LncRNA SNHG15: A new budding star in human cancers

Abstract Objectives Long non‐coding RNAs (lncRNAs) represent an important group of non‐coding RNAs (ncRNAs) with more than 200 nucleotides in length that are transcribed from the so‐called genomic “dark matter.” Mounting evidence has shown that lncRNAs have manifested a paramount function in the pathophysiology of human diseases, especially in the pathogenesis and progression of cancers. Despite the exponential growth in lncRNA publications, our understanding of regulatory mechanism of lncRNAs is still limited, and a lot of controversies remain in the current lncRNA knowledge.The purpose of this article is to explore the clinical significance and molecular mechanism of SNHG15 in tumors. Materials & Methods We have systematically searched the Pubmed, Web of Science, Embase and Cochrane databases. We provide an overview of current evidence concerning the functional role, mechanistic models and clinical utilities of SNHG15 in human cancers in this review. Results Small nucleolar RNA host gene 15 (SNHG15), a novel lncRNA, is identified as a key regulator in tumorigenesis and progression of various human cancers, including colorectal cancer (CRC), gastric cancer (GC), pancreatic cancer (PC) and hepatocellular carcinoma (HCC). Dysregulation of SNHG15 has been revealed to be dramatically correlated with advanced clinicopathological factors and predicts poor prognosis, suggesting its potential clinical value as a promising biomarker and therapeutic target for cancer patients. Conclusions LncRNA SNHG15 may serve as a prospective and novel biomarker for molecular diagnosis and therapeutics in patients with cancer.

splicing mediator, post-transcriptional processor, competing endogenous RNAs (ceRNAs) for miRNAs and chromatin remodeler in tumorigenesis and progression. 8,11,12 Based on the targeting mechanism, lncRNAs could be classified as signal, scaffold, decoy and enhancer. 3 Interestingly, lncRNAs provide a novel way of regulating the gene expression at transcriptional, post-transcriptional, and epigenetic levels. 10,[13][14][15][16] Additionally, lncRNAs can regulate a variety of cancerrelated signalling networks though interacting with protein, such as wnt/β-catenin signalling pathway, epithelial-mesenchymal transition (EMT) signalling pathway, NF-kB signalling pathway and Hippo signalling pathway. [17][18][19][20] For instance, linc00673 augmented the binding between DEAD box RNA helicase DDX3 and casein kinase 1ε (CK1ε), thus activating wnt/β-catenin signalling and causing aggressiveness of lung adenocarcinoma (LAD). 21 Accumulating studies demonstrate that dysregulated lncRNA expression could exert oncogenic or tumour-suppressive roles in cancer progression. 3,22 For example, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as a well-known lncRNA, has been shown to be either upregulated or downregulated in human cancers. 3,22 Previous in-vitro assay and xenograft studies revealed contradictory effects of MALAT1 on cancer phenotype. [23][24][25][26][27][28] Similarly, lncRNA SNHG15 was previously described by many papers as a cancer-promoting and metastasis-promoting lncRNA, while other report demonstrated a tumour-suppressing function of SNHG15. [29][30][31][32][33] Its dysregulation was closely correlated with carcinogenesis, affecting the prognosis of cancer patients. [34][35][36] Although these inconsistent findings could be of the limitation in sample size or the difference in tumour origin but also highlight the necessity of more research in SNHG15 in various types of cancer. Recently, it is notable that the aberrant gene expression in circulating tumour cells (CTCs) can influence the prognosis of cancer patients, such as mesenchymal markers. 37 Cai et al identified the status of cyclooxygenase-2 (COX-2) expression in CTCs and revealed its correlation with clinical and pathological factors of CRC patients. 38 This interesting observation may also remind us to explore the molecular basis of other critical genes in CTCs, such as lncRNAs, thus establishing theoretical foundation for future translational research.
In this review, we aim to summarize the latest knowledge about the characteristics of SNHG15 in the biological effects and molecular mechanism of human cancers and further debate the prognostic and therapeutic values of SNHG15 in human cancers.

| IDENTIFI C ATI ON AND CHAR AC TERIZ ATI ON OF LN CRNA S NHG15
SNHG15, a strongly conserved lncRNA which was initially reported in 2012, is located at 7p13 with a length of 860 bp. 39 Studies raised the possibility that the stability of ncRNAs could reflect their potential function, based on the existed findings between the half-life of each mRNA and its physiological function. 39 Originally, a novel genomewide method, 5'-bromo-uridine immunoprecipitation chase-deep sequencing analysis (BRIC-seq), was used to determine the half-lives of ncRNAs and mRNAs in HeLa Tet-off (TO) cells. 39 Through analysing the relationship between the half-life of RNA and functional categories, RNAs with a short half-life (t (1/2) < 4 hours) contained known regulatory ncRNAs and regulatory mRNAs. 39 LncRNA SNHG15 was screened out as a short-lived non-coding transcripts (SLiTs) with a short half-life (t (1/2) < 4 hours), and likely to be involved in cell proliferation. 39 Additionally, the prediction of SNHG15 structure based on minimum free energy (MFE) and partition function can be obtained from RNA-fold website(http://rna.tbi.univie.ac.at//cgi-bin/ RNAWe bSuit e/RNAfo ld.cgi?PAGE=3&ID=TryBo 7KkMy ).
Further research indicated that SNHG15, as a critical member of short-lived lncRNAs, participated in the molecular mechanisms associated with responses to cellular stresses. 39 The expression level of SNHG15 was elevated due to prolonged decay rates in response to chemical stressors and interruption of RNA degradation pathways. 39 It has been proposed that SNHG15 has the potential to be surrogate indicators of cellular stress responses. 39 Of note, SNHG15 was dysregulated in various tumour tissues and cell lines, such as CRC, GC, pancreatic cancer (PC) and thyroid cancer (TC). 19,32,33,40,41 Several aspects of tumorigenicity, such as cell proliferation, apoptosis, migration and metastasis, have been evaluated in relation to SNHG15 expression in human cancers. 30,[42][43][44] In addition, aberrant SNHG15 expression displayed close correlation with tumour size, tumour node metastasis (TNM) stage, lymph node metastasis and prognosis of cancer patients. 29,35,36,42 The expression pattern, functional role and regulatory mechanism of SNHG15 are presented in Table 1.

| Colorectal cancer
CRC is the third most common cancer, with approximately 1.3 million new cancer cases and 690,000 mortalities worldwide each year. 45 Despite tremendous progress in the treatment of CRC in recent decades, the prognosis remains unsatisfactory, especially in advancedstage tumours with distant metastasis. 45,46 Current evidences show that approximately 25% of CRC patients present with synchronous liver metastases at diagnosis. 47 The survival and prognosis of these patients with liver metastasis is extremely poor, with a 5-year survival rate less than 10%. 47,48 Thus, it is extremely necessary to gain a better understanding of carcinogenesis and identify novel and sensitive biomarkers for diagnosis and treatments in CRC patients.
LncRNA SNHG15 has been found in several studies to be dramatically upregulated in CRC tissues and cells. 19,[49][50][51] CRC patients with larger tumour size, advanced TNM stage and lymph node metastasis show higher SNHG15 expression. 19,49,50 Furthermore, higher SNHG15 expression is correlated with a worse survival. 42,50,51 Both univariate and multivariate analysis confirmed that SNHG15 expression was significantly associated with overall survival (OS) in CRC patients, suggesting that SNHG15 could be used as an independent prognostic factor and potential biomarker for CRC patients. 42,50,51 Functional assays further demonstrated that knockdown of SNHG15 could inhibit CRC cell proliferation, activate cell apoptosis and suppress cell migration and invasion both in vitro and in vivo. 19,[49][50][51] Recently, SNHG15 has been shown to present a downside tendency on regulating miR-141, which downregulates sirtuin 1 (SIRT1) in CRC cells. The promotion effects of tumour growth and metastasis driven by SNHG15 overexpression can be significantly reversed by miR-141 inhibitor. 19 Besides, wnt/β-catenin signalling pathway was found to be involved in SNHG15-mediated carcinogenesis and could act as a downriver regulator in CRC. 19 These findings suggest that SNHG15/ miR-141/SIRT1 axis exerts oncogenic functions in CRC. 19 Similarly, Min et al found that SNHG15 mediated CRC proliferation through SNHG15/miR-338-3p/FOS/RAB14 axis. 19 Interestingly, Saeinasab et al demonstrated that SNHG15 is more highly expressed in CRC tissues with high levels of MYC expression. 49 Mechanistically, MYC protein binds to two E-box motifs on SNHG15 sequence, illuminating that the transcription of SNHG15 is directly activated by the oncogene MYC. 49 In-vitro assays found that decreased SNHG15 expression could inhibit tumorigenic capacity of CRC cells and increased SNHG15 expression could display can mediate the stability of Slug, which is a critical transcription factor involved in tumorigenesis, EMT, embryonic development and stem cell reprogramming. [51][52][53][54] The stability of Slug determines its biological functions and can be controlled by various regulatory mechanism, including the interaction with lncRNAs. [55][56][57] Jiang et al uncovered that SNHG15 can interact with Slug and inhibit its degradation via the ubiquitin-proteasome pathway (UPP). 51 As a stabilizer of Slug, SNHG15 can also participate in the process of EMT. 51 As for the impacts of SNHG15 on drug resistance, it was shown that SNHG15 overexpression could increase the resistance to 5-Fu, while its downregulation could activate the sensitiveness to 5-FU in CRC cells. 49 There is increasing evidence that lncRNAs play significant roles in the regulation of colorectal liver metastasis (CLM). [58][59][60] Another study reported by Huang et al have been illuminated the potential role of SNHG15 in CLM. 42

| Gastric cancer
GC is the third leading cause of cancer-related death around the world. 61 It is extremely a huge burden worldwide with high morbidity and high mortality, especially in East Asia. 61,62 The overall 5-year relative survival rate for advanced GC patients is still lower than 5%. 63 It is also known that most patients with GC have reached their advanced stage at initial diagnosis because of the lack of novel molecular biomarkers for diagnosis. 63,64 Thus, it has been a central issue to clarify the regulatory mechanism critical for the GC carcinogenesis and tumorigenesis. More importance should be attached to identify effective biomarkers for GC diagnosis and treatment.
SNHG15 was firstly recognized as a novel prognostic factor in GC patients. 63, 64 Chen et al tested the expression level of SNHG15 in 106 pairs GC tissue and matched adjacent non-tumour tissues using qRT-PCR assay. 40 The results showed that SNHG15 expression levels were higher in GC tissues than in the corresponding non-cancerous tissues, and there was a close correlation between SNHG15 expression and clinical-pathological factors in GC patients.
High SNHG15 expression was closely associated with invasion depth, TNM stage and lymph node metastasis in patients with GC. 40 Importantly, the expression level of SNHG15 was also in close correlation with OS and disease-free survival (DFS). Kaplan-Meier analysis demonstrated that elevated SNHG15 expression contributed to poorer OS and DFS of GC patients. 40 And multivariate survival analysis validated that SNHG15 could be an independent prognostic marker of OS and DFS in GC patients. 40 Besides, SNHG15 was overexpressed in GC cells, compared with GES-1 cell. 40 Upregulation of SNHG15 contributes to tumour-promoting activities, while its downregulation plays tumour-suppressing functions in GC. Chen et al revealed that knockdown of SNHG15 suppressed cell proliferation and invasion and induced a strong apoptotic response in GC cells. 40 Additionally, SNHG15 amplification could promote GC cell proliferation and invasion and largely increase the expression level of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9) at protein levels. 40 These results showed that elevated expression of SNHG15 could facilitate GC development and progression partly through modulating MMP2 and MMP9. 40 However, the molecular mechanism between SNHG15 and MMP2/MMP9 is not clear. Further investigations are required to determine the effects of SNHG15 on tumour growth and metastasis in vivo and to illuminate the exact regulatory mechanism of SNHG15 in GC progression.

| Pancreatic cancer
PC is the fourth most common cause of cancer mortality worldwide, leading to approximately 227 000 deaths annually. 65 29 The serum SNHG15 expression level could act as a potential biomarker for screening PDAC patients from healthy controls (AUC = 0.727). The optimal cut-off value for SNHG15 in sera of PDAC patients was 6.82 with a sensitivity of 68.3% and a specificity of 89.6%. 29 Kaplan-Meier analysis revealed that the 5-year OS rate for high SNHG15 group was lower than those in the low SNHG15 group. 29 Based on the univariate analysis and multivariate Cox proportional models, SNHG15 was screened out as an independent prognostic factor for patients with PDAC. 29 As a dysregulated lncRNA in PC, knockdown of SNHG15 could impair PC cell proliferation, cause G1/G0 phase arrest and activate apoptosis. 41 Besides, overexpression of SNHG15 was observed to boost the proliferative capacity of PC cells through regulating cell cycle and apoptosis correlated proteins, presenting as the reduction of P15 and KLF2. 41 The SNHG15 impact can be partly reversed by overexpression of P15 or KLF2. 41 Consistently, SNHG15 exhibited a negative correlation with P15 or KLF2 in PC tissues. Upon in-vivo assay, SNHG15 knockdown could exhibit suppressive effects on tumour growth in PC. 41 Mechanistically, a SNHG15/EZH2/P15/KLF2 axis was identified in PC, shedding new light on lncRNA-based diagnosis and therapeutic in PC. 41

| Hepatocellular carcinoma
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death worldwide in 2018. 61 It is predicted that 841 000 new cases and 782 000 deaths occur annually. 61 HCC accounts for 75%-80% of all liver cancer cases, and half of the cases are discovered in China. 61

| Lung cancer
Lung cancer is the leading cause of cancer-related deaths worldwide. 61 Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung malignancies and includes lung adenocarcinoma (LUAD), squamous cell carcinoma and large cell lung cancer. 61,75,76 Although there are various ways for diagnosis and treatments, the rate of 5-year OS of advanced lung cancer patients is less than 15%. 77 Therefore, it is essential to find valuable tumour makers for early diagnosis and therapy.
Recently, lncRNA SNHG15 emerges as an important regulator in lung cancer. Dong et al revealed that SNHG15 was highly elevated in NSCLC tissues compared with controls. 36,78 Analysis of correlation between SNHG15 expression and clinicopathological data showed that high expression level of SNHG15 was positively related to the tumour size, lymph node status and TNM stage in NSCLC patients. 36,78 Kaplan-Meier survival analysis of OS and DFS revealed that NSCLC patients with higher SNHG15 expression had a relatively poor prognosis compared with the low SNHG15 group. 36,78 The information regarding SNHG15 expression may be useful to predict the survival of NSCLC patients. In-vitro assays revealed that decreased SNHG15 expression could obviously impair proliferative capacity of NSCLC cells, cause G0/ G1 phase arrest and increase the ratio of apoptotic NSCLC cells. 36,78 Moreover, downregulation of SNHG15 substantially inhibited the invasive and metastatic ability of NSCLC cells. 36,78 The pro-metastatic effects of SNHG15 were induced by the regulation of the expression of a number of genes involved in cell metastasis and EMT progress. Depletion of SNHG15 was involved in the downregulation of MMP2 and MMP9 expression, while the underlying mechanism was still unclear. 36 Another study discovered that SNHG15 induced lung cancer proliferation through regulating miR-211-3p, which was predicted to interact with SNHG15. Further research confirmed that miR-211-3p can bind to SNHG15 and its downregulation can partly rescued the proliferation promotion driven by SNHG15 overexpression in A549 and H1799 cells. 78 Moreover, SNHG15 could upregulate CDK14 expression via sponging miR-486, thus contributing to NSCLC tumorigenesis. 44 These findings elucidated that SNHG15 can activate the malignant phenotypes of NSCLC cells through a mechanism involving miRNAs.
However, more efforts should be devoted to clarifying other regulatory mechanisms and clinical implication of SNHG15 in lung cancer in the future.

| Thyroid cancer
TC continues to be the most common endocrine malignant tumour and has emerged as a major health issue. 79 It is estimated that more than 60 000 people of TC occur annually in the United States. 79,80 TC is the sixth most common malignant tumour in the female population of China, where the incidence of TC is about 6.6 per 100 000 people. 81 The major subtypes of TC include papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) originate from follicular cell-derived thyroid cells. PTC accounts for more than 85% of TC patients, and approximately 10%-15% of patients with PTC exhibit relapse and metastasis after therapy, leading to poor outcome. 83 Among these subtypes, ATC is the most aggressive and deadly thyroid cancer with only 3-5 months overall survival after initial diagnosis. 83 The studies of molecular mechanism correlated with TC greatly facilitate the understanding of TC cancer pathogenesis. 82,84,85 Thus, it is of great significance to identify potential biomarkers and therapeutic targets involved in TC tumorigenesis.
Expression profile data of various cancers from The Cancer Genome Atlas (TCGA) data set showed that only TC specimens displayed lower levels of SNHG15 expression. 32  Similarly, SNHG15 was significantly decreased in TC cell lines compared with normal thyroid cell and able to mediate tumour initiation, proliferation and metastasis in TC. 32 The findings elucidated that increased SNHG15 expression dramatically repressed cell proliferation, migration and invasion in TC, revealing the tumour-suppressive role of SNHG15 in TC. 32 Another study identified that SNHG15 could act as a key target of miR-510-5p, which was proposed to be an oncogenic regulator in TC tumorigenesis. 86 And a negative correlation between SNHG15 and miR-510-5p expression was revealed in TC tissues. 86 Mechanistically, miR-510-5p directly interacted with SNHG15 and obviously repressed SNHG15 expression, thus contributing to TC cell proliferation, migration and invasion. 86 Interestingly, a recent study uncovered by Wu et al also focused on the biological role of SNHG15 in PTC. 33 Wu and his colleagues tested the expression levels of SNHG15 in 92 paired PTC tissues and corresponding normal tissues. 33 Inconsistently, an obvious upregulation of SNHG15 was found in PTC tissues compared with control group. SNHG15 elevation was positively correlated with gender, larger tumour size, advanced TNM stage and positive lymph node metastasis. 33 Meanwhile, high SNHG15 expression level was negatively correlated with the OS rate of PTC patients, suggesting its prognostic value for PTC patients. 33 Knockdown of SNHG15 can dramatically activate apoptosis and obviously suppress cell proliferation migration and EMT progress in PTC. 33 In addition, YAP1 is known as a core regulator of Hippo signalling pathway, which can be inactivated by SNHG15. 33

| Prostate cancer
Prostate cancer (PC) is the most common malignancy in male, with more than 29 000 men killed by PC in 2018 in the united states. 65 Owing to lack of specific and sensitive methods for early prostate cancer screening, most patients have been in the terminal stage at first diagnosis, with a 5-year survival rate of only 29% in PC patients. 65,87 Serum prostate specific antigen (PSA), as an essential serum marker, has been widely utilized in the early detection and subsequent treatment. 88

| Osteosarcoma
Osteosarcoma (OS) functions as one of the most common primary bone malignancies among adolescent cohort. 30 in OS cells. 31 The above results revealed that SNHG15 play a promoting role in OS cell proliferation, migration, invasion and autophagy, which was contrary to the influence of miR-141 enrichment. 31 It suggested that overexpressed miR-141 can effectively reverse the promotion of OS tumorigenesis and autophagy induced by SNHG15 overexpression. 31 Liu and his colleague proposed a mechanistic model that SNHG15 promotes OS tumorigenesis and autophagy partly through negatively regulating miR-141. 31 The SNHG15/ miR-141 axis may provide a potential marker and target for OS patients. 31 However, the expression level of SNHG15 was only tested in 35 pairs OS tissue and matched non-cancerous tissues. More OS samples should be involved to determine the expression pattern of SNHG15. Importantly, the correlation between SNHG15 level and clinicopathologic feature or survival of OS patients was still unclear.
In the future, researchers should attach more importance on investigating the clinical significance, prognostic value, as well as mechanistic model of SNHG15 in OS development and progression.

| Glioma
Glioma is one of the most prevalent types of primary intracranial carcinoma. 97 It can be classified as grade II and grade III astrocytic tumours, oligodendroglioma, the grade IV glioblastoma (GBM) and diffuse glioma of childhood. 97 Glioma is characterized by rapid cell proliferation and angiogenesis. [98][99][100] Despite progress in diagnosis and therapy, the rate of recurrence and mortality 101 is still high. 97 Thus, extensive attention should be paid to finding prospective biomarkers and reliable therapeutic targets for glioma patients.
Tumour angiogenesis has been revealed to be involved in mediating tumour growth and metastasis. 102,103 The high level of microvessel density can be identified as an independent prognostic indictor for glioma patients. 104, 105 Ma et al identified SNHG15 as a novel lncRNA involved in the growth of glioma microvascular endothelial cells. 106 Their study demonstrated that SNHG15 was significantly increased in glioma-mediated human cerebral microvascular endothelial cells (hCMECs), which was cultured in the glioma conditioned medium (GCM) to simulate the glioma microenvironment. 106 Conversely, miR-153 expression was obviously decreased in glioma-induced hCMECs, compared with that in the hCMECs in the primary astrocyte cell conditioned medium (ACM). 106 Interestingly,

SNHG15 knockdown can induce the inhibition of VEGFA and
Cdc42, and miR-153 knockdown can significantly upregulate the expression of VEGFA and Cdc42, which were recognized to activate angiogenesis. 103,[106][107][108] Then, a series of functional assays were performed to clarify the biological effects of both SNHG15 and miR-153 on proliferation, migration and tube formation of glioma vascular endothelial cells. They showed that decreased SNHG15 expression can suppress proliferative and migratory capacity of glioma vascular endothelial cells. 106 As for tube formation, the results showed that knockdown of SNHG15 can effectively reduce the relative tubule length and relative number of branches, suggesting the promotion effects of SNHG15 on tube formation of glioma vascular endothelial cells. 106  Moreover, a recent study also revealed the role of lncRNA SNHG15 in the tumour microenvironment (TME). High level of SNHG15 was shown to be associated with a significantly higher risk of developing GBM, which represents the largest and most lethal subgroup of brain tumours. 109 Li et al also found that knockdown of SNHG15 can obviously inhibit tumorigenesis, self-renewal and elevate temozolomide (TMZ) sensitivity. 110 It is determined that TMZresistant (TMZ-R) GBM cells are able to promote M2-polarization of glioma associated microglia (GAMs), which are functionally similar to tumour-associated macrophages in the peripheral system and interact with GBM cells through intracellular communications. 110 Intriguingly, the treatment of palbociclib, CDK6 inhibitor, can effectively decrease the generation of M2 GAM and glioma stem cells mediated by TMZ-R cells through downregulating SNHG15 and upregulating miR-627. 110 Consistently, M1 markers (IFN-γ and TNF-α) were prominently increased in the GAMs co-cultured with SNHG15silenced TMZ-R cells, whereas M2 markers (IL-6 and TGF-β) were significantly decreased in the GAMs co-cultured with SNHG15-silenced TMZ-R cells. 110 Overall, the molecular axis of SNHG15/ CDK6/miR-627 may help to overcome the resistance of TMZ, supporting the usage of palbociclib for TMZ-resistant GBM cases. 110  114 It was found that SNNHG15 was overexpressed in breast cancer tissues. Ectopic SNHG15 expression was found to be remarkably associated with TNM stage, lymph node metastasis in BC patients. 114 And there was no significant correlation between SNHG15 level and age of BC patients. 114 Kaplan-Meier analysis showed that breast patients with higher SNHG15 expression was positively correlated with poor survival. 114 In-vitro and in-vivo assays both validated that SNHG15 knockdown can efficiently suppress cell proliferation, enhanced apoptosis and inhibit migration and invasion of BC cells. 114 Moreover, their study revealed that SNHG15 knockdown can decrease vimentin expression and increase E-Cadherin in BC cells. 114 It suggested that the pro-metastatic function of SNHG15 was determined to be correlated with EMT regulation. Mechanistically, Kong et al proved that SNHG15 can bind with miR-211-3p, which was determined to be significantly downregulated in BC tissues. 114 And a negative correlation was determined between SNHG15 expression and miR-211-3p expression in BC tissues. 114 Besides, rescue assays demonstrated that miR-211-3p downregulation can partly reversed the inhibition of tumorigenesis induced by SNHG15 knockdown in BC cells. 114 Kong and his colleagues uncovered that lncRNA SNHG15 exerts oncogenic role through negatively regulating miR-211-3p in BC progression, which may give new insight into molecular diagnosis and treatment. 114 However, the sample size in this study is limited and the listed clinical parameters only include tumour size, TNM stage, lymph node metastasis and age. In the future, more efforts should be made to determine the underlying mechanism and clinical value of SNHG15 in BC.

| Renal cell carcinoma
Renal cell carcinoma (RCC), as the most common type of kidney cancer, accounts for 2%-3% of all cancer cases worldwide. 115  However, the number of cases with lymphatic invasion or metastasis was too small to perform statistical analysis.

| Ovarian cancer
Epithelial ovarian cancer (EOC) is the second most common gynaecological malignancy in women worldwide, accounting for a third of all gynaecological malignant tumours. 118

| Upstream regulator essential for aberrant expression of SNHG15
Mounting evidences have demonstrated that transcription factors, and genetic alterations can lead to the aberrant expression of lncRNAs. 120,121 Previous study declared that there are two E-box (CACGTG) binding motifs for transcription factor MYC on the first exon and first intron of SNHG15. 122 Analysis of ChIP-seq data from ENCODE confirmed that transcription factor MYC can bind to the mentioned E-box in various cancerous cells. 49 Saeinasab et al further explored the RNA-seq data correlated with colorectal adenocarcinoma from TCGA data set and found that SNHG15 displayed significant upregulation in CRC tissues with highly expressed MYC expression. 49 Consistently, knockdown of MYC can significantly decreased SNHG15 expression in CRC cells, illuminating that MYC can activate the transcription of SNHG15 in CRC cells. 49 In summary, MYC is involved in the transcription of SNHG15 overexpression. However, more upstream modulators need to be uncovered in the future.

| SNHG15 as ceRNA with potential roles in the context of post-transcriptional regulation
It is currently known that the transcripts, which harbour miRNA response elements (MREs), may have a potential to act as ceRNAs, including lncRNAs, pseudogenes, circular (circ)RNAs and mRNAs. [123][124][125][126][127] The theory of ceRNA implies that there are regulatory networks lying foundation for crosstalk between ncRNAs and coding RNAs through miRNA involvement. 128,129 Particularly, lncRNA-miRNA-mRNA network has been shown to play critical roles in the development and progression of various neoplasms. 130,131 LncRNA SNHG15, as an essential regulator in human cancer, has been elucidated to be involved in ceRNA network, thus impacting biological and pathological activities in cancer progression ( Figure 2).

| LncRNA SNHG15/miR-338-3p/ mRNA FKBP1A
Zhang et al reported that SNHG15 can act as a ceRNA to regulate miRNA-mRNA axis in prostate cancer. 30 This study indicated the miR-338-3p silencing through SNHG15, which holds binding elements for miR-338-3p at its 3′-UTR, leading to ectopic expression of FKBP1A. 30 The overexpression of miR-338-3p can significantly decrease the luciferase activity of the wild-type FKBP1A, but exhibit no influence on the mutant type FKBP1A. 30 In summary, SNHG15 elevated FKBP1A expression by sponging miR-338-3p at post-transcriptional level, thus regulating the biological processes of prostate cancer.

| LncRNA/miR-338-3p/mRNA FOS-RAB14
Li et al elucidated that SNHG15 can stimulate CRC proliferation through miR-338-3p/FOS/RAB14 axis. 50 Mechanistic study showed that SNHG15 could directly interact with miR-338-3p, which can directly target FOS-RAB14 and exert anti-tumour functions in CRC. 50 Ectopic expression of SNHG15 can significantly restored the inhibitory effects on proliferation and promoting effects on apoptosis mediated by miR-388-3p. 50 Moreover, there was a positive correlation between SNHG15 level and FOS-RAB14 in CRC tissues. 50 Of note, knockdown of FOS and RAB14 can impair the proliferation promotion mediated by SNHG15 overexpression or miR-388-3p silencing. 50 These findings support the notion of SNHG15/miR-388-3p/FOS/RAB14 in CRC tumorigenesis.

| LncRNA SNHG15/ miR-141/mRNA SIRT1
Another ceRNA study of SNHG15 in the CRC development via sponging miR-141. 19 In this study, SNHG15 was found to act as ceRNA for decreasing miR-141, resulting in the overexpression of SIRT1. 19 Moreover, further research validated that knockdown of SNHG15 can effectively suppressed the protein level of wnt1, cmyc, cyclin-D1 and β-catenin, which are critical proteins correlated with wnt/β-catenin signal. 19 Consistently, decreased miR-141 expression can obviously reverse the suppressive effects of wnt/βcatenin signal-related proteins induced by SNHG15 knockdown. 19 Collectively, SNHG15 can play an oncogenic role in CRC development via brisking wnt/β-catenin signal and the regulatory network mediated by SNHG15/miR-141/SIRT1 axis can pave a new sight in understanding CRC biology. 19 As for osteosarcoma, the mechanis-

| LncRNA SNHG15/ miR-486/mRNA CDK14
Jin et al found that SNHG15 induced NSCLC tumorigenesis and metastasis through activating CDK14 expression via competitively F I G U R E 2 SNHG15-involved ceRNA network in cancer progression binding with miR-486. 44 The ceRNA role of SNHG15 is responsible for the progression of NSCLC cells through suppressing miR-486, which can decrease CDK14 expression. 44 These findings highlighted that SNHG15 as essential regulator of SNHG15/ miR-486/ CDK14 axis plays key roles in NSCLC progression and metastasis. 44

| LncRNA SNHG15/miR-211-3p/ mRNA ZNF217
Kong et al have clarified the oncogenic function SNHG15 in regulating cell proliferation, migration and EMT by acting as ceRNA to sponge miR-211-3p. 114 In contrast, miR-211-3P was decreased in BC tissues and cells and exhibited tumour-suppressive roles in BC. 114 Notably, there was an opposite correlation between SNHG15 and miR-211-3p in BC tissues. 114

| LncRNA SNHG15/miR-153/mRNA VEGFA/ Cdc42
One of the key regulatory mechanism linked to glioma is the lncRNA SNHG15/ miR-153/VEGFA/Cdc42 ceRNA network revealed by Ma et al 106 Overexpression of SNHG15 play a promoting role in regulating glioma vascular endothelial cell proliferation, migration and tube formation through competitively sponging miR-153. 106 And miR-153 can directly target the 3'-untranslated region of VEGFA and Cdc42, leading to obvious downregulation of VEGFA and Cdc42. 106

| LncRNA SNHG15/miR-200a-3p/mRNA YAP1
Wu et al revealed that SNHG15 could act as a ceRNA by competitively binding with miR-200a-3p in PTC cells, thus upregulating the expression of YAP1, which was a key downstream regulator of Hippo signalling pathway. 33 Wu and his colleagues have demonstrated that SNHG15 exerts pro-oncogenic roles in regulating cell proliferation, migration and EMT progress in PTC. 33 The distribution of SNHG15 is mainly located in the cytoplasm, which highlights the regulatory mechanism of SNHG15 at post-transcriptional level. 33 There was a negative association between SNHG15 and miR-200a-3p expression in PTC tissue samples. 33

| SNHG15 and EZH2 interaction at transcriptional level
A rapidly growing body of data have indicated that lncRNA could interact with the Polycomb-repressive complex 2, which can mediate histone methylation and mainly consists of EZH2, SUZ12 and EED. 132

| SNHG15 involvement in controlling protein stability
Current evidences have revealed roles of several lncRNAs in the post-transcriptional regulation of gene stability. 140 These findings revealed a novel mechanism underlying the control of Slug stability by demonstrating that oncogenic lncRNA SNHG15 interacts with and blocks Slug degradation via the ubiquitin-proteasome system. Thus, SNHG15 is expected to serve as a target for CRC therapy.

| THE INVOLVEMENT OF S NHG1IN MULTIPLE S IG NALLING PATHWAYS
Recent discoveries have highlighted the importance of lncRNA SNHG15 in mediating various signalling pathways. The involvement of SNHG15 in multiple pathways in various cancers is listed in Table 2.

| Regulations of EMT signalling pathways in human cancers
Tumour metastasis is considered to be a major cause of dismal prognosis in patients suffered with cancer, in which many factors are involved. The initial step of this cascade is orchestrated by the induction of the EMT process, which is tightly regulated by multiple signalling pathways, such as WNT/β-catenin, NF-kB and TGF-β signalling pathways. 55,[142][143][144] Currently, lncRNAs have emerged in the regulation of EMT-associated signalling pathways.

| WNT/β-catenin signalling pathway in EMT
The WNT/β-catenin signalling pathway has been recognized to be indispensable for EMT regulation, and its briskness is recurring encountered during the initiation and progression of various cancers, including CRC. 143

| The common inducible factors in EMT
The process of EMT involves the decrease of epithelial marker (Ecadherin, Zo-1, and claudin1) and increase of mesenchymal marker (vimentin, ZEB1, N-cadherin, Slug, Snail and NF-κB). 148 Moreover, it is known that the activation of NF-κB can transcriptionally regulate the expression of MMP-9, MMP-2, uPA and VEGF, contributing to the acquisition of EMT phenotype. 149 Current investigations have demonstrated that lncRNA SNHG15 can enhance malignant phenotypes through MMP2/MMP9 in both GC and NSCLC cells. 36,40 Interestingly, Jiang et al uncovered that lncRNA SNHG15 can interact with transcription factor Slug and keep its stability in living cells, thus regulating EMT and promoting colon cancer progression. 51 Overall, it is notable that the existence of a novel mechanism by which lncRNA SNHG15 is integrated with the EMT-associated signalling pathways to mediate the progression of multiple cancers, offering a novel rationale for lncRNA-directed cancer therapeutics. However, the role and molecular basis of SNHG15 in other EMT-associated signalling pathways still needs to be clarified in the future research.

| YAP-Hippo pathway
The Hippo signalling pathway is an evolutionarily conserved pathway, with YAP (Yes-associated protein) as its main effector molecule. 150 The inactivation of Hippo signalling pathway can lead to downregulation of MST1/LATS1 (the core factors of Hippo pathway) and upregulation of YAP1. 20 The dysregulation of Hippo signalling has been recognized in a multitude of human tumours and closely associates with the acquisition of malignant traits. 20  ples. 33 The current evidence for the existence of SNHG15/miR-200a-3p/YAP1/Hippo axis indicates that combined targeting of YAP1/ Hippo signalling pathway may provide a potential direction for PTC treatment. 33 However, extensive questions remain to be answered before transferring these notions into the clinical setting.

| CON CLUS I ON S AND FUTURE PER S PEC TIVE S
Extensive research has highlighted the critical roles of lncRNAs in tumour occurrence and progression. 151,152 The lncRNA SNHG15 has been revealed to be dysregulated in various cancers, and the expression trend of SNHG15 in various cancers are not completely consistent. SNHG15 is reported to significantly upregulated in most types of cancers and serves as an oncogenic regulator in cancer development and progression, including CRC, GC, HCC and PC. [40][41][42][43]74 However, SNHG15 can also act as a tumour suppressor in TC tissues compared with normal tissues. 32 The diversity of these stud- In conclusion, SNHG15 can serve as an independent prognostic indicator in many cancers and may be a prospective and effective biomarker for cancer diagnosis and treatment. Despite mounting studies to illuminate the biological function and molecular mechanism of SNHG15 in various cancers, the current work is still at preliminary stage. Importantly, the lack of rescue assay is a major pitfall for existing published papers of SNHG15. In the future, more tissue samples should be used to further determine the expression pattern of SNHG15 in different cancers and further clarify the correlation among SNHG15 level, clinicopathological characteristics and prognosis of cancer patients. Multiple effects between SNNHG15 and molecular targets should be explored in depth, thus facilitating the clinical implication. Furthermore, the expression pattern and molecular mechanism of SNHG15 in body fluids are completely unknown, which are also needed.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
Research data are not shared.