Tumors were typically formed and progressed due to unrestricted tumor cell proliferation resulting from either oncogene activation or tumor suppressor gene inactivation (72).

High expression of SNHG15 could up-regulate ZNF217 by adsorption of miR-211-3p, and inhibit miR-486 to promote CDK14 expression and ultimately stimulate the proliferation of NSCLC cells (36–38). In vivo, the xenograft model indicated that SNHG15 silencing dramatically inhibited NSCLC cell growth (38). In thyroid papillary carcinoma, exogenous overexpression of SNHG15 significantly blocked cell proliferation. SNHG15 served as a competitively endogenous RNA (ceRNA) in modulating the YAP1-Hippo pathway through binding with miR-200a-3p, among which YAP1 was a well-known oncogene (66). Moreover, SNHG15 has been well-studied in digestive system diseases. Chen et al. disclosed that SNHG15 manifested its oncogenic properties in the progression of GC by impairing miR-506-5p (46). A putative binding site for miR-506-5p was identified in the SNHG15 3’-untranslated region (3’-UTR) and further validated by the dual-luciferase reporter (DLR) assay. Through interaction with AIF, SNHG15, a bifunctional MYC-regulated lncRNA, induced the growth of LoVo and SW620 tumor cells in CRC (45). SNHG15 expression was significantly increased in liver cancer tissues and cell lines, whereas its downregulation inhibited in vitro tumor cell proliferation (39–41). By sponging miR-141-3p, SNHG15 could facilitate zinc finger E-box binding homeobox 2 (ZEB2) and E2F transcription factor 3 (E2F3) expression, thus mediating tumorigenesis (41). Several subsequent studies suggested that SNHG15 was also involved in the regulation of HCC cell proliferation through the miR-18b-5p/LMO4 axis and miR-490-3p/HDAC2 axis (39, 40).

The present results provided compelling evidence that SNHG15 functioned as an active regulator of cell cycle G1/S transition to promote cancer cell growth in vitro and in vivo. In pancreatic cancer, the knockdown of SNHG15 resulted in G0/G1 phase block, thereby inhibiting cell proliferation in vitro, similar to the roles of SNHG15 in ovarian cancer (48, 63). Mechanically, SNHG15 recruited EZH2 to suppress P15 and KLF2 expression and promoted pancreatic cancer proliferation (48). P15, one of the universal cyclin-dependent kinases (CDK) inhibitor proteins, has been revealed related to blocking cell cycle progression at the G0/G1 checkpoint (73). Molecular pathway analysis indicated a potential route for SNHG15 to promote ovarian cancer proliferation was by inhibiting tumor suppressor, miR-370-3p which leads to activation of CDK6 (63). CDK6 was a component of the core cell cycle complex that phosphorylates the corresponding proteins to drive cell proliferation (74).

Although the pathways or interactions by which SNHG15 promoted malignant cell proliferation are not consistent, it did appear to regulate cell proliferation through the function of ceRNA in numerous cancer types and its influence on cell cycle progression, which might represent a therapeutic vulnerability that warrants further investigation.

Apoptosis, an evolutionarily conserved form of programmed cell death, played a massive role in the maintenance of tissue homeostasis by controlling cellular deletion to balance cell proliferation (75, 76).

Knockdown of SNHG15 significantly promoted the apoptosis of osteosarcoma cells, mainly due to a resulting increase in expression of apoptosis-related protein Bax, cleaved caspase-3, and downregulation of anti-apoptotic Bcl-2. Mechanistically, SNHG15 functioned as a ceRNA to sponge miR-346 and negatively regulate its expression in OS (56).

Suppression of SNHG15 increased the proportion of cells in the G0/G1 phase and apoptotic rate, which suggests that cell death eventually occurred through cell cycle arrest and subsequent apoptosis of cancer cells (38, 39, 51, 64). In breast cancer, SNHG15 induced caspase-dependent apoptosis in vitro and in vivo through the upregulation of Bax and Bcl-2 via the miR-411-5p/VASP axis (51). Silencing SNHG15 reduced the expression of CDK14 in A549 and H460 lung cancer cells, with CDK14 being the gene involved in regulating cell cycle progression (38, 77). Further in another study, SNHG15 was capable of upregulating the expression of the caspase-3 and PARP, elevating the ratio of Bax/Bcl-2, suggesting the involvement of intrinsic mitochondrial apoptotic pathway (37).

Based on functional analyses of multiple tumor types, SNHG15 interacted with multiple molecular mechanisms and signaling pathways to impair apoptosis. We anticipate that targeting apoptotic pathways that remain operative in specific types of cancer cells and restoring apoptotic defense mechanisms, which would result in substantial therapeutic benefits in the promising future.

In recent years, mounting studies have indicated that aberrant expression of lncRNA is related to cell autophagy in diverse cancers (78, 79). Autophagy was a catabolic process by which subcellular membranes undergo dynamic morphological changes that result in the degradation of cellular proteins and cytoplasmic organelles (80).

Notably, SNHG15-driven autophagy through negative regulation of miR-141, according to a study performed by Liu et al., appeared to contribute significantly to osteosarcoma development (57). Markedly, miR-141 repression alleviated the reduction of levels of Atg5, LC3-II, and the ratio of LC3-II/LC3-I and the rise in levels of p62 by SNHG15 knockdown in U2OS cells. Both ATG5 and LC3 were associated with autophagosome formation, while ubiquitin-binding protein P62 was an autophagy substrate, and degradation of P62 implies enhanced levels of autophagy (81, 82).

In addition to contributing to the origin of cancer, the ability to escape cell death also played a fundamental role in therapy resistance, relapse, and metastasis (83). Generally, SNHG15 facilitated the survival of malignant cells by promoting autophagy and was a promising target for anti-cancer treatments in patients against sensitive malignant cells.

Metastasis, a hallmark of cancer, was a complicated multistep process involving cell adhesion, invasion, and migration (84). It has been documented that SNHG15 modulates tumor metastasis primarily by regulating EMT, a pro-metastasis process that enabled cells to migrate more efficiently and invade the underlying mesenchyme (85).

Transcription of SNHG15 was regulated by MYC oncogene, and overexpression of SNHG15 promoted the invasion of colon cancer by interacting with AIF (45). In another separate research, SNHG15 maintained the stability of Slug in tumor cells by impeding its ubiquitination and degradation via interaction with the zinc finger domain of Slug (44). Since Slug was a key regulator of EMT, SNHG15 as a stabilizer of Slug was expected to serve an essential role in the regulation of EMT (44, 86). After the silencing of SNHG15, the expressions of E-cadherin and β-catenin were memorably increased, while the N-cadherin and Vimentin were decreased, suggesting that SNHG15 was also involved in the development of OSCC (59), bladder cancer (28), BC (54), and OC (63). Based on bioinformatics data, SNHG15 upregulation has been identified from tissue samples of CRC with liver metastasis, indicating that high expression of SNHG15 is significantly associated with liver metastasis of CRC (43).

As matrix metalloproteinases, MMPs have been intensively investigated in cancer invasion and metastasis due to their universal function of degrading the protein components in the extracellular matrix (ECM) (87, 88). Western blot assay exhibited that SNHG15 interference significantly decreased the expression of migration and invasion-related proteins VEGF, MMP-9, and MMP-14, further supporting the emphasis on SNHG15 in BC (51). For in vitro studies, SNHG15 knockdown resulted in reduced migration of GC (24, 46) and NSCLC (35, 37)cells. Subsequent experiments concerning that cells with SNHG15-depleted had lower expression of MMP2, and MMP9, indicating the role of MMPs in SNHG15-induced enhancement of migration and invasion (24, 37, 46). In addition to conventional cell-level analysis, tumor metastasis and invasion-related proteins were detected in nude mouse tumorigenesis tissues, and the results showed the expression of MMP2, MMP9, Sail1, and Vimentin was lower in tumor tissues derived from SNHG15-deficient BC cells, while the expression of E-cadherin was high. Kong et al. explored the molecular mechanism of SNHG15 in breast cancer, revealing that SNHG15 acted as a miR-211-3p sponge in carcinogenesis. In line with this, tail vein injection of stable SNHG15-depleted BC cells in nude mice resulted in reduced tumor cell colonization in the lung compared to the control group (53).

Transcription factors are closely involved in EMT, which is a fundamental phenotypic transition (89). In the nucleus, the NF-κB complex binds to sequence-specific gene promoters and modifies the expression of several target genes, including those encoding for transcriptional modulators involved in EMT (Slug, Snail, Twist), thus promoting migration and invasion (90). The expression of NF-κB related proteins detected by Western blot analysis showed that the expression levels of Snail1, Slug, and ZEB1 in RCC cells transfected with SNHG15 siRNA were decreased significantly compared with that in the control group (50). In general, studies of SNHG15 modulating NF-κB and NF-κB-mediated EMT in particular, have opened up avenues for the potential targeted oncogenic NF-κB signaling therapy in metastatic cancers.

Solid tumors have somehow managed to avoid the elimination of various weapons of the immune system or have been able to limit the amplification of immune lethality, thereby evading eradication (91). The various means by which cancer cells bypass the immune system include immune checkpoint inhibitions that accrue myriads of immunosuppressive molecules consisting of programmed death 1 (PD-1) or its ligand PD-L1 (92, 93).

Of note, SNHG15 was positively correlated with PD-L1, and overexpression of SNHG15 significantly reduced the apoptosis rate of HGC-27 cells after incubated with peripheral blood mononuclear cells (PBMC) for 24 h when compared to NC, suggesting that SNHG15 promoted the immune escape of gastric cells to PBMC by regulating the expression of PD-L1. Further analysis confirmed that upregulated SNHG15 inhibited the expression of miR-141, an inhibitor of PD-L1, leading to increased expression of PD-L1, which resulted in resistance of gastric cancer cells to immune response. This study suggested a novel lncRNA-mediated mechanism for gastric cancer cells to evade the immune response, and SNHG15/miR-141/PD-L1 has the potential to be a new target for gastric cancer therapy (47).

Cancer immunotherapy (CIT), primarily represented by PD-1/PD-L1 inhibitors, has become a fashionable treatment approach and made substantial breakthroughs in the treatment of multi-solid tumors (94–96). Under the control of tumor microenvironment complexity and plasticity, lncRNAs enabled tumor evasion from immune surveillance and uncontrolled development of metastasis and drug resistance (97). Targeting SNHG15 with specific inhibitors provided a strategy for studying and improving the efficacy of immunotherapy.

Tumor angiogenesis is a pivotal process in cancer progression, with glioblastoma generally considered to be one of the most vascularized tumors in humans (98). It has been shown that lncRNAs are involved in the regulation of tumor vascular endothelial cell function (99).

SNHG15 was highly expressed in glioma vascular endothelial cells and knockdown of the ncRNA inhibited proliferation, migration, and tube formation in vitro. Survival analysis approved that SNHG15 was a potential prognostic factor for patients with glioma and negatively affected the overall survival of patients with primary glioma (61). Tumor-derived expression of vascular endothelial growth factor (VEGF) was considered a leading candidate in tumor expansion and vascular function (100). Cdc42, a small GTPase that regulates cytoskeletal dynamics, cell shape, and many other cellular processes, was shown to improve VEGF-driven angiogenesis as well (101). Mechanistically, SNHG15 elevated VEGFA and Cdc42 expression by sponging miR-451 at the post‐transcriptional level, facilitating the angiogenesis of glioma. Based on this study, miR-451 silencing occurred via SNHG15, which has binding elements for miR-451 at its 3′‐UTR, leading to aberrant expression of VEGFA and Cdc42. Despite a significant decrease of luciferase activity in the wild-type VEGFA and Cdc42 upon overexpression of miR-51, there was no effect on the mutant type. In a nutshell, lncRNA SNHG15 promoted the growth of glioma microvascular endothelial cells primarily by positively regulating the miR-451/VEGFA/Cdc42 axis, thereby pointing to possible diagnostics and therapeutics based on the axis (61).

In light of the hypervascular nature of glioblastoma, it is promising that antiangiogenic treatment agents could be identified by exploring the regulatory factors of tumor-suppressor genes (102). As a whole, this finding reported by Ma et al. revealed a plausible mechanism responsible for tumor angiogenesis, a complex process with clear relevance to tumor progression and metastasis, thus supporting the notion that SNHG15 may be a novel target for clinical treatment for glioma patients.

Therapeutic resistance was a major challenge in cancer treatment; however, this could be improved by modulating key cellular signaling pathways that conferred drug resistance to increase the treatment sensitivity of tumors (103). Since SNHG15 was closely related to many cellular signaling processes, its expression could be regulated to improve tumor sensitivity.

Cisplatin was a commonly used drug in neoadjuvant chemotherapy and adjuvant chemotherapy for tumors, however, drug resistance posed a major challenge to the clinical application of cisplatin in cancer therapy (104, 105). SNHG15 was overexpressed in cisplatin (DDP) resistant breast cancer cells and tissues, enhancing DDP resistance of breast cancer cells by sponging miR-381 (52). In cervical cancer, both in vitro and in vivo studies have shown that SOX12-induced SNHG15 promotes cervical cancer tumorigenesis and resistance to cisplatin via the miR-4735-3p/HIF1a pathway (65). Likewise, SNHG15 suppressed cisplatin-induced apoptosis and ROS accumulation through the miR-335-3p/ZNF32 axis and was involved in p53-mediated cisplatin resistance in OS cells (58). Interestingly, SNHG15 might also target the miR-381-3p/GFRA1 axis to reduce apoptosis by inducing autophagy, leading to chemotherapy resistance to doxorubicin (55). Several findings above may provide new insights into the discovery of strategies for OS treatment. In studies investigating the resistance of glioblastoma to temozolomide (TMZ), overexpression of SNHG15 was associated with poor patient survival, and knockdown of SNHG15 effectively inhibited the tumorigenic properties of TMZ-R cells via the regulation of miR-627/CDK6 pathway, increasing TMZ-R cell sensitivity to TMZ as well as decreasing TMZ-R’s capacity to generate M2 GAM and glioma stem cells. In conclusion, the present study suggested that SNHG15 may serve as a prognostic marker for TMZ resistance, and Palbociclib, a CDK6 inhibitor, could be used as an adjuvant for overcoming TMZ resistance and shifting microglial cells towards an M1 polarization (60). In addition, knockdown of SNHG15 in gefitinib-resistant A549/GR and H1975/GR cells resulted in sponging miR-451 to up-regulate MDR-1 expression, thus modulating EGFR-TKI acquired resistance in lung adenocarcinoma (34). In studies targeting CRC, inhibition of SNHG15 sensitized LoVo and HCT116 cells to 5-FU, which was the basal chemotherapeutic agent for CRC treatment. Elevated levels of SNHG15 were correlated with the ability of CRC cells to cope with cytotoxic stress induced by 5-FU, which might be mediated in part by its interaction with AIF (45).

Overall, SNHG15 was up-regulated in drug-resistant cancer tissues and cell lines (34, 45, 52, 55, 58, 60, 65). Several findings above may provide new insights into the discovery of strategies for treatment. Overexpressed SNHG15 could promote the occurrence of drug resistance in tumors and reduce the sensitivity of cancer cells to chemotherapy drugs, suggesting its potential as a crucial prognostic factor to predict tumor drug resistance.

The early and accurate diagnosis was undoubtedly crucial to prolong the lifespan of cancer patients, yet current methods do not fully meet the demand for early diagnosis (106, 107). Numerous studies revealed that serum lncRNA could serve as an effective biomarker for cancer detection (108, 109).

Han et al. collected serum specimens from patients with NSCLC, patients with benign pulmonary lesions, and healthy volunteers, respectively, and ROC analysis indicated that serum exosomal lncRNA SNHG15 might well distinguish all stage NSCLC, early-stage (I/II) patients or advanced stage (III/IV) patients from normal controls (110). Further, in combination with CEA, SNHG15 displayed higher accuracy in the early diagnosis of NSCLC. In pancreatic ductal adenocarcinoma (PDAC), the serum level of SNHG15 was significantly higher in patients than in healthy controls (111). With an AUC of 0.727, ROC curve analysis illustrated that serum SNHG15 level might serve as a biomarker for screening PDAC patients from controls.

Despite the considerable interest in the differential expression of SNHG15 for multiple cancers, SNHG15 was less likely to help distinguish between specific origins of tumors. These findings emphasized the need for SNHG15 in combination with other specific biomarkers that could further enhance the diagnostic value of different cancers.

Despite the progression of innovative treatment technologies such as targeted therapy and immunotherapy, the prognosis of cancer remains dismal (112, 113). Profiling potential biomarkers for cancer prognosis and elucidating their functional roles and molecular mechanisms will greatly impact the precision treatment of patients.

It was shown that the aberrant expression of SNHG15 was closely associated with tumor prognosis ( Table 3 ). High expression of SNHG15 in cancer tissue samples exerted an extremely promising potential to predict the adverse prognosis of cancer patients (25, 29, 43, 111, 114, 115). According to Zhang et al., SNHG15 expression was associated with histological grade, TNM stage, and venous invasion in HCC. An analysis of K-M data revealed that patients with high expression levels of LncRNA SNHG15 had poorer overall survival rates. In a brief, high expression of SNHG15 was an independent predictor of poor prognosis in patients with HCC (25). However, in thyroid cancer, the DFS time of patients with lower SNHG15 expression levels was significantly shorter than that of patients with strong levels (67). Moreover, several meta-analyses explored the potential associations between SNHG15 and prognostic attributes and clinicopathological parameters. Several literature findings revealed that SNHG15 overexpression increased the risk of short OS, DFS, and recurrence-free survival (RFS), but without significant heterogeneity (31, 116–118). Furthermore, SNHG15 expression was positively correlated with TNM stage, histological grade, lymphatic metastasis, and distant metastasis. Subgroup analysis confirmed that the high expression of SNHG15 was associated with a significant decrease in OS in patients with digestive cancer, but not LC (116). The study by Zhang et al. suggested that SNHG15 can be a particularly powerful molecular biomarker with prognostic potential in gliomas compared with other known related neoplastic diseases (31). Furthermore, whether there was an association between SNHG15 and tumor volume size remains controversial due to the different criteria for inclusion in the analysis.

The upregulation of lncRNA SNHG15 was significantly associated with poorer prognosis and clinical features, suggesting that SNHG15 may be a novel prognostic factor in various cancers. However, the current deficiency was that most of the subjects included were from China, with small case numbers of certain cancer types and the sample size was still limited. Thus, subsequent prospective studies with high-quality and large-sample sizes were warranted to further confirm the prognostic role of SNHG15 in cancer.

While decades of intensive research into cancer have been conducted, no effective strategy existed to drastically cut the rates of cancer recurrence and mortality (119–121). More interesting was that the SNHG15 expression appears to be differentially modulated in different cancer types and correlates with tumorigenesis, tumor aggressiveness, and stage of cancer, which makes it a candidate for cancer therapies.

The downregulation of SNHG15 and its associated miRNA network overexpression inhibited tumor progression, suggesting SNHG15 as a promising therapeutic target. SNHG15 mediated several events in CRC pathogenesis (42, 44). As well, overexpression of SNHG15 led to an increase in resistance of CRC cells through strong binding to the transcription factor MYC (45). Several in vitro studies indicated that SNHG15 silencing could significantly inhibit the proliferation, migration, and invasion of HCC and RCC cells, induce cell cycle arrest in G1/G0 phase and promote cell apoptosis (39, 122). Furthermore, suppression of SNHG15 inhibited breast xenograft tumor growth in the nude mouse model and reduced tumor weight, exhibiting a strong anti-tumor effect.

Despite these major advances, the oncogenic mechanisms of SNHG15 remain obscure. There was still a long way to go before its application in clinical treatment, including exploration and elucidation of the precise mechanism of action underlying the anti-tumor effect of SNHG15.

Accumulating evidence manifested that genetic alterations and key transcription factors contributed to lncRNA dysregulation in human cancers (123, 124). To our surprise, some upstream transcriptional regulators of SNHG15 have been preliminarily explored in recent years ( Table 4 ).

Prior work declared that two resident E-box motifs are binding platforms for transcription factor MYC on the SNHG15. Chromatin immunoprecipitation (ChIP)-seq data from ENCODE confirmed that MYC is bound to these boxes in different cancerous cell lines. The depletion of MYC in the LoVo cell line resulted in a significant decrease in the level of SNHG15, stating that MYC can activate the transcription of SNHG15 in CRC cells (45). Notably, as predicted by the JASPAR database, ZEB1 could bind to the promoter region of SNHG15 to transcriptionally accelerate its expression in gefitinib-resistant lung adenocarcinoma (LUAD) cells (34). Silencing of the P53 gene in human osteosarcoma U2OS cells significantly increased SNHG15 expression compared to control (58). Consistently, fundamental experiments confirmed that the binding of P53 protein to the SNHG15 promoter was diminished in P53 knockdown cells. In ovarian cancer, tumor cells that were knocked down for SOX12 showed reductions in SNHG15 expression and vice versa. Luciferase reporter gene analysis corroborated the interaction between SOX12 and SNHG15 promoter. Taken together, SOX12 was involved in the transcription of SNHG15 overexpression (65). Ultimately in clear cell renal cell carcinoma (ccRCC), DNA hypomethylation might play a notable role in elevating SNHG15 transcription by substantially modulating its expression level. In the human medulloblastoma cell line DAOY, SNHG15 was modulated by EphrinA5-induced signal transduction, with EphrinA5 stimulation significantly reduced SNHG15 expression which might be relevant for the regulation of tumorigenic processes in the context of glioma (126).

The field of epitranscriptome analysis is becoming increasingly popular among scientists (127). It has been found that RNAs possess more than 170 types of chemical modifications required for their proper function in pre-mRNA splicing, nuclear exporting, transcript stability, and translation initiation (128, 129). N6-Methyladenosine (m6A), the most abundant internal chemical modification of eukaryotic mRNAs, was catalyzed by the m6A methyltransferase complex (MTC) and removed by FTO and ALKBH5 (130). The authors demonstrated that overexpression of lncRNA SNHG15 in myeloma cells rescued the cell proliferation inhibition, cell migration inhibition, and accelerated apoptosis caused by ALKBH5 knockdown (125). Based on renal samples from a cohort, the correlation between the SNHG15 expression and the methylation status of CpG sites was analyzed by gene microarray (26). Using the methylation data, the methylation levels of 3 sites (cg00953154, cg03440944, and cg16459265) were negatively associated with SNHG15 expression respectively, followed by validation in clinical samples.

Compared with the abundant research on downstream mechanisms, the upstream exploration of SNHG15 was still far from sufficient or complete. With the growing number of lncRNAs annotated in genomes by high-throughput sequencing technologies, the list of transcripts with unknown upstream transcriptional regulatory mechanisms was increasing, which provides the possibility for further exploration. Shortly, the cascades of transcriptional regulators upstream of SNHG15 were promising to be determined by fully mining the database and conducting co-expression network studies.

Several studies have highlighted that lncRNAs were able to regulate the expression of target genes by interacting with RNA-binding proteins (131, 132).

SNHG15 could function as protein decoys to recruit proteins in transcriptional gene regulation, either coordinately or in a complex. Ma et al. elucidated that SNHG15-mediated oncogenic effects are partly due to epigenetic inhibition of P15 and KLF2 expression (48). Experimental assays validated that SNHG15 recruited EZH2 to P15 and KLF2 promoters and inhibited transcriptions of these genes via modifying H3K27me3 in PC cells. In short, SNHG15 suppressed P15 and KLF2 expression to promote PC proliferation through EZH2-mediated H3K27me3.

In colorectal cancer, diverse experimental methods have confirmed that SNHG15 interacted with the Slug zinc finger domain and affected Slug protein levels in a post-transcriptional dependent manner (44). Certainly, these findings manifested a novel mechanism underlying the control of Slug stability, where SNHG15 interacted with and blocked Slug degradation along the ubiquitin-proteasome system, ultimately accelerating colon cancer progression.

AIF is a bifunctional protein that exhibits distinct subcellular localizations consistent with its known roles in cellular stress or apoptosis program (133, 134). After translation in the cytosol, AIF was transported to the mitochondria, where it has a strong impact on various cellular stress and survival pathways (135). Assays have confirmed that SNHG15 interacts with AIF based on protein translation, and then participates in the stress response of colorectal cancer cells to 5-FU. Given the full length of the AIF protein interacting with SNNH15, and the subcellular localization of the lncRNA, SNHG15 might interact with AIF in the cytosol, coupling it to the correct mitochondrial translocation and ultimately increasing the sensitivity of the cell to 5-FU (45).

AGO2 is an indicator protein of lncRNA acting as a sponge, which can form a ternary complex of ncRNA-miRNA-AGO2 protein with adsorbed miRNA (136). In hepatocellular carcinoma, RIP experiments confirmed that SNHG15 and miR-141-3p were preferentially enriched in AgO2-containing micronucleus proteins, while this suggests that SNHG15 and miR-141-3p interact in an AgO2-dependent manner (41). In a short, SNHG15 might serve as a scaffold for RNA binding proteins (RBP) to form RNA-protein complexes that ultimately affect protein translation and post-translational modifications.

Currently, available knowledge already reveals an intricate network of lncRNA-protein interactions whose deregulation is frequently associated with pathology. The interaction network was anticipated to expand, providing invaluable clues about lncRNA cellular mechanisms and their diseases-associated variations.

In addition, there are some molecules reported to be mediated by SNHG15, including MMP2 and MMP9. Experimental results appeared that mRNA or protein expression of MMP2 and MMP9 were decreased when SNHG15 was blocked compared with the control groups respectively. In light of these data, MMP2/MMP9 were positively regulated by SNHG15 at both transcription and translation levels. In brief, ectopic expression of SNHG15 contributed to the proliferation and invasion of gastric cancer cells in part through the regulation of MMP2 and MMP9 (24).

Theoretically, any type of RNA with miRNA response elements (MREs), including lncRNAs, could perform the function of ceRNA to degrade miRNAs and compete for the mRNA binding (137, 138). CeRNA was an important biological pathway that regulated RNA gene expression by interacting with the target of the mRNA 3’-UTR, resulting in adenylation, alterations in mRNA stability, and translation inhibition (139, 140). For instance, the upregulation of SNHG15 in prostate cancer tissues resulted in a rapid progression of the disease by increasing the expression of FKBP1A via miR-338-3p absorption. The luciferase activity of the wild-type SNHG15 reporter gene was appreciably reduced after transient co-transfection with miR-338-3p mimics but had no effect on the mutant. The miR-338-3p was capable of interacting directly with the non-coding region of FKBP1A, evoking a significant down-regulation of FKBP1A. Simply put, SNHG15 was involved in the regulation of the miR-338-3p/FKBP1A axis, thus encouraging the malignancy and tumorigenesis of prostate cancer (49). This review mainly summarized the lncRNA-miRNA-mRNA regulatory network formed by SNHG15 acting as a ceRNA in the whole process of sequential carcinogenesis ( Figure 2 ).

We explored the literature on the signaling pathways involved in tumor development for SNHG15 to identify future serve as an early diagnostic biomarker or as a target for gene therapy or other curative treatments. Current studies from different groups suggested that SNHG15 exerted tumor-promoting effects by regulating YAP-Hippo, AKT-mTOR, and NF-κB signaling pathways ( Figure 3 ).

The Hippo pathway is an evolutionarily conserved regulator of tissue growth and cell fate, and YAP1 is thought to be a major terminal effector of the pathway (141, 142). Not surprisingly, dysregulation of the Hippo pathway could induce tumors in model organisms and has been implicated in a broad range of human cancers. A recent study conducted by Wu et al. has confirmed the oncogenic regulatory axis of SNHG15/miR-200a-3P/YAP1 pathway in PTC progression (66). Wu and his colleagues pointed out that decreased SNHG15 expression effectively inhibited the briskness of the YAP1 signaling pathway and EMT process during PTC promotion. Moreover, MST1 and LATS1, the core factors of the Hippo pathway, are negatively regulated by SNHG15 at both the mRNA level and protein level in PTC cells. Given the frequent dysregulation of the Hippo pathway in cancer, targeting this way represented a very promising strategy for cancer treatment. The essential oncoprotein YAP, which was the ultimate common conduit of the Hippo pathway, was the most appealing therapeutic target. Considering the pro-tumor role of SNHG15/miR-200A-3p/YAP1/Hippo axis, combined targeting of the YAP1/Hippo signaling pathway might offer a promising treatment direction for PTC.