Molecular mechanisms of syncytin-1 in tumors and placental development related diseases

Studies found that syncytin-1 and its receptor SLC1A5 are localized at the acrosomal region and equatorial segment of the sperm, and SLC1A5 is also expressed in human oocytes [ 42 ]. Therefore, the interaction of syncytin-1 and its receptor could promote membrane fusion of sperm and egg cells, facilitating the formation of fertilized eggs. Syncytin-1 is also expressed in the trophectoderm underlying the inner cell mass in human trophoblast cells [ 49 ], indicating that syncytin-1 could play a vital role in embryo implantation. In addition, syncytin-1 shows dynamic expression during embryonic (fetal) development. The syncytin-1 mRNA is significantly increased since the late first trimester (9–12 weeks of gestation) compared to the early first trimester (5–7 weeks of gestation), but then significantly decreased in the late third trimester (37–40 weeks of gestation) [ 50 ]. As we all know, the main functions of the placenta are transport, metabolism, protection and endocrine [ 51 ]. These changes during different periods of gestation reflect the relationship between fetal development and placental demand. In a word, it is the structure and function of syncytin-1 that determine its importance in placental development. The role of syncytin-1 in placental development could be affected by various factors. The expression of syncytin-1 is influenced by methylation of CpG islands in the 5′LTR [ 52 ], and DNMTs is involved in DNA methylation [ 53 ]. Transient DNA hypomethylation in the first trimester of pregnancy can promote syncytin-1-mediated cell fusion and differentiation, while DNA hypermethylation at term reduces syncytin-1-mediated cell fusion [ 54 ]. In addition, changes in posttranslational modification of histones are also regulating the expression of syncytin-1. Interestingly, histone modification and DNA methylation often coexist and affect each other [ 55 ]. Acetylate glia cells missing a (GCM1) is essential for placental development [ 56 , 57 ], and it can promote syncytin-1-mediated trophoblast fusion [ 58 ]. Its transcript and phosphorylation levels of the GCM1 gene were activated by the cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA) signal pathway and CREB-binding protein (CBP) plays an auxiliary role in this process. In addition, the increased acetylation, decreased ubiquitination, and improved stability of GCM1 protein were regulated by CBP. The changes in GCM1 expression and structure could upregulate syncytin-1-mediated trophoblast fusion [ 59 ]. Moreover, human chorionic gonadotrophin (hCG) and corticotropin-releasing hormone (CRH) all can activate cAMP-PKA signal pathway, regulating the expression of syncytin-1 [ 60 – 62 ]. Syncytin-1 is involved in the proliferation of cytotrophoblasts through cell cycle [ 28 ], and also mediates the fusion of the villous cytotrophoblast into multinucleated syncytiotrophoblasts [ 36 , 63 , 64 ], the insufficient expression levels of syncytin-1 may lead to defects in the structure and function of the syncytium. In addition, studies have shown that syncytin-1 could also have non-fusogenic activities by participating in the proliferation, differentiation and apoptosis of the trophoblast [ 65 ]. In summary, the expression of syncytin-1 is regulated by methylation, cAMP-PKA-GCM1 signal pathway. Syncytin-1 maintains the homeostasis balance in syncytium through its non-fusion and fusion functions, and plays a vital role in the human placenta. Studies have shown that syncytin-1 can be present in trophoblast/placenta-derived microvesicles and shed from the placenta into the maternal circulation, involved in microvesicles-mediated activation of immune cells and immune cell responses to lipopolysaccharide stimulation [ 66 ]. The syncytin-1 protein not only affects early innate immune response but also influences adaptive response, therefore, increasing the susceptibility to infection [ 67 ]. The leukocytic syncytin-1 expressed in all four leukocyte types, blasts, granulocytes, lymphocytes and monocytes [ 68 ], and syncytin-1 can also promote the activation of monocytes [ 69 ]. Syncytin-1 in astrocytes and microglia can trigger the activation of c-reactive protein through the toll-like receptor 3 (TLR3)-Interleukin-6 (IL-6) signal pathway, inducing inflammatory responses [ 33 ]. In conclusion, syncytin-1, in addition to its role in the placenta, could also be involved in the occurrence of infections and immune responses.

Molecularly targeted therapy has increasingly become a research hotspot. Although syncytin-1 plays a role in placental development related diseases and tumors, its molecular mechanisms and signal pathways need further study. Syncytin-1 is a membrane glycoprotein, so future studies could be focused on exploring antibody inhibitor drugs targeting syncytin-1 and its receptors, to inhibit the occurrence of diseases. Furthermore, studies have shown that syncytin-1 can be detected in the blood, which may serve as a diagnostic marker in the future. Syncytin-1 can participate in the formation of placental syncytiotrophoblasts through cell fusion, and could also play an important role in proliferation, migration and invasion of tumor, so its specific mechanisms need to be further explored in the future.

Syncytin-1 can promote the fusion of villous cytotrophoblast into syncytiotrophoblast, and play an essential role in human placenta development. And it also promotes tumor cell proliferation, anti-apoptotic, invasion, and migration through its fusogenic and non-fusogenic activities. Syncytin-1 abnormally expressed in placental development related diseases and tumors, including PE, infertility, IUGR, hydatidiform moles, NB, EnCa, endometriosis, testicular cancer, seminoma and NSCLC. Caffeine, aspirin, medium micro-environment, steroid hormones, cAMP, PPARγ/RXRα agonists and inhibitors, ATO, DNA methylation levels can all affect the transcription level of syncytin-1. And syncytin-1 can also affect various signal pathways to induce tumorigenesis, such as TRPC3, DISC1, SK3, Akt and Erk1/2, promoting the proliferation and invasion of tumor cells and improving the ability of distant metastasis. The following points need to be further considered deeply in this review. (1) Syncytin-1 is highly expressed in both NB, EnCa, endometriosis, testicular cancer, seminoma, NSCLC, urothelial cell carcinoma tissues of the bladder and colorectal cancer. But it is low expressed in pancreatic cancer, infertility and IUGR. Though studies have shown that syncytin-1 expression is associated with PE, high or low expression of syncytin-1 in PE remains controversial. So, it is necessary to further explore the more specific molecular mechanisms of syncytin-1 through experiments. (2) The expression of syncytin-1 is high in NB, EnCa, testicular cancer and other diseases, can syncytin-1 be directly used as a diagnostic marker for diseases? (3) Syncytin-1 is a membrane glycoprotein, which may inhibit tumorigenesis by applying inhibitor drugs to inhibit the activity and signal pathways of syncytin-1 and its receptors. In conclusion, whether syncytin-1 can become a new biological marker and potential therapeutic target and whether it can be more effective than the currently confirmed target requires further experimental and clinical research.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, accounting for more than 15% of cancer-related deaths in children [ 93 ]. And it is caused by developing sympathetic NB cells with a high degree of malignancy and unique biological heterogeneity [ 94 ]. Radiation therapy is now the standard of care for high-risk NB, and this treatment is important for local lesion clearance and prevention of local recurrence [ 95 ], but the detection of other metastatic lesions in vivo and the degree of prognosis remain unclear. Treatment failure and poor prognosis are often marked by resistance to chemotherapy or immunotherapy in patients with advanced metastatic NB [ 96 ]. Therefore, the identification of reliable biomarkers is of great significance for understanding and treating NB. All these studies have shown that syncytin-1 is highly expressed in NB cell lines (Table 2 ). Chen et al. and Li et al. all found that the expression of syncytin-1 in NB cell lines SH-SY5Y and IMR-32 was significantly higher than that in normal cells [ 97 , 98 ]. Hu et al. came to the same conclusion in NB cell lines SH-SY5Y, IMR-32, SK-N-DZ [ 99 ], Wieland et al. in SH-SY5Y, IMR-32, SiMa [ 96 ], and Liu et al. in SH-SY5Y [ 100 ]. Although syncytin-1 is overexpressed in NB cell lines, further studies in NB tumor tissues are needed in the future. Table 2 Relationship between high expression of syncytin-1 and neuroblastoma Type of cancer Specimen Cell lines Methods Upstream factors Downstream factors Signal pathway Oncogenic effect Ref. Neuroblastoma Cell SH-SY5Y Semi-qPCR qRT-PCR WB Caffeine aspirin unk unk Proliferation [ 100 ] Cell SH-SY5Y SK-N-AS SK-N-DZ qRT-PCR Oxygen tension DNA methylation unk unk Proliferation [ 99 ] Cell SH-SY5Y IMR-32 SiMa qRT-PCR Culture medium micro-environmnt unk unk Proliferation invasion [ 96 ] Cell SH-SY5Y IMR-32 qPCR WB unk Calcium influx TRPC3 DISC1 Proliferation [ 97 ] Cell SH-SY5Y IMR-32 qRT-PCR WB unk Calcium influx SK3 Proliferation migration [ 98 ] unk   unknown; WB  Western Blot Relationship between high expression of syncytin-1 and neuroblastoma Semi-qPCR qRT-PCR WB Caffeine aspirin SH-SY5Y SK-N-AS SK-N-DZ Oxygen tension DNA methylation SH-SY5Y IMR-32 SiMa Culture medium micro-environmnt Proliferation invasion SH-SY5Y IMR-32 qPCR WB TRPC3 DISC1 SH-SY5Y IMR-32 qRT-PCR WB Proliferation migration unk   unknown; WB  Western Blot Syncytin-1 induces tumorigenesis by multiple factors (Fig.  3 ). Firstly, the study found that aspirin and caffeine could increase the mRNA level and protein expression of syncytin-1 in the SH-SY5Y cell line. And the luciferase activity assay showed that caffeine could also induce the activation of HERV-W environmental promoter, improve the transcription level of syncytin-1, thus promoting the proliferation of NB cells [ 100 ]. Several studies suggested that caffeine could play roles in different pathways, such as releasing calcium stored [ 101 ], activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway [ 102 ], inhibiting cellular mTOR/P70S6K/4E-BP1 [ 103 ] or inducing vascular endothelial growth factor expression [ 104 ]. Secondly, treatment of the SK-N-DZ cell line with hypoxia-reoxygenation or DNA methylation inhibitor 5-azacytidine could increase the expression of syncytin-1 [ 99 ]. Thirdly, changes in the medium micro-environment can also affect the expression of syncytin-1. The expression of syncytin-1 in the NB cell line SH-SY5Y was significantly increased in serum-free stem cell medium, and RNA analysis found that the overexpression of HERV was associated with the overexpression of the immune checkpoint molecule CD200 in NB tumors [ 96 ], indicating that serum-free stem cell medium promotes NB cell invasion [ 105 ]. Therefore, caffeine, aspirin, oxygen tension, DNA methylation and the medium micro-environment changes both can affect the expression of syncytin-1. Fig. 3 Molecular mechanisms and signal pathways of syncytin-1 overexpression in neuroblastoma (NB) Aspirin and caffeine can promote the transcription of syncytin-1, thereby promoting the proliferation of NB cells. The stromal interaction molecule 1 (STIM1) protein in the endoplasmic reticulum (ER) recognizes the depletion of stored calcium and activates the plasma membrane calcium ion channel (ORAI1) in the plasma membrane, establishing a calcium release-activated calcium channel (CRAC), causing calcium influx. The calcium that re-enters the cytoplasm is stored in the endoplasmic reticulum (ER). As the concentration of calcium in the cytoplasm increases, protein kinases such as Src and PP2A are activated, thus promoting cell proliferation. Syncytin-1 can induce calcium influx by activating the TRPC3 channel, SK3 channel and down-regulating DISC1 expression to promote the proliferation and invasion of NB cells. Phosphorylated CREB can also induce tumor cell proliferation, gluconeogenesis and promote microphthalmia-associated transcription factor (MITF) expression Molecular mechanisms and signal pathways of syncytin-1 overexpression in neuroblastoma (NB) Aspirin and caffeine can promote the transcription of syncytin-1, thereby promoting the proliferation of NB cells. The stromal interaction molecule 1 (STIM1) protein in the endoplasmic reticulum (ER) recognizes the depletion of stored calcium and activates the plasma membrane calcium ion channel (ORAI1) in the plasma membrane, establishing a calcium release-activated calcium channel (CRAC), causing calcium influx. The calcium that re-enters the cytoplasm is stored in the endoplasmic reticulum (ER). As the concentration of calcium in the cytoplasm increases, protein kinases such as Src and PP2A are activated, thus promoting cell proliferation. Syncytin-1 can induce calcium influx by activating the TRPC3 channel, SK3 channel and down-regulating DISC1 expression to promote the proliferation and invasion of NB cells. Phosphorylated CREB can also induce tumor cell proliferation, gluconeogenesis and promote microphthalmia-associated transcription factor (MITF) expression Syncytin-1 affects NB progression through multiple molecular mechanisms. Store-operated calcium entry mechanism is one of the mechanisms of calcium influx. The stromal interaction molecule 1 protein in the endoplasmic reticulum recognizes the depletion of stored calcium and activates the calcium release-activated calcium channel protein 1 in the plasma membrane, establishing a calcium release-activated calcium channel, causing calcium influx. Calcium re-entering the cytoplasm is stored in the endoplasmic reticulum. As the concentration of calcium in the cytoplasm increases, protein kinases such as tyrosine-protein kinase (Src) and protein phosphatase 2 (PP2A) are activated, thus promoting cell proliferation and other processes [ 106 , 107 ]. Syncytin-1 can promote the proliferation of NB cells by affecting calcium influx. Whole-cell patch clamp experiments showed that in NB cell lines SH-SY5Y and IMR-32, syncytin-1 could promote calcium influx by directly activating transient receptor potential channel 3 (TRPC3) channels and indirectly activating TRPC3 channels by downregulating the expression of DISC1, thereby promoting cell proliferation [ 97 ]. And syncytin-1 could also activate the phosphorylated cyclic-AMP response binding protein (CREB) site on the small conductance Ca2+ -activated K+ channel protein 3 (SK3) promoter, causing downstream gene SK3 transcription, and inducing calcium influx via a voltage-independent pathway, finally causing proliferation and migration of NB cells [ 98 ]. CREB is phosphorylated and activated by PKA, inducing several physiological processes through the formation of homodimers or heterodimers, such as upregulating microphthalmia-associated transcription factor [ 108 , 109 ], promoting gluconeogenesis [ 110 ] and the proliferation of cancer cells. Furthermore, different types of transient receptor potential channel proteins overexpression were also found in pancreatic, ovarian and lung cancers, and overexpression of voltage-gated calcium channels has been found in testicular, prostate, colorectal, gastric cancers [ 111 ]. All in all, syncytin-1 can cause calcium influx by acting on TRPC3, CREB, SK3 and so on, prompting the proliferation and migration of NB cells. In summary, syncytin-1 overexpression can be induced by extracellular factors such as drugs and culture micro-environment, and syncytin-1 overexpression can also activate channels that promote calcium influx and thus have an effect on NB. These results illustrate that syncytin-1 has the potential to become a prognostic marker for NB, but more definite mechanisms need to be further investigated. Endometrial cancer (EnCa) is one of the most common malignant invasive cancers in the world, often occurring in women with postmenopausal bleeding [ 112 ]. Studies have shown that the expression of syncytin-1 in EnCa tissues and cells is higher than that in normal tissues and cells (Table 3 ). Strick et al. found that both steroid hormones and cAMP can induce a significant increase in syncytin-1 mRNA and protein expression in EnCa cells. Steroid hormone-induced syncytin-1 promotes cell proliferation, and syncytin-1 promotes cell–cell fusion in the absence of transforming growth factor β. Similarly, cAMP also induces syncytin-1 to promote cell–cell fusion [ 113 ]. In addition, hypomethylation of the HERV-W 5′LTR region can increase syncytin-1 expression, and the tumor staging and histological grading of EnCa can also have an impact on syncytin-1 expression [ 114 ]. The overexpression of syncytin-1 promotes EnCa cell proliferation by rapidly transitioning from G2 to the M phase. And it also promotes cell migration and invasion by inducing the expression of epithelial-mesenchymal transition (EMT)-related gene proteins, such as waveform protein and E-cadherin protein. This result suggested that syncytin-1 as a fusogenic gene could promote cell migration and invasion by inducing EMT progress. Kaplan–Meier analysis found that high syncytin-1 expression was often associated with poor survival and prognosis [ 115 ]. This suggests that syncytin-1 is involved in the early oncogenic process of EnCa. Table 3 Relationship between high expression of syncytin-1 and endometrial cancer Type of cancer Specimen Number of cases Methods Upstream factors Downstream factors Oncogenic effect Relationship between high expression of syncytin-1 and endometrial cancer: Ref. Clinical parameter Relevance Endometrial cancer Tissue 48/(E:24,N:24) qPCR RT-PCR Northern Blot Steroids CAMP unk Fusion proliferation unk unk [ 113 ] Tissue 67/(E:38,N:29) qPCR Hypomethylation unk Proliferation TNM staging  +  [ 114 ] Histological grading  +  Tissue cell 167/(E:130,N:37) RT-PCR unk Waveform E-adhesion Fusion proliferation migration unk unk [ 115 ] unk  unknown; E  endometrial cancer; N  normal; + positive correlation Relationship between high expression of syncytin-1 and endometrial cancer qPCR RT-PCR Northern Blot Steroids CAMP Fusion proliferation TNM staging Waveform E-adhesion Fusion proliferation migration unk  unknown; E  endometrial cancer; N  normal; + positive correlation Endometriosis is an estrogen-dependent chronic gynecological disease, it is characterized by the presence of endometrial tissue outside its normal location [ 116 ]. Similar to EnCa, syncytin-1 may also influence the development of endometriosis lesions. Zhou et al. found that syncytin-1 is overexpressed in endometriosis tissues via hypomethylation in the LTR promoter region. The alternations in DNMT3B isoforms can result in hypomethylation of the syncytin-1 promoter, and the overexpression of syncytin-1 can upregulate the human somatomammotropin (hCS) gene [ 117 ]. In addition, the RNA levels of syncytin-1 were increased only in eutopic endometrium from patients with endometriosis [ 118 ]. This suggests that syncytin-1 may play an essential role in the morphological development of the human endometrium. Testicular cancer is a common solid malignant tumor in young men. Testicular germ cell tumors (TGCT) account for about 98% of all testicular malignancies, and seminomas account for about 60% of TGCT [ 119 ]. Gimenez et al. found in the custom HERV genechip microarray that syncytin-1 mRNA expression was not observed in normal testicular tissues, while the expression of syncytin-1 was up-regulated in testicular cancer tissues [ 120 ]. Another study found that the mRNA levels of syncytin-1 in seminoma tissues were higher than those in seminoma-matched controls and non-seminoma GCTs. The expression of tet methylcytosine dioxygenase 1 is highly increased in most seminomas, which results in hypomethylation of the syncytin-1 promoter, increasing the expression of syncytin-1. The interaction of syncytin-1 and its receptor SLC1A4/SLC1A5, and the transcriptional factor glial cells missing transcription factor 1 (GCM1) are all able to influence most tumorigenesis, nevertheless, the interaction has not been found in TGCT or seminomas [ 121 ]. So, the overexpression of syncytin-1 may be associated with the development of testicular cancer and seminoma, but further research is needed. The expression of syncytin-1 is high in NB cell lines, EnCa, testicular cancer and seminoma, and also abnormally expressed in other tumors. Studies have shown that when cell apoptosis or necrosis, chromosomal DNA is cleaved into large amounts of circulating free DNA, which is released into the serum and plasma [ 122 , 123 ]. In non-small cell lung cancer (NSCLC), the syncytin-1 gene is increased expression due to chromosome activation and nucleosome depolymerization. Thus, the circulating free DNA of syncytin-1 is increased in the serum of NSCLC patients [ 124 ]. And the expression of syncytin-1 was significantly higher in NSCLC tissues than in para-carcinoma tissues. The hypomethylation of the syncytin-1 promoter could promote the expression of syncytin-1 in NSCLC [ 32 ]. The transcription factor SP1 can promote the expression of syncytin-1 in NSCLC cells. And the downregulation of the SP1/Syncytin-1 axis can reverse the epithelial-mesenchymal transition process by inhibiting the activity of Akt and Erk1/2 signal pathways in NSCLC cells, inhibiting cell proliferation and migration, promoting cell apoptosis [ 125 ]. Our previous study found that the expression of syncytin-1 in urothelial cell carcinoma tissues of the bladder is more than in tumor-adjacent tissues. The transcriptional activator c-Myb interacts with the mutated 3'-LTR of syncytin-1, upregulating the levels of mRNA and protein of syncytin-1, inducing urothelial cell carcinoma tumorigenesis and tumor cell proliferation [ 126 ]. Syncytin-1 expresses in breast cancer cells, and the corresponding D-type retroviral receptor SLC1A5 expresses in endothelial cells. Syncytin-1 can facilitate breast cancer-endothelial cell fusions. The downregulation of syncytin-1 expression highly inhibits cell fusion. And inhibitory syncytin peptides can also inhibit cell fusion. Therefore, syncytin-1 could be a potential therapeutic target to inhibit tumor cell fusion [ 127 ]. The expression of syncytin-1 is higher in colorectal cancer tissues than in normal tissues [ 128 ]. Li et al. found that arsenic trioxide (ATO) can increase the expression of transcription factor GCM1, which in turn increases the expression of syncytin-1 and its receptor SLC1A5, mediating cell fusion, inducing the formation of the polyploid giant cancer cells (PGCCs) in colorectal cancer, promoting the migration, proliferation and invasion of colorectal cancer cells. The expression level of syncytin-1 gradually increased with tumor grades increasingly. It was thought that the expression of syncytin-1 could be closely related to the pathological grade, clinical stage and distant metastasis of colorectal cancer tissues [ 129 ]. Syncytin-1 is also expressed in mycosis fungoides, a primary cutaneous T-cell lymphoma [ 130 , 131 ]. Interestingly, the mRNA and protein levels of syncytin-1 in pancreatic cancer are lower than in normal tissues. And the decrease of syncytin-1 expression is related to the hypermethylation of CpG sites on 5′LTR [ 132 ]. Taken together, the expression of syncytin-1 is high in NSCLC, urothelial cell carcinoma tissues of the bladder, breast cancer and colorectal cancer, but low in pancreatic cancer. And syncytin-1 has the potential to be a molecular marker for their diagnosis in the future.

Syncytin-2 is an env glycoprotein of the HERV-FRD family. It plays an important role in placental development through its involvement in the formation of the syncytiotrophoblast [ 133 ]. The abnormal expression of syncytin-2 has also been associated with human diseases. The MFSD2A is a syncytin-2-mediated cell fusion cognate receptor. Studies have found that syncytin-2 is expressed in the breast cancer cell line MCF-7. Interestingly, the ectopic expression of the transcription factor GCM1 can upregulate the activity of the MFSD2A promoter, promote the expression of MFSD2A genes, and also bind to GCM1-binding sites (GBSs) in syncytin-2 gene (SYN2GBS) at the CpG site of 5'-LTR to induce syncytin-2 hypomethylation, transactivate the promoter of syncytin-2, and promote its transcription. The interaction of syncytin-2 and MFSD2A can eventually promote the fusion of MCF-7 cells [ 134 ]. Furthermore, the high expression of syncytn-2 is also associated with colorectal cancer [ 128 ], EnCa [ 114 ] and seminoma [ 121 ]. Therefore, the physiological and pathological role of syncytin-2 predicts that it could become an important molecular biological marker in the future.

Human endogenous retroviruses were acquired through multiple infections and integration of extinct exogenous retroviruses during primate evolution. This ancestral infection specifically affects the germline, and the resulting endogenous retroviral proviruses can transmit vertically. HERVs become a stable part of the human genome by continuous Mendelian inheritance, accounting for approximately 8% of human DNA [ 1 , 2 ]. According to the types of tRNA recognized by the primer-binding site [ 3 ], HERV can be divided into at least 31 families, including HERV-W, HERV-T [ 4 ], HERV-K [ 5 ], HERV-F [ 6 ], HERV-E [ 7 ] and so on. Although HERV family members have not been identified as replication-competent, they share substantial structure similarity with exogenous retroviruses, for example, HERV-K retains three of the four intact ORFs with the potential to encode proteins or peptides [ 8 ]. Most genes in HERV families are silenced, but some genes remain their function. Studies have found abnormal expression of HERV is associated with various diseases such as prostate cancer [ 9 ], breast cancer [ 10 ], AIDS [ 11 ], colorectal cancer [ 12 ], multiple sclerosis [ 13 ] and neurodegenerative disorders [ 14 ]. The classical HERV provirus structure consists of two identical long terminal repeats (LTRs) and four typical viral genes, gag, pro, pol and env (Fig.  1 A) [ 15 ]. LTRs have the promoter and transcription termination signals to regulate the expression of the virus gene and adjacent gene [ 16 – 21 ]. The gag gene encodes a viral core structural protein [ 22 ]. It can participate in viral RNA encapsidation and particle formation [ 23 ]. The abnormal expression of gag may be associated with pituitary adenomas [ 24 ] and lichen planus [ 25 ]. The pol gene encodes viral enzymes such as reverse transcriptase and integrase [ 26 – 28 ], which abnormal expression may be related to mixed connective tissue disease and systemic sclerosis [ 29 ]. The env gene encodes viral envelope glycoprotein, which is important for receptor recognition and membrane fusion [ 28 ]. Its abnormal expression is greatly associated with lymphoma [ 30 ], melanoma [ 31 ], non-small cell lung cancer [ 32 ], schizophrenia [ 33 ] and leukemia [ 34 ]. Fig. 1 Structure and function of syncytin-1. A The general structure of HERV consists mainly of two identical LTR sequences and four typical viral genes, gag, pro, pol and env. And there is a transcriptional promoter at the end of the 5'LTR. The structure of syncytin-1 and syncytin-2 mainly includes SU domains and TM domains. B Syncytin-1 could promote the fusion of somatic cells and cancer cells Structure and function of syncytin-1. A The general structure of HERV consists mainly of two identical LTR sequences and four typical viral genes, gag, pro, pol and env. And there is a transcriptional promoter at the end of the 5'LTR. The structure of syncytin-1 and syncytin-2 mainly includes SU domains and TM domains. B Syncytin-1 could promote the fusion of somatic cells and cancer cells Env is a membrane glycoprotein and forms the spike glycoprotein on the surface of retroviral particles [ 35 ]. Syncytin-1 is an env protein of the HERV-W family, which receptor is solute carrier family 1 Member 4 and 5 (SLC1A4 and SLC1A5) [ 36 ], and syncytin-2 is an env protein of the HERV-FRD family, which receptor is major facilitator superfamily domain containing 2A (MFSD2A) [ 37 ]. They are homologous membrane glycoproteins with a similar structure, involved in forming the placental syncytiotrophoblast (Fig.  1 A) [ 38 ]. Syncytin-1/2 could promote cell fusion effect between tumor cells and normal cells, and might be associated with tumor metastasis (Fig.  1 B). Therefore, both syncytin-1 and syncytin-2 can play important roles in pathological and physiological processes. According to published articles, no systematic analysis of the molecular mechanisms of syncytin-1 in placental development-related diseases and tumors has been reported. Therefore, we will focus on the networks and signal pathways of syncytin-1 during the placental development related diseases and tumors.