, where it functions as a miR-338-3p sponge to subsequently upregulate the expression of HIF-1α, thereby contributing to the progression and metastasis of CC [34]. CircC6orf132 promotes gastric cancer proliferation, migration, invasion, and glycolysis under hypoxic conditions. Mechanistically, CircC6orf132 adsorbs miR-873-5p and elevates the expression of PRKAA1, a protein kinase AMP-activated alpha 1 catalytic subunit [35]. circSETDB1, a hypoxic tumor-derived exosomal circRNA, is upregulated in lung adenocarcinoma (LUAD), which is associated with the LUAD stage in serum exosome patients. circSETDB1 promotes LUAD development and EMT via the miR-7/Sp1 axis [36]. Feng et al. reported that hsa-circ-0000211 is upregulated in LUAD cells and promotes the migration of LUAD via the miR-622/HIF1-α axis [37]. Additionally, Su et al. confirmed that hypoxia promotes the expression of circDENND2A in gliomas. Functional assays indicate that circDENND2A promotes the invasion and migration of gliomas by sponging miR-625-5p [38]. Furthermore, Liang et al. demonstrated the elevation of the circDENND4C levels in breast cancer cells. In vitro assays have established that silencing circDENND4C inhibits the proliferation of breast cancer cells in hypoxic microenvironments [39]. circZFR is another circRNA that promotes the malignant progression of breast cancer. The silencing of circZFR inhibits BC cell viability, colony formation, migration, invasion, and glycolysis via the miR-578/HIF1A axis [40]. A recent one revealed that circHIF1A (hsa_circ_0004623) promoted cancer cell proliferation and metastasis in triple-negative breast cancer (TNBC). Mechanistically, circHIF1A regulates the expression and translocation of NFIB through post-transcriptional and post-translational modifications, resulting in activation of the AKT/STAT3 signaling pathway and the repression of P21. The RNA-binding protein FUS regulates the biosynthesis of circHIF1A by interacting with flanking introns, and FUS is transcriptionally regulated by NFIB, forming a circHIF1A/NFIB/FUS positive feedback loop [41].

2.2. Hypoxic circRNAs Regulate Therapeutic Resistance

Currently, cancer treatment is synonymous with chemotherapy, radiotherapy, and immunotherapy. However, radiotherapy and chemotherapy have many limitations, including disease relapse and metastasis due to the development of therapeutic resistance [42]. These effects in patients undergoing radiotherapy and chemotherapy may be related to primary, secondary, or acquired resistance [43]. Extrinsic factors within the tumor microenvironment that promote resistance to chemoradiotherapy include hypoxia, the extracellular matrix, and angiogenesis. circRNAs may also potentially play a role in these processes [3]. Several it has been demonstrated an association between circRNAs in hypoxic tumor microenvironments and resistance to radiotherapy and chemotherapy, which culminates in adverse clinical outcomes.

2.3. Hypoxic circRNAs Regulate Angiogenesis

Blood vessels provide nourishment and oxygen to tissues in the human body and are lined by endothelial cells (EC). While those in a healthy human body are stable, the formation of new blood vessels is aggressively promoted to deliver nutrients and oxygen to hypoxic tissues under pathological conditions [44]. Angiogenesis is a complex multi-step process that is stimulated by various proangiogenic factors (such as vascular endothelial growth factor, VEGF), where the original dynamic balance of the vascular network is perturbed, the capillary basement membrane is degraded, and the ECs migrate and proliferate, resulting in the formation of new primary capillary networks [45][46]. Angiogenic factors, including members of the VEGF family, such as vascular endothelial growth factor A (VEGFA), and the vascular endothelial growth factor receptor (VEGFR) family, promote EC migration and proliferation. Several have been demonstrated that hypoxia-responsive circRNAs affect the proliferation or apoptosis of ECs by regulating the downstream targets [47][48]. Here, it was summarized that the available one on the regulation of ECs by hypoxia-related circRNAs (Figure 3C).
VEGFA, a key regulator of angiogenesis, is regulated by certain oncogenes and transcription factors (HIF-1) during hypoxic stress [49]. The activation of VEGFR-1 and VEGFR-2 mediates the proangiogenic activity of VEGFA [50]. It has been demonstrated that circRNAs can induce phenotypic changes as a part of hypoxic regulation. For instance, Boeckel et al. reported that cZNF292 promoted angiogenesis in hypoxia in vitro. The overexpression of cZNF292 resulted in increased globular sprouting and the tube formation of ECs [47]. Furthermore, circ-Erbin facilitates angiogenesis via the miR-125a-5p-5p/miR-138-5p/4EBP-1 axis and contributes to HIF-1α activation in CRC [51]. circRNAs can positively or negatively modulate the proliferation of ECs in hypoxic microenvironments by adsorbing miRNAs or by directly acting on VEGFA. For instance, the overexpression of cZBTB44 promotes EC viability, proliferation, migration, and tube formation under hypoxic stress in vitro. Mechanistically, cZBTB44 increases the expression of VEGFA and vascular cell adhesion molecule 1 (VCAM1) by competitively binding to miR-578 in order to regulate EC functions [48]. Similarly, hsa-circ-0007623 expression is elevated in human umbilical vein endothelial cells (HUVECs) under hypoxia stress, which facilitates EC proliferation, migration, and angiogenesis. Further, the sponging of miR-297 by hsa-circ-0007623 promotes VEGFA expression. The hsa-circ-0007623/miR-297/VEGFA axis aids in the repair of the heart after acute myocardial ischemia and plays a protective role [52]. On the contrary, cZFP609 inhibits endothelial angiogenic function in response to hypoxia. Mechanistically, exosomal cZFP609 is delivered to ECs from the VSMCs, thereby suppressing angiogenesis post-ischemia via the inhibition of HIF-1α activation [53].
circRNAs are also known to exert their modulatory effects on EC via other molecules (MEF2A, IGF-1, and HIF-1α). cZNF609 is upregulated in low-oxygen and high-glucose environments and enhances the expression of its downstream target MEF2A by competitively binding to miR-615-5p. The cZNF609/miR-615-5p/MEF2A axis has been confirmed to inhibit the tube formation, proliferation, and migration of ECs [54]. Dang et al. found that hsa-circ-0010729 interacts with miR-186/HIF-1α to promote the proliferation and migration of HUVECs [55]. Furthermore, the expression of circHIPK3 is elevated under oxidative conditions in vitro. circHIPK3 adsorbs miR-29a to promote the expression of IGF-1, thereby reducing CMVEC dysfunction induced by oxidative stress [56].

2.4. Hypoxic circRNAs Influence Energy Metabolism

The energy metabolism of tumor cells differs from that of normal cells in that they preferentially utilize glucose. This is known as the Warburg effect, which results in increased glycolysis and lactic acid production irrespective of the oxygen availability [57]. The Warburg effect is considered one of the emerging signs of cancer, as it endows tumor cells with specific metabolic characteristics while rendering them resistant to apoptosis and rapid growth [58]. Hypoxia signals induce tumor cells to reprogram gene expression and metabolic activities via the transcriptional regulation of HIFs. Reprogramming of the glucose flux is critical in establishing the tumor microenvironment, since it results in the elevation of the HIF-1α levels in response to hypoxia in rapidly growing cancer cells [59].
circRNAs influence the energy metabolism by regulating a series of signal transduction pathways in the pathological responses to hypoxia (Figure 3D). For instance, circMAT2B was reported to be upregulated in HCC, where it sequesters miR-338-3p and upregulates the downstream gene, PKM2. PKM2, in turn, encodes a key enzyme involved in glycolysis and HCC progression [60]. Another one confirmed that circRNF20 was markedly upregulated in breast cancer and promoted the Warburg effect and cellular proliferation. Mechanistically, circRNF20 competitively binds to miR-487a and elevates HIF-1α expression and promotes the transcription of hexokinase II (HK2), thereby regulating the Warburg effect and proliferation of breast cancer cells [61]. CircDENND4C is another hypoxia-related circRNA that regulates breast cancer glycolysis. Functional assays indicate that circDENND4C is upregulated in breast cancer. Mechanistically, circDENND4C promotes glycolysis in, as well as the invasion and migration of, breast cancer in hypoxic microenvironments by competitively binding to miR-200b and miR-200c [62].

2.5. Other Regulations by Hypoxic circRNAs

Preliminary investigations have highlighted the role of circRNAs in hypoxic microenvironments of tumors but have not yet elucidated the detailed mechanisms of their actions. For example, 65 circRNAs were identified to be differentially expressed in hypoxic lung cancer cells. Among them, circFAM120A (hsa-circ-0008193) is downregulated and may be involved in the occurrence of lung cancer [63]. It was indicated that 12 circRNAs may be involved in the development of osteosarcoma. A functional analysis revealed that hsa-circRNA-103801 is involved in multiple cancer pathways, including the VEGF, angiogenesis, and HIF-1 pathways [64]. Additionally, using an analysis pipeline, Di Liddo et al. found that the expression of 64 circRNAs are markedly altered upon exposure to hypoxic stress in the tumor microenvironment [65]. Although it is on the mechanisms of circRNA actions in cancer cell lines in hypoxic microenvironments is limited, hypoxia-related circRNAs have been confirmed to contribute to the complex pathogenesis of tumors. Future one is essential to reveal the mechanistic details of hypoxia-related circRNA functions in various diseases, which may potentially be exploited as biomarkers or therapeutic targets in clinical applications.

3. Potential Clinical Applications of circRNAs in Human Diseases

The current methods used for the early detection of cancer, including those that utilize levels of blood biomarkers, carcinoembryonic antigen, and prostate-specific antigen, lack specificity and sensitivity. This severely limits the early diagnosis and treatment of cancer patients. Recently, the detection of circRNAs in tumor biopsies has generated considerable interest [66]. With the widespread use of high-throughput RNA sequencing (RNA-seq), many circRNAs have been postulated to be potential diagnostic biomarkers [3][67]. The characteristics and expression patterns of circRNAs (conservation, specificity, versatility, and stability) make them ideal biomarker candidates [3]. Additionally, circRNAs are found abundantly in saliva and blood samples, which renders sampling and detection easier. Consequently, utilizing circRNAs as disease biomarkers in terms of the early diagnosis, treatment selection, and prediction of recurrence has gradually become a hotspot [68]. Hypoxia-related circRNAs can be exploited not only as biomarkers but also as potential therapeutic targets. For instance, the combination of circ-CDYL with HIF1AN and HDGF has been shown to be an effective biomarker for HCC, with odds ratios of 1.09 (95% confidence interval (CI), 1.02−1.17) and 124.58 (95% CI, 13.26−1170.56), respectively [32]. It has been indicated that circ-calm4 and mmu-circ-0000790 may be utilized as promising biomarkers for HPH [69][70].
As circRNAs promote or suppress disease progression, strategies that involve the specific targeting of circRNAs may be promising clinical therapeutic options. Currently, RNA-based therapies primarily utilize RNA interference (RNAi) and antisense oligonucleotides, which are designed to target specific regions and diverse RNAs. Gene silencing or overexpression approaches may be used to target circRNAs in preclinical one. Specific shRNAs or siRNAs have been used to target the post-splice junction or the intronic sequences of intron-circularized circRNAs. This process involves the meticulous designing of complementarily paired siRNAs to knock down circRNA expressions [71][72]. For suppressive circRNAs, overexpression vectors that foster back-splicings consist of flanking introns with reverse complementary sequences and circRNA-forming exons [73]. This provides a new repertoire of candidates for RNA-founded therapeutics that target specific circRNAs. Therefore, targeting circRNAs in hypoxic microenvironments may broaden therapeutic strategies for many complex and heterogeneous diseases. For instance, circPIP5K1A and circDENND4C may be promising therapeutic targets for NSCLC and breast cancer, respectively, in hypoxia [33][62]. Additionally, cZBTB44 may be a promising therapeutic target for vascular injury and neovascularization-related diseases induced by hypoxic stress [48]. Therefore, circRNAs are promising therapeutic targets that can be used to promote the development of alternate treatment strategies for multiple disorders.

This entry is adapted from the peer-reviewed paper 10.3390/cells11091381

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