Cancer has become a global health problem. In recent years, the incidence of cancer has been increased year by year. According to WHO estimates, 14.1 million new cancer patients and 8.2 million deaths from cancer occurred worldwide in 2012 and more than 20 million new cases of cancer will be expected as early as 2025 (Ferlay et al., 2015). At present, cancer treatment includes surgery, radiotherapy, chemotherapy andetc., but the 5 years survival rate is still not ideal, especially some patients with lymph node metastasis or high stage tumor (Saika and Sobue, 2013). Therefore, it is important to find a new biological target that plays a guiding role in the carcinogenesis to detect cancer. It is also more conducive to early detection, early diagnosis and early treatment of tumor patients.

Long non-coding RNAs (lncRNAs) are noncoding RNAs with a length of more than 200 nucleotides that regulate gene expression (Mattick and Makunin, 2006). They were described as “noise,” and did not attract much attention in the past few decades (Ponjavic et al., 2007). With the application of whole genome sequencing and microarray, lncRNAs have attracted more and more attentions (Batista and Chang, 2013; Tang et al., 2013). The increasing evidence show that lncRNAs play a pivotal role in the development and progression of tumors, which means that they can be used as biomarkers for some tumors (Fang et al., 2017; Liu et al., 2017; Sun et al., 2017; Yang et al., 2017). However, only a few number of lncRNAs have corresponding functional features, and most of the functions of lncRNAs remain unclear.

The growth arrest-specific transcript 5 (GAS5) is a rising star among tumor-suppressive lncRNAs among all the kinds of lncRNAs (Ma et al., 2016). Recent studies have shown that GAS5 plays a key role in a variety of human diseases and participates a variety of biological processes, such as cell proliferation, cell apoptosis, epithelial-mesenchymal transition and etc. (Tan et al., 2017; Tao et al., 2017; Wen et al., 2017; Yang et al., 2017). Meanwhile, GAS5 is also involved in the progression of many types of cancer, such as bladder cancer (BC) (Zhang et al., 2017), colorectal cancer (CRC) (Yin et al., 2014; Li et al., 2017), non-small cell lung cancer (NSCLC) (Shi et al., 2015; Wu et al., 2016), breast cancer (BRC) (Li W. et al., 2016), hepatocellular carcinoma (HCC) (Tu et al., 2014; Chang et al., 2016; Hu et al., 2016), epithelial ovarian cancer (EOC) (Gao et al., 2015), gastric cancer (GC) (Sun et al., 2014), cervical cancer (CEC) (Cao et al., 2014), and head and neck squamous cell carcinoma (HNSCC) (Gee et al., 2011). The clinic pathological features of the patients, such as overall survival (OS), lymph node metastasis (LNM) and high tumor stage (II/III/IV) (HTS), are also highly correlated with the level of GAS5 expression in these cancers (Gee et al., 2011; Cao et al., 2014; Sun et al., 2014; Tu et al., 2014; Yin et al., 2014; Gao et al., 2015; Shi et al., 2015; Chang et al., 2016; Hu et al., 2016; Li J. et al., 2016; Wu et al., 2016; Droop et al., 2017; Li et al., 2017; Zhang et al., 2017). All these indicate that GAS5 can be a novel prognostic biomarker in unique cancer. To shed light on the relationship between GAS5 and cancer prognosis, the meta-analysis on the association between the expression of GAS5 and the prognosis of cancer is required. Although a meta-analysis has reported that the expression of GAS5 predicts poorer survival outcomes, only 4 literatures have been included in that work and the results may be incidental (Song et al., 2016). To verify the accuracy of the previous results, the present meta-analysis with 14 studies may provide a more accurate conclusion.

GAS5 has been reported to be down-regulated in multiple cancers, leading to changes in tumor cell production, proliferation, apoptosis, metastasis, and survival time (Chang et al., 2016; Hu et al., 2016; Zhang et al., 2017). In our meta-analysis, we explored the relationship between the level of GAS5 expression and cancer prognostic parameters. The results demonstrated that low expression levels of GAS5 predicted poor OS in various cancers and patients with low GAS5 expression in tumor tissues were more prone to lymph node metastasis. Meanwhile, we found patients with low GAS5 expression in cancerous tissues were more prone to high tumor stage. Our results showed that low expression levels of GAS5 could be a molecular biomarker of poor prognosis in cancer patients.

As shown in Figure 2, GAS5 and OS are positively related in OS analysis without heterogeneity and publication bias: the low expression of GAS5 predicts poorer survival outcomes. To investigate whether the above analysis was applicable in separate cancers, we made a subgroup analysis. The results was HCC (HR = 1.893, 95% CI: 1.103–3.249, P = 0.021, P(H) = 0.902), UC (HR = 1.653, 95% CI: 1.185–2.306, P = 0.003, P(H) = 0.268) which meant that the above conclusions applied equally in HCC and UC. Meanwhile, we investigated the association between the GAS5 expression levels and LNM and HTS, and we found that low GAS5 expression in cancerous tissues were more prone to LNM and HTS (Figures 3, 4). However, in LNM analysis we found that the included studies existed significantly heterogeneity. So we performed a subgroup analysis according to tumor type, and the results showed that the heterogeneity disappeared obviously in CRC(P for heterogeneity = 0.211, I² = 36.1%, random-effects model), and other types of cancer(P for heterogeneity = 0.516, I² = 0.0%, random-effects model), while the heterogeneity still existed in NSCLC(P for heterogeneity = 0.107, I² = 61.6%, random-effects model) which might be caused by the different cut-off value methods which were adopted to define the high GAS5 expression group or low GAS5 expression group. In conclusion, all these results provided strong evidence for GAS5 as a potential biomarker for the prognosis of various cancers.

Nowadays, many lncRNAs have been found to be abnormally expressed in cancer. Therefore, many meta-analysis articles, like our study, have been used to reveal the correlation of lncRNAs and cancer prognosis. Several lines of studies, meanwhile, have revealed that a lot of lncRNAs play a important role in cancer prognosis, such as TUG1, SPRY4, MALAT1 (Wang et al., 2015, 2017; Yu et al., 2017). For instance, Wang et al. found that SPRY4 is remarkably upregulated in various cancer. Thus, they performed the meta-analysis to examine the association between the SPRY4-IT1 expression level and prognosis in cancer patients. Finally, they suggested the prognostic role of SPRY4-IT1 in human cancers, and increased SPRY4-IT1 expression was closely associated with advanced features of human cancers (Wang et al., 2017). Likewise, NEAT1, as a novel lncRNA, has been recently found to be up-regulated in several cancers, contributing to tumor proliferation, apoptosis, metastasis and survival. Chen et al. conduct a meta-analysis to clarify the association between high NEAT1 expression and poor prognosis. Eventually, they concluded that NEAT1 may serve as a molecular marker and a prognostic factor for patients with various cancers (Chen et al., 2017). Additionally, among these studies, it can be found that different lncRNA has specific signaling pathways in cancers. They move the extracellular signaling molecules into the cell and then, in some way, further affect cell phenotypic changes, such as cell metabolism, proliferation, invasion, apoptosis, and so on (Wang et al., 2015, 2017; Yu et al., 2017). To further investigate the value of GAS5, we analyzed and screened the signaling pathways and mechanisms of action from all GAS5 related literatures, which will be useful for future studies on tumorigenesis (Table 4).

There are several limitations in our study that should be acknowledged. Firstly, the present study used the summary data rather than a specific patient data. Secondly, the methods for distinguishing the cut-off value of GAS5 in high and low expression groups were inconsonant which inevitably could cause heterogeneity. Thirdly, most of the HR values were not directly reported in these included studies. We extracted and calculated them according to the survival curves, so inevitably there might be errors. Fourthly, different treatment methods for different types of cancer patients after surgery might have great influence on the survival time, which leaded to the heterogeneity of the researches. Fifthly, we only included English related literatures that could not be so comprehensive. Sixthly, most of the studies were from China, so the conclusion might not necessarily apply in other areas. Seventhly, we only included related studies reporting OS, LNM and HTS, and the articles on other prognostic indicators were thus excluded. In the light of the above deficiencies, a more comprehensive study covering larger samples, more regions, and more indicators will be needed to confirm our results.

In conclusion, our meta-analysis found that lncRNA GAS5 could sever as a molecular biomarker to predict the prognosis of various cancers and the low GAS5 expression could indicate the poor prognosis.

QG and HX performed Data extraction, HZ and JL did the data analysis. YL and WH designed the project and QG wrote the paper. YL supervised the project. WH provided financial support for the project.