Long noncoding RNA SNHG4: a novel target in human diseases

In 2011, Salmena and colleagues first proposed a hypothesis about ceRNA: it forms a large-scale regulatory network that plays a role in both physiological and pathological conditions [ 112 ]. Theoretically, ceRNAs include all RNAs that contain microRNA response elements (MREs) and can recognize and bind miRNAs. At present, the most common ceRNAs are lncRNAs, circRNAs and pseudogene RNAs [ 113 – 115 ]. It is common knowledge that miRNAs mainly inhibit the expression of target genes by binding to mRNAs. ceRNAs can competitively bind to and inactivate miRNAs through MREs, thereby affecting the mRNA level of target genes [ 116 – 118 ]. Multiple studies have shown that lncRNAs, as ceRNAs, play an important role in malignant tumours and other diseases. This paper mainly summarized the lncRNA-miRNA-mRNA regulatory network formed by SNHG4 acting as a ceRNA (Table 2 ) (Fig.  3 ). Fig. 3 Function and molecular mechanisms of lncRNA SNHG4 in a variety of diseases. MiRNAs can cause gene silencing by binding to mRNAs, while ceRNAs can regulate gene expression by competitively binding to miRNAs. SNHG4 can serve as a ceRNA and sponge miRNA, thereby affecting the expression of target genes Function and molecular mechanisms of lncRNA SNHG4 in a variety of diseases. MiRNAs can cause gene silencing by binding to mRNAs, while ceRNAs can regulate gene expression by competitively binding to miRNAs. SNHG4 can serve as a ceRNA and sponge miRNA, thereby affecting the expression of target genes

SNHGs are the host genes of snoRNAs (small nucleolar RNAs), including exons and introns [ 10 , 25 ]. The introns are mainly processed into snoRNAs, while the exons are reassembled and play roles in the cytoplasm [ 10 , 26 ]. Zimta et al. [ 27 ] first summarized the five main molecular mechanisms of SNHGs. SNHGs can influence DNA methylation, regulate transcription, repress translation, act as ceRNAs and prevent protein ubiquitination. LncRNA SNHG4, which is located at 5q31.2 [ 28 ], is a member of the SNHG family. SNHG4 also consists of exons and introns [ 23 ] (Fig.  1 ). In 2014, Chaudhry [ 29 ] first found that SNHG4 expression was increased in irradiated TK6 cells but was downregulated in bystander cells versus control cells. SNHG4 has been reported to be abnormally expressed in many diseases. It is downregulated in patients with neonatal pneumonia (NP) [ 30 ], diabetic retinopathy (DR) [ 19 ], acute cerebral infarction (ACI) [ 20 ], and acute myeloid leukaemia (AML) [ 21 ] and is upregulated in gastric cancer (GC) [ 31 ], renal cell carcinoma (RCC) [ 32 ], glioblastoma (GBM) [ 33 ], neuroblastoma [ 34 ], colorectal cancer (CRC) [ 35 ], etc. The aberrant expression of SNHG4 has been proven to be closely related to the genesis, occurrence and progression of various diseases. Fig. 1 A The structure of the SNHG family members and the synthetic pathway of snoRNAs. B SNHGs are present in the cytoplasm and nucleus. They have five main types of molecular mechanisms of action A The structure of the SNHG family members and the synthetic pathway of snoRNAs. B SNHGs are present in the cytoplasm and nucleus. They have five main types of molecular mechanisms of action

In recent years, there have been a variety of studies on lncRNAs. Researchers have focused on exploring the relationship between specific lncRNAs and diseases, especially cancer, as a breakthrough to provide new ideas for disease diagnosis and treatment [ 119 ]. Although lncRNAs do not encode proteins, they can regulate the expression of protein-coding genes in a variety of ways, most commonly through the ceRNA mechanism [ 120 , 121 ]. LncRNAs can act as molecular sponges of miRNAs to negatively regulate their expression, resulting in the inhibition of miRNA targets, thus participating in a variety of important biological processes, such as embryonic development, stem cell maintenance, cell proliferation, differentiation, tumorigenesis, and cancer progression [ 122 , 123 ]. SNHG4, a newly discovered lncRNA and one of the members of the SNHG family, has attracted great attention from researchers. First, researchers explored its expression in diseases and found that SNHG4 is highly expressed in most diseases and low in DR, ACI, and AML. They found that high expression of SNHG4 is closely associated with the clinicopathologic features and prognosis of some cancers. SNHG4 may therefore be used as a prognostic biomarker for these diseases. Next, they conducted a series of in vitro and in vivo studies to investigate the biological behaviour of SNHG4 in diseases. Experiments have proven that SNHG4 can promote cell proliferation, invasion, migration, and EMT and inhibit apoptosis. Targeted inhibition of SNHG4 seems to be beneficial for inhibiting the survival and development of tumour cells, thereby achieving therapeutic effects. Therefore, SNHG4 is expected to become a potential therapeutic target for various diseases. Finally, they revealed the molecular mechanism of SNHG4 in the pathogenesis of diseases. SNHG4 mainly acts as a sponge for miRNA. For example, SNHG4 sponges miR-204-5p and then upregulates RRM2 expression to exert a tumorigenic effect in GC. Similarly, the miR-148a-3p/c-Met axis and miR-let-7e/KDM3A/p21 axis play a role in the occurrence and development of CC and NSCLC, respectively. Although there have been many types of research on SNHG4 and cancer, they are mainly in the basic research stage and more clinical application research needs to be carried out in the future. In addition, there are few reports of SNHG4 in non-neoplastic diseases; therefore, future research may be tilted towards non-neoplastic diseases. The development of lncRNA detection technology is very important for the diagnosis and treatment of diseases. The latest advances in CRISPR/Cas9 gene knockout, knock-in, and point mutation technologies may help us better understand the biological effects of lncRNAs to develop and apply clinically targeted therapeutic drugs. Currently, there is no approved or tested drug-related to SNHG4, however, as summarized in Fig.  3 , SNHG4 regulates many miRNAs, thereby affecting the mRNA level of downstream target genes and promoting the expression of target genes. Targeted inhibition of SNHG4 or downstream genes such as STAT6, PTEN, RRM2, etc. may play an important role in inhibiting proliferation, invasion, migration, etc., and alleviate disease progression. In conclusion, SNHG4 is a novel target for disease diagnosis, treatment and prognosis evaluation, although the specific targeting mechanism and its true clinical application deserve further investigation.

RNA is mainly divided into coding RNA and noncoding RNA (ncRNA). According to transcriptome sequencing data, 70–90% of the human genome is involved in transcription; only 2% of the transcripts encode proteins, while the majority are non-protein-coding RNAs [ 1 , 2 ]. ncRNAs principally include ribosomal RNA (rRNA), long noncoding RNA (lncRNA), transfer RNA (tRNA), microRNA (miRNA), small nuclear RNA (snRNA), circular RNA (circRNA), small nucleolar RNA (snoRNA), and piwi-interacting RNA (piRNA) [ 3 ]. Among them, lncRNAs, accounting for approximately 80% of ncRNAs [ 4 ], are the most studied. LncRNAs are ncRNAs that are more than 200 nucleotides in length and do not encode proteins [ 5 , 6 ]. They have been reported to participate in many pathophysiological processes, including gene expression, protein activity, cell proliferation, apoptosis, and inflammation [ 7 , 8 ]. Multiple studies have been published on the association between the expression of lncRNAs and the progression of human diseases. LncRNA small nucleolar RNA host gene 4 (SNHG4) is a member of the SNHG family. SNHGs are the host genes of snoRNAs present in the nucleus and cytoplasm [ 9 ]. To date, it has been reported that the SNHG family has 22 members, from SNHG1 to SNHG22 [ 10 ]. They play significant roles in human cancers and other diseases. Xu et al. [ 11 ] pointed out that SNHG3 is a novel oncogenic lncRNA, which is aberrantly expressed in osteosarcoma, hepatocellular carcinoma (HCC), lung cancer, etc. Upregulation of SNHG3 contributes to biological functions, including tumour cell proliferation, migration, and invasion. Thin [ 12 ], Huang [ 13 ], and Xiao [ 14 ] have published reviews on SNHG1. They mainly summarized the relationship between SNHG1 and cancer and revealed that SNHG1 may act as a useful biomarker for the diagnosis, prognosis and treatment of human cancer. In addition, SNHG5, SNHG7, SNHG12, and SNHG16 have all been reported to promote the progression of cancers [ 15 – 18 ]. In this paper, we mainly summarized the research progress regarding SNHG4 in most tumours and some non-tumour diseases. Although an increasing number of studies on SNHG4 and human diseases have been published, they still do not cover all diseases. For example, there is no research report on SNHG4 in pancreatic cancer, breast cancer, etc. at present. In addition, there is a clear gap between existing research and clinical practice. In the future, more large-scale and multifaceted studies are needed to further verify the role of SNHG4 in various diseases. SNHG4 mainly plays a carcinogenic role in tumours. Reducing the expression of SNHG4 can inhibit the proliferation of tumour cells and is expected to become a potential target for cancer treatment. In some non-neoplastic diseases, in addition to affecting proliferation, SNHG4 is closely related to the immune response and can play dual pro-inflammatory and anti-inflammatory roles [ 20 , 22 ]. In cerebral ischaemia–reperfusion injury, the SNHG4/miR-449c-5p/STAT6 axis participates in and inhibits the inflammatory process. In contrast, SNHG4 can also increase the levels of pro-inflammatory factors (IL-6, IL-12, and TNF-α) and promote neuroinflammation. In addition, Horikawa et al. [ 23 ] disclosed a transcript containing an intron sequence of SNHG4, which is expressed in podocytes. Podocytes play an indispensable role in the kidney [ 24 ]. Overall, we summarize the function of SNHG4 from many aspects, including human studies and in vivo and in vitro studies. Some mechanisms by which SNHG4 acts as a competing endogenous RNA (ceRNA) are also discussed, and it is finally speculated that SNHG4 may be used as a target for disease treatment, diagnosis and prognosis evaluation.