Long non-coding RNA SNHG15 in various cancers: a meta and bioinformatic analysis

Cancer is a severe health problem and is the leading cause of death worldwide, with annually increasing incidence and mortality rates. According to the latest statistics reported in CA cancer journals, 1,806,590 new cancer cases and 606,520 cancer deaths are expected to occur in the United States in 2020 [1]. Although multidisciplinary treatments, such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, of malignancies have improved greatly in recent years, prognosis and early diagnosis remain extremely challenging [2]. As such, there is an urgent need to identify innovative and effective targets for investigating the signalling pathways in tumours, which may ultimately play an indispensable role in therapeutic decision-making for cancer patients.

Long non-coding RNAs (lncRNAs), which were initially speculated to be transcriptional noise with no specific biological function, have emerged as a novel category of non-coding RNAs (ncRNAs) exceeding 200 nucleotides in length that are transcribed by RNA polymerase II but do not encode proteins due to the lack of an open reading frame [3]. Nonetheless, a growing body of work has demonstrated that aberrant expression of lncRNAs is correlated with biological processes, including tumour progression, angiogenesis, metastasis, and invasion, indicating that lncRNAs can serve as tumour suppressors or oncogenes for cancer control [4, 5]. Recently, small nucleolar RNA host gene 6 (SNHG6), linc00152, and opa-interacting protein 5 antisense RNA 1(OIP5-AS1) have been identified as potential prognostic biomarkers involved in the modulation of tumour-related genes and specific molecular mechanisms in human cancers [6‐8].

Small nucleolar RNA host gene 15 (SNHG15), which is located at 7p13 and is 860 base pairs long, was initially reported as a lncRNA with a short half-life [9]. As a tumour oncogene, lncRNA SNHG15 functions as a competing endogenous RNA (ceRNA) to sponge miR-153, miR-38, miR-141, and miR-141-3p, which consequently promotes cell proliferation, migration, invasion, autophagy, and cisplatin resistance in glioma, breast cancer, osteosarcoma, and hepatocellular carcinoma [10‐13]. Furthermore, SNHG15 enhances tumour development or drug resistance in glioblastoma multiforme, colorectal carcinoma, and prostate cancer through the SNHG15/CDK6/miR-627, SNHG15/miR-141/SIRT1/Wnt/β-catenin, SNHG15/miR-338-3p/FKBP1A, and SNHG15/miR-338-3p/FOS-RAB14 axes [14‐17]. Additionally, it was found that SNHG15 could facilitate cell proliferation, invasion, and drug resistance in colorectal cancer by acting as a bifunctional MYC-regulated noncoding locus encoding an lncRNA that interacts with AIF. Similarly, it was demonstrated that SNHG15 promoted tumour progression in colon cancer by stabilising the transcription factor Slug [18, 19]. However, only one report has found SNHG15 to be downregulated in thyroid cancer tissue samples and cells, suggesting its role as a tumor suppressor and the reduced expression of SNHG15 enhanced cell proliferation, migration, and invasion in vitro [20].

Collectively, most studies have demonstrated that SNHG15 is involved in gene regulation by acting as an oncogene in various malignancies, and its elevated expression might be associated with the prognosis and clinicopathological parameters of gastric cancer, hepatocellular carcinoma, lung cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic ductal adenocarcinoma, breast cancer, papillary thyroid carcinoma, colorectal cancer, and epithelial ovarian cancer [21‐31].

However, given the discrepancies between published studies, the small number of patient samples, and the different detection methods used, the prognostic value of SNHG15 remains unclear at this time. Therefore, we conducted this meta-analysis and bioinformatic validation to determine whether SNHG15 could be used as a non-invasive prognostic marker of tumours and attempted to reach a consensus regarding the prognostic value of this gene.

LncRNAs were initially thought to be “transcriptional noise” or “junk DNA” and received little attention in the previous few decades [32]. However, as next-generation genome-wide sequencing and microarrays have been widely applied in clinical settings in recent years, new research has suggested that aberrant expression of lncRNAs may promote or suppress tumour growth, leading to carcinogenesis and cancer progression [33, 34]. For example, some lncRNAs, such as NOC2L-4.1, TUG1, and MALAT1, are well established to promote tumour growth, while other lncRNAs, such as ASMTL-AS1, LINC02381, and LINC02499 have been found to inhibit tumour progression [35‐40].

SNHG15, a promising new cancer-related lncRNA, has been found to be upregulated in a diverse array of malignant tumours. It has been demonstrated that elevated expression of SNHG15 is significantly related to tumour size, TNM stage, and lymph node metastasis in pancreatic cancer patients [41]. However, the definitive prognostic role of this gene was previously unclear. In our meta-analysis, we investigated the potential association between SNHG15 expression and prognostic attributes and clinicopathological parameters by integrating data from 11 studies. We found that SNHG15 overexpression increased the risk of shorter OS and DFS with no conspicuous heterogeneity. Simultaneously, we demonstrated that patients with increased SNHG15 expression were more likely to develop advanced TNM stage and positive lymph node metastasis, while these effects were not associated with age, sex, or tumour size. Additionally, no evident publication bias in OS was identified throughout the study, and the robustness of the results was verified via sensitivity analysis. Furthermore, validating the TCGA datasets revealed that high SNHG15 expression levels were observed in COAD, DLBC, KIRC, PAAD, READ, TGCT, and THYM. We also evaluated the TCGA cohort to confirm the prognostic role of SNHG15 in various cancers, and the elevated expression of SNHG15 in 33 types of tumour tissues was associated with worse OS and DFS. In some cancers, including ACC, KIRC, MESO, and UVM, SNHG15 overexpression indicated shorter OS. Moreover, survival plots revealed that ACC, PRAD, and UVM patients with SNHG15 upregulation exhibited worse DFS. Taken together, these results indicate that SNHG15 could serve as a biological modulator and novel biomarker of poor prognosis in cancer patients.

LncRNAs can indirectly regulate the expression and function of target genes via ceRNA. Thus, we constructed a ceRNA network to assess the potential function and molecular mechanism of SNHG15 in cancers. The results of our functional analysis demonstrated that target genes indirectly affected by SNHG15 may be involved in some of these signaling pathways, and promoted the proliferation, invasion and metastasis of tumour cells. Accordingly, the potential molecular mechanism involved in tumour progression may be investigated in the future to better understand the association between altered SNHG15 expression and poor prognosis (Table 3). In gastric cancer, SNHG15 upregulation promotes cell proliferation and invasion by modulating the expression of MMP2/MMP9 [21]. In lung cancer, it has been reported that SNHG15 overexpression enhances tumour occurrence and development by targeting miRNA-211-3p to regulate cell proliferation and migration in vitro [23]. Similarly, in non-small cell lung cancer, two studies have demonstrated that SNHG15 knockdown suppresses tumorigenesis by inhibiting the expression of EMT, MMP2, and MMP9 and regulating the miR-486/CDK14 axis [24, 25]. Meanwhile, another study has identified that SNHG15 facilitates renal cell carcinoma invasion and migration through the NF-κB signalling pathway and by inducing the EMT process [26]. In breast cancer, it has been shown that SNHG15 functions as a ceRNA to sponge miR-211-3p, thereby promoting cell proliferation, migration, and invasion and inhibiting apoptosis [28]. Additionally, SNHG15 has been reported to act as a ceRNA to modulate the miR-200a-3p/YAP1-Hippo axis in papillary thyroid carcinoma [29]. Consistently, functional assays have revealed that upregulation of SNHG15 facilitates the migration, invasion, proliferation, and chemoresistance of epithelial ovarian cancer cells [31]. However, the signalling pathways involved in in HCC, PDAC, and colorectal cancer remain unclear; therefore, additional studies are needed to explore the potential mechanisms by which SNHG15 expression predicts survival across diverse malignancies [22, 27, 30].

Several key points from our paper should be noted. First, our meta-analysis was the first study to exhaustively investigate the association between SNHG15 expression and clinical outcomes in cancer patients. In addition, only one random-effect model was employed in the analysis, indicating that the results are credible and accurate. Furthermore, we determined rigorous inclusion and exclusion criteria to enrol only high-quality studies.

Nonetheless, several limitations in our study should be considered. First, all the included subjects were from China, with small case numbers of certain cancer types and a small sample size, which led to our results being only applicable to Asia. To address this, we further validated these results using the GEPIA database to support our conclusion as broadly as possible. Further, HRs with 95% CIs were retrieved from K-M curves in six studies, which may inevitably exaggerate the prognostic value of SNGH15 and introduce bias. Moreover, the lack of articles with negative results may have caused an overestimation of the clinical value of this gene. Additionally, the inconsistent cut-off values may introduce heterogeneity among the studies.

Taken together, despite the above limitations, our study revealed that SNHG15 overexpression is significantly associated with unfavourable prognosis and advanced clinical features. However, high-quality studies with standardised methods and larger sample sizes from different countries are still needed to confirm our results.