Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)
- Authors:
- Published online on: June 26, 2018 https://doi.org/10.3892/ijmm.2018.3744
- Pages: 1203-1214
Abstract
1. Introduction
Prostaglandin E2 (PGE2) receptor 2 subtype (EP2) is a G protein-coupled plasma membrane receptor for PGE2, which acts through numerous signaling pathways to regulate various physiological functions, including tumor occurrence, invasion and metastasis, angiogenesis, chronic inflammation, tumor immunity and cell apoptosis (1). Recently, various studies have focused on identifying the specific EP2 receptors and signaling pathways that regulate the pleiotropic activities of the cyclooxygenase-2 (COX-2)/PGE2/EP2 pathway (2-5).
Over the past 10 years, COX-2 and its prostaglandin products have attracted increasing attention due to their important roles in the progression of tumors of the lung, head and neck, prostate, colon, ovary, chest and liver (2,6–8). However, inhibition of COX-2 using non-steroidal anti-inflammatory drugs (NSAIDs) and specific COX-2 inhibitors is associated with various side effects, including gastric ulcers and myocardial infarction (9), which have limited the use of these drugs (10). As a primary prostanoid derived from COX-2, PGE2 can also promote the activities of tumor cells (11); therefore, inhibition of the biological activities of PGE2 at different levels may maintain the anticancer properties of COX-2 inhibition and also help prevent side effects (12). Among four pharmacologically different G protein-coupled plasma membrane receptors of PGE2, the EP2 subunit is an important mediator of numerous physiological and pathological processes, and may be the most useful targeted receptor in anticancer treatment (13). The present review aimed to highlight the potential role of EP2 in cancer (Fig. 1).
2. Structure of the EP2 receptor
EP2 (53 kDa) (14) is a PGE2 receptor encoded by the human PTGER2 gene. The PTGER2 gene contains two introns and three exons, and is located on human chromosome 14 at position p22.1 (14q22.1) (15).
The human EP2 receptor consists of 358 amino acids, whereas the mouse EP2 receptor consists of 632 amino acids (16). It belongs to the family of G protein-coupled receptors (GPCRs), which constitute a large protein family of receptors that detect molecules outside the cell and activate internal cellular responses (17). EP2 is an integral membrane protein that has an extracellular N-terminus and an intracellular C-terminus (18,19). It has seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular (EL-1 to EL-3) loops (20). The EP2 is bound to a heterotrimeric G protein complex consisting of the G stimulatory (Gsub.) α and the tightly associated Gβγ subunits (21,22). Binding of an agonist to EP2 results in activation of the Gsα subunit, which regulates the cAMP-dependent pathway by stimulating the production of cAMP from ATP (23) (Fig. 2). Both EP2 and EP4 are bound to Gsα subunits (24).
3. Biological activity of the EP2 receptor
The expression of EP2 receptor EP2 is widely distributed in humans (25)
The EP2 protein is expressed in the human small intestine, lung, media of arteries and arterioles of the kidney, thymus, uterus and cerebral cortex (26). In addition, its mRNA is widely expressed in fibroblasts, aorta, the corpus cavernosum of the penis and articular cartilage, among others (27-29) (Fig. 3). In rats, EP2 receptor protein and/or mRNA have been detected in the lung, spleen, intestine, skin, kidney, liver, long bones, and rather extensively throughout the brain and other parts of the central nervous system (30). Therefore, the EP2 receptor appears to serve a key role in biological development.
Desensitization
Activated GPCRs can be phosphorylated by G protein-coupled receptor kinases (GRKs) (31), which modifies G protein-dependent signaling by initiating receptor desensitization, internalization and resensitization (32). However, EP2 differs from all other prostaglandin receptors in that it does not undergo homologous desensitization (33). When EP4 is expressed in Chinese hamster ovary cells, EP4 receptors are found to undergo rapid PGE2-induced desensitization, which is not observed with EP2 receptors (32). Due to its failure to become desensitized, EP2 can act over more prolonged periods of time compared with other prostaglandin receptors and, therefore, may be able to contribute to more delayed and chronic phases of cellular and tissue responses (34).
Positive feedback regulation
PGE2 signaling through EP2 can in turn boost expression of COX-2 in polyp tissues (35), and it has been suggested that EP2 may regulate phosphorylated (p)-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), p-protein kinase B (Akt) and p-glycogen synthase kinase 3β (GSK-3β) expression, and increase nuclear translocation of β-catenin in LoVo cancer cells (36). The levels of the cofactors lymphoid enhancer-binding factor-1 (LEF-1) and transcription factor 4 (TCF-4) have also been reported to be upregulated by EP2 in the nucleus, resulting in upregulation of COX-2 expression (37). Using genetically engineered animal models lacking EP2, or using EP2 antagonists in animals and animal and human tissues, it has been reported that a lack of EP2 may downregulate the expression of p-PI3K, p-Akt and p-GSK-3β, and reduce the levels of β-catenin and cofactors LEF-1 and TCF-4 (5,38,39). Therefore, inhibition of EP2 may reduce the proliferation and invasion of cancer cells.
4. Regulating the function of the EP2 receptor in cancer
The function of the EP2 receptor
Numerous studies have demonstrated that EP2 is abnormally expressed in cancer, including colon, prostate, liver and breast cancer (5,40–43) (Fig. 4). Furthermore, EP2 is associated with poor survival in chronic obstructive pulmonary disease (Fig. 5). The aberrant expression of EP2 has been found to be closely associated with factors associated with cancer development, including chronic inflammation, immunoregulation, angiogenesis, metastasis and multidrug resistance.
EP2 induces chronic inflammation
It was recently demonstrated that inflammation serves a key role in cancer, and ~60% of cancers are associated with inflammation (44). The inflammatory response may create a partial microenvironment that promotes alterations in the genome and stimulates the formation of tumors. Some tumor cells release cytokines and chemotactic factors to attract monocytes and macrophages (45). The infiltrating macrophages in turn secrete growth factors to promote tumor progression, recruit secondary leukocytes, and enhance and maintain the interaction between inflammatory and tumor cells (46).
As a main inflammatory mediator derived from COX-2, PGE2 can induce several proinflammatory factors, including cytokines, chemotactic factors, inducible nitric oxide synthase (iNOS) and even COX-2 (47). These factors can promote cell proliferation, survival, angiogenesis, invasion, migration and metabolism (48). In addition, EP2 activation can significantly induce the expression of proinflammatory factors, such as interleukin (IL)-1β and IL-6 in tumor cells (42,49). IL-1β can promote tumor growth, invasion and angiogenesis (50). Under normal conditions, IL-6 levels are increased in patients with several types of cancer, including prostate, colon, breast and ovarian cancer (51). The PGE signals initiated by EP2 or EP4 can exacerbate symptoms of inflammation by increasing the expression levels of IL-23, and decreasing the levels of IL-12 and IL-27 (52). PGE, together with IL-1β and IL-23, promotes the differentiation and cytokine expression of T helper (Th)17 cells (53). Recent research has revealed that hepatic stellate cells increase the numbers of Th17 cells and regulatory T cells via the PGE2/EP2 pathway (54). Hepatic Th17 and regulatory T cell numbers are also increased in patients with advanced-stage hepatitis B virus-associated liver fibrosis, which potentially leads to hepatocellular carcinoma (55,56). In addition, PGE signals can affect the skin microenvironment through enhancing blood flow by regulating ultraviolet (UV)-induced acute skin inflammation (57,58). As a result, small-molecule antagonists of EP2 can mitigate chronic inflammation in tumor tissues to provide an anti-inflammatory mechanism for the treatment of cancer (56).
In colon tumors, EP2 is expressed by infiltrating neutrophils and tumor-associated fibroblasts in the stroma (39). The expression levels of tumor necrosis factor-α (TNF-α), IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), COX-2, and other proinflammatory genes acting synergistically with TNF-α, are upregulated by EP2 (42,49). These results indicate that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by exerting a proinflammatory effect and regulating the tumor microenvironment (59,60).
EP2 contributes to cancer immunotherapy resistance
Since EP2 has an important role in the differentiation of DCs (3), and it also has an important role in the function and immunoregulation of PGE2 suppression; therefore, the elimination of EP2 receptors can suppress the growth of tumors and prolong survival (7). PGE2 contributes to immune evasion and cancer immunotherapy resistance by suppressing the function of macrophages, neutrophils and Th1 cells. PGE2 also markedly inhibits the production of Th1 cytokines, including interferon-γ (IFN-γ), TNF-α and IL-2 (61). The immunoregulation of PGE2 is initiated through EP2 receptor signaling. Activation of EP2 can downregulate the expression of IFN-γ and TNF-α by immune cells, such as natural killer T cells, neutrophilic granulocytes and macrophages (62), and adversely affects the immunocompetence of these immune cells (47).
The signals initiated by the EP2 receptors can be transduced by the same Gsα stimulating protein and the concentration of cAMP in cells is increased by activation of EP2 (63). Cluster of differentiation (CD)4+ Th cells are a key effector in the adaptive immune system to control cancer (64) and the increase in cAMP is associated with a decrease in Th1 cells and IFN-γ (65). In addition, PGE2 can suppress the activities of natural killer cells and cytotoxic T lymphocytes, which are part of antitumor immunity (66).
Apart from the direct suppression of immune cell activities, EP2 signaling can promote the development of regulatory T cells, which are efficient inhibitors of the immune system and can suppress the activity of numerous immune cells, including DCs (67). DCs have a key role in the initiation of the tumor-specific immune response (52). The signals of EP2 (and EP4) not only block DC activity, but can also block the generation of DCs, resulting in development of the immuno-suppression of myeloid-derived suppressor cells (68).
Knockout of the EP2 receptor can reduce tumor progression and prolong the survival of mice injected with MC26 or Lewis lung carcinoma cells (69). This mechanism appears to be associated with the failure of PGE2 to suppress differentiation of DCs, leading to induction of the antitumor cytotoxic T-lymphocyte response (70). In a mixed lymphocyte model of the cellular immune response, it was reported that EP2 and EP4 could regulate the functions of antigens, indicating that EP2 receptors can directly inhibit immune cell proliferation (71).
EP2 increases angiogenesis
EP2 can induce angiogenesis in cancer, whereas the deletion of EP2 receptors can down-regulate the expression of angiogenic factors, including vascular endothelial growth factor (VEGF), and inhibit tumor angiogenesis (72). Apart from VEGF induction by EP2 activation, EP2 signaling in endothelial cells can regulate the activity and survival of endothelial cells and promote tumor angiogenesis in vivo (73). PGE2 signaling triggers hyperplasia of the mammary gland and regulates VEGF induction in breast tumors in mice (53). In addition, EP2 signaling can directly regulate tumor angiogenesis and survival by enhancing the activity of epithelial cells (1,74). It can also regulate hypertrophy and tumor invasion as a response to UV stimulation and induce the growth of skin tumors (57). In addition, PGE2 facilitates tube formation through EP2 signaling (23), indicating the involvement of EP2 in luteal angiogenesis and the progression of ovarian cancer (75).
EP2 promotes tumor invasion and metastasis
In addition to its association with angiogenesis and immune suppression in cancer, a recent study demonstrated that EP2 receptor activation by PGE2 significantly enhances hepatocellular carcinoma cell invasion and migration by upregulating the expression levels of Snail (76). It has also been demonstrated that treatment with various concentrations of prostaglandin promotes the migratory ability of human LoVo colon cancer cells via the EP2 receptor (40).
The PI3K signaling pathway has a key role in the regulation of cell proliferation, differentiation, migration and trafficking (77). The PI3K/Akt cell survival pathway has been revealed to be upregulated by EP2 and EP4 activation (78,79), thereby upregulating the level of matrix metalloproteinases, which has been observed in several types of human cancer and regulates the efficacy of various therapies (5). In breast cancer, EP2 receptors are also associated with metabolism, which may alter the response of cells to transforming growth factor-β (TGF-β), which can maintain the balance of tissues by inducing cell cycle arrest, differentiation and apoptosis (80). However, during tumorigenesis, genetic and epigenetic events convert TGF-β from a tumor suppressor to a promoter of cell growth, invasion and metastasis (16). The altered response to TGF-β may be attributed to the suppression of TGF-β-induced Smad2/3 nuclear localization and signaling by PGE2, followed by uncoupling TGF-β from activating Smad3 (16).
In addition, EP2 has been reported to regulate metastasis via downregulation of solute carrier family 19 member 3 in triple-negative breast cancer (81). In addition, EP2 ablation suppresses skin tumor development by limiting angiogenesis and promoting apoptosis (82-84), whereas the overexpression of EP2 accelerates skin tumor development. EP2 also accelerates the invasion of prostate tumor cells, which is inhibited by the EP2 antagonist, TG4-155 (85). In laryngeal carcinoma, upregulated EP2 expression has been detected in highly aggressive tumors, which are identified by deeper invasion of the submucosa or cartilage (86).
EP2 promotes multidrug resistance (MDR) in cancer
Epidermal growth factor receptor (EGFR) is also involved in the pathogenesis and development of various types of cancer (87). The activation of EGFR accelerates the uncontrolled proliferation and metabolism of cancer cells (88), whereas an inhibitor of EGFR can be used to treat non-small cell lung cancer, and pancreatic, breast and colon cancer (89). Despite the initial dynamic response to these inhibitors, the majority of patients ultimately develop resistance to therapy (90). It has been reported that PGE2 results in tyrosine kinase inhibitor resistance in some patients with cancer through EP2 transactivation of EGFR (91). Although the potential underlying mechanism remains unclear, accumulating evidence suggests that PGE2 is associated with MDR in cancer (92). However, clinical trials combining specific COX-2 inhibitors, including celecoxib and aproxicoxib, with EGFR inhibitors, such as erlotinib, have not produced promising results. By contrast, they result in toxicity in a proportion of patients (91,93). Therefore, more studies are required to elucidate how to use the EP2 receptor as a target to attenuate MDR in cancer.
5. Involvement of EP2 receptor signaling pathways in cancer
EP2 receptor signaling pathways
An increasing number of studies has demonstrated that EP2 regulates cancer development various signaling pathways (Fig. 6).
EP2 receptors mediate second messenger signaling
As a Gs-coupled receptor, EP2 activation by PGE2 can activate adenylate cyclase, thus resulting in an increase in cAMP levels and protein kinase A (PKA) activation. In response to cAMP binding, PKA activates and phosphorylates downstream transcription factors, including cAMP response element-binding protein (CREB), which regulate a wide range of biological processes. In cells expressing EP2, 1 µM PGE272 is activated to form cAMP (94). In addition, aromatase-dependent estrogen synthesis is associated with hormone-dependent breast cancer (81), and EP2 can regulate the cAMP/PKA/CREB pathway, in turn regulating cytochrome P450 aromatase (75).
EP2-Gs-axin-pathway
EP2 can also activate the GSK3β and β-catenin pathways, in turn increasing the transcription of several genes associated with cancer, including c-myc, cyclin D1 and VEGF. When PGE2 activates EP2, a Gs subunit directly binds with a structural region, also referred to as the regulator of G protein signaling (RGS). As a consequence, it can promote the release of GSK-3β (95). Furthermore, EP2 receptors activate β/γ subunits to release Gαs subunits and stimulate Akt by PI3K, resulting in the phosphorylation and inactivation of GSK-3β (96). However, this inactivation can lead to the accumulation of β-catenin in the cytoplasm and migration to the cell nucleus, where it can interact with TCF and LEF to activate genetic transcription promoting tumor growth (57).
Castellone et al (39) reported that EP2 receptors are involved in the PI3K/Akt and axin/β-catenin pathways activating colon tumor growth. It was revealed that when the Gαs subunit was bound to the RGS domain, free G protein β/γ subunits could stimulate PI3K and Akt to activate β-catenin and proliferation of DLD-1 cells, resulting in the mutation of adenomatous polyposis coli (APC) genes. It appears that GPCR signaling pathways can interact with APC-β-catenin-TCF. Numerous proteins, including Dsh, axin, GSK-3β and APC, are involved in the Wnt pathway and can interact with G proteins (39).
Crosstalk with other signaling pathways
It has been demonstrated that EP2 can activate G protein-independent signaling pathways through the formation of EP2 and β-arrestin complexes. β-arrestin serves as a regulator that switches signals to G protein-independent signaling pathways (97). It was recently reported that EP2 can regulate β-arrestin signaling to initiate the PI3K, Akt, Src, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and EGFR pathways; therefore, it may have an important role in the proliferation and migration of cells. Through PI3K and Akt, rather than through conventional cAMP signaling, EP2 can inhibit the occurrence of tumor immunity (98).
Previous studies have demonstrated that the crosstalk between EP2 and EGF pathways increases the complexity of the EP receptor pathways (97,98). EGFR is located on the surface of cells and can activate EGF and TGF-α through binding with ligands. EP receptors promote the transactivation of EGFR and involve activation of c-Src genes. Phosphorylation can directly or indirectly activate EGFR and EGFR ligands, in order to stimulate the EGFR signaling network. Activation of EGFR can activate several signal transduction pathways, including mitogen-activated protein kinase, PI3K/Akt, signal transducer and activator of transcription and phospholipase C, thus leading to the proliferation, differentiation, migration and survival of cells. iNOS, ERK1/2 and EP2 can be activated through indirect activation of EGFR to promote the growth of squamous cell tumors (93). In addition, β-arrestin can cause the phosphorylation of JNK, upregulate profilin 1, increase the expression of f-actin, and promote the migration and proliferation of tumor cells (99).
In conclusion, these signaling routes in the nucleus promote the expression of genes associated with the growth, survival, immune evasion, angiogenesis, infiltration and metabolism of cancer cells.
6. Regulation of EP2 receptor signaling by genetic engineering
Genetic ablation strategies and biochemistry studies provide tools for elucidating EP2 signaling. In addition, studies in EP2-knockout mice suggest that EP2 signaling has a key role in cancer (59,60). A recent study on EP2-null mice undergoing a two-stage chemical carcinogenesis protocol revealed that EP2-null mice may develop fewer tumors (50%) and smaller tumors compared with in wide-type mice. In addition, macrophage infiltration was decreased, as was the expression of IL-1α in the epidermis, and angiogenesis. Mice deficient in EP2 receptors also exhibit low incidence rates of lung, skin and breast cancer (59).
Gene knockout strategies have been used to study the potential functions of EP2 in colon cancer. In a mouse model of familial adenomatous polyposis, a genetic ablation in EP2 resulted in an ~100% incidence of colon cancer. Although genetic ablation of the EP2 receptor does not affect the formation of aberrant crypts, it affects the formation of polyps and tumor angiogenesis through Wnt/β-catenin pathway (59). In addition, genetic ablation of EP2 reduces the size and number of intestinal polyps in APC1309 mice, simulating the gene disruption or inhibition of COX-2 in the same model. Similar to Min mice, APCD716 mice also harbored a mutation in the same tumor suppression gene, which may result in the development of colon cancer (39).
In order to investigate the major gene expression alterations in tumor tissues, in a previous study, EP2-knockout mice were implanted with EP2+/+ epithelial-like tumors. As a result, tumor growth, acute inflammation and IL-6 expression were suppressed in EP2-knockout mice. The expression of several genes, including long non-coding RNAs, was also decreased in tumors from the EP2-knockout mice (2).
7. Development of agonists, antagonists and targeted drugs for EP2
The following standard prostaglandins can activate EP2, with a binding efficacy in the following order: PGE2>PGF2α≥PGI2>PGD2 (100). Receptor-binding affinity, expressed as the dissociation constant, is ~13 nM for PGE2 and ~10 nM for PGE1 for the human receptor, and ~12 nM for PGE2 for the mouse receptor (101).
Apart from endogenous prostaglandins, three classes of EP2 receptor agonists have been discussed. These agonists are useful for the study of the function of EP2 and may be clinically useful for the treatment of certain diseases, including glaucoma and inflammatory bowel disease, and for the stimulation of hair growth and the stimulation of hair to terminal hair transformation (102). The first one comprises ligands that are similar in structure to the endogenous ligand PGE2. In order to enhance potency and selectivity, the ω-lipophilic chain has been modified, such as in the free acid metabolite of butaprost (102). However, in binding studies, the selectivity of butaprost for EP2 was only ~18-fold of that for EP3 (103). Due to its chemical instability and weak potency relative to PGE2, ONO-AE1-259-01 (R=allyl; Ki=1.7 nM, EC50=1.8 nM) has been developed, introducing a 9β-chloro group in the place of the C9-carbonyl moiety (104). The second class of agonists is a series of pyridylsulfonamide derivatives, such as PF-04217329 and CP-544326. The latter class is a set of pyridylaminoacetic acids, one of which is TG3-95-1, which is only weakly active (EC50=7.8 mM), but it may be worth mentioning as it represents the only identified EP2-selective class of allosteric potentiators. Apart from the natural agonist of EP2, a number of PGE2 agonists, such as butaprost, CAY10399 and ONO-AE1-259-01, and compounds with a non-prostanoid structure, such as CP-533536, can also activate EP2 (105).
Due to the lack of selective antagonists for EP2, the majority if studies focusing on the function of EP receptors in cancer have been based upon genetic deletion and knockout studies (106). Although the genetic deletion of prostanoid receptors is very useful, it is overcomplicated and may result in hypertension. Numerous small-molecule ligands targeted to EP2 have been developed to complement this strategy (107,108).
The non-selective EP receptor antagonist AH6809 has been widely applied to explore the roles of PGE2/EP2 signaling under normal and pathological conditions (109). Although AH6809 acts as an antagonist of EP2, it may also serve as an antagonist of EP1 and DP1 (110); it is neither selective nor potent, and is therefore unsuitable for in vivo studies (111). However, it has been demonstrated that allosteric potentiators and selective antagonists of the EP2 receptor with non-prostanoid structure can explain the physiological functions of prostaglandin receptors (112). These EP2 small-molecule modulators, such as PF-04418948 (Ki=16 nM), TG4-155 (Ki=9.9 nM), TG8-4 and TG6-129, which have been used for studies in animal models of human diseases, enable differentiation of EP2 from other prostanoid receptors (113). The increasing number of tools for studying EP2 may enable a better understanding of the role of this receptor under normal and pathological conditions (Fig. 7).
8. Conclusions and prospects
COX is a rate-limiting enzyme in biosynthetic pathways. Although drugs targeting COX enzymes, such as NSAIDs or specific COX-2 inhibitors, have been clinically used to treat various diseases, they may be associated with numerous side effects, including gastric ulcers and myocardial infarction. Therefore, these adverse reactions limit the use of such drugs. In the COX-2 downstream signaling pathway, EP2 is an important mediator in several physiological and pathological events. It has been demonstrated that EP2 can interact with G proteins through the formation of EP2 and β-arrestin (β-inhibitory proteins act as modulators), and signaling can be switched to the G protein-independent pathway. The update on selective EP2 antagonists may be helpful in explaining the functions of EP2 to supplement genetic knockout studies (114). Furthermore, nano-drug delivery technology and EP2-targeted drugs may be applied in the treatment of cancer. By establishing drug-loaded nanoparticles targeting EP2, a novel nano-drug delivery system may be established to increase drug targeting. In conclusion, studying EP2 may help elucidate the mechanisms underlying cancer invasion and metastasis, angiogenesis, chronic inflammation, tumor immunity and apoptosis, and may aid the development of novel molecular targeting therapeutic strategies.
Acknowledgments
The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: [https://www.gtexportal.org/home/] the GTEx Portal on 04/22/17 and dbGaP accession number phs000424.v7.p2 on 04/22/2017. The RNA-Seq datasets used by GEPIA are based on the UCSC Xena project (http://xena.ucsc.edu), which are computed by a standard pipeline.
Funding
This study was supported by the International Cooperation Key Project of the National Natural Science Foundation of China (grant no. 81520108031 to Q.L.), the Science Foundation of Shanghai Committee of Science Project (grant no. 14430722900), and the Program for Outstanding Medical Academic Leader and Shanghai Academic Research Leader (grant no. 16XD1403600).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
XS compiled the information and wrote the review, QL revised the manuscript critically for important intellectual content.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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