Long Noncoding RNA PVT1 as a Novel Predictor of Metastasis, Clinicopathological Characteristics and Prognosis in Human Cancers: a Meta-Analysis

With the incidence and mortality increased year by year, cancer is becoming a major public health problem and a leading cause of death worldwide. According to GLOBCAN 2012, there were 14.1 million new cancer cases and 8.2 million cancer deaths in 2012 worldwide [1]. In the United States, cancer is the second leading cause of death with an estimated 1,685,210 new cases and 595,690 deaths cancer in 2016 [2]. In China, cancer has been the leading cause of death with an estimated 4,292,000 new cases and 2,814,000 death cases in 2015 [3]. Lymph node metastasis, distant metastasis and clinical stage play an important role in the progression of cancer and are closely related to the prognosis of cancer. The presence of lymph node metastasis and distant metastasis also determines the treatment of cancer, such as surgery, radiotherapy or chemotherapy. Therefore, looking for molecular markers associated with metastasis, clinical stage and prognosis is becoming imminent for the therapy of cancer.

Long noncoding RNAs (lncRNAs) are a class of RNAs with a length greater than 200 nucleotides and no protein coding ability. Recently, with the rapid development of high throughput sequencing technology, lncRNAs have been found to be abnormally regulated in various types of cancer and played an indispensable role in the metastasis, advanced clinical stage and prognosis of cancer [4]. Plasmacytoma variant translocation1(PVT1) was first discovered in 2013 in human colorectal cancer and was a copy number amplification associated lncRNA which located on chromosome 8q24 and near MYC [5]. Accumulating evidence revealed that PVT1 was unregulated and played vital regulatory roles in a variety of cancers, including colorectal [6], pancreatic [7], breast and ovarian cancer [8]. High PVT1 expression was strongly correlated with clinicopathologic characteristics, such as metastasis, clinical stage and prognosis [9, 10]. However, since the results of the studies were not consistent (15 articles displayed positive results and 9 articles showed negative results) and small sample size in individual study, we collected relevant publications and performed a meta-analysis to investigate the relationship between PVT1 expression and metastasis, clinical stage or prognosis, aiming to further evaluate whether the PVT1 could be served as a potential molecular biomarker for cancers.

PVT1 was a novel lncRNA which was first discovered in 2013 in human colorectal cancer. In recent years, a growing number of studies have shown that PVT1 upregulated in several cancers. The further comprehensive mechanism between PVT1 and cancers was reported in continuance. PVT1 involved in tumor proliferation, invasion, migration and apoptosis and played an important role in tumor progression, metastasis and prognosis. In order to combine previous research results about PVT1 and cancers to arrive at a summary conclusion, we clarified the relationships between PVT1 expression levels and metastasis, clinical stage or prognosis in cancers in this meta-analysis. As far as we know, this is the first meta-analysis providing comprehensive insights into the correlation of PVT1 and cancer clinical stage. Results showed that the risk of lymph node metastasis and distant metastasis in high PVT1 expression group was 2.83 and 3.60 folds than those with low PVT1 expression group, respectively. The risk of developing into advanced clinical stage in PVT1 over expression patients was 4.37 times higher than those with low PVT1expression. PVT1 over expression patients with poor prognosis were 2.08 times lower in patients with low PVT1 expression. The same results were also shown in the subgroup analysis of different system tumors.

First, in respiratory system tumors, Wan et al. found that Over expression PVT1 inhibited the expression of LATS2 by binding to enhancer of zeste homolog 2 (EZH2) and promoted cell proliferation in non-small cell lung cancer [15]. Digestive system tumors such as in esophageal cancer, PVT1 upregulation decreased E-cadherinexpression and increased N-cadherin and vimentin expression, and induced epithelial-to-mesenchymal transition (EMT) process [12]. In gastric cancer, Xu et al. suggested that PVT1 facilitated gastric cancer cell proliferation and metastasis, and fulfilled its oncogenic functions in a FOXM1-mediated manner [26]. In hepatocellular carcinoma, Lan et al. demonstrated that PVT1 over expression was significantly correlated with vascular invasion, liver cirrhosis and TNM stage. Mechanism studies showed that PVT1 served as an endogenous sponge for miR-186-5p to reduce its inhibiting effect on yes-associated protein 1 and thus promoted the tumorigenesis of hepatocellular carcinoma [29]. In colorectal cancer, Takahashi et al. demonstrated high PVT1 expression exhibited greater lymph node metastasis, venous invasion and a poor OS compared with low PVT1 expression [21]. In pancreatic carcinoma, Zhao et al. found that PVT1 functions as an endogenous ‘sponge’ by competing for miR-448 binding to regulate the miRNA target SERBP1and therefore promotes the proliferation and migration of pancreatic carcinoma cells [28]. Furthermore, PVT1 expression levels were significantly correlated with metastasis and advanced clinical stage in urinary system tumors, such as bladder cancer and renal carcinoma. Huang et al. showed that high PTV1 expression was correlated with lymph node metastasis, advanced TNM stage and shorter OS. Knock down PVT1 decreased cell proliferation and enhanced cell apoptosis. Finally, PVT1 also functioned as critical regulator in the prognosis of other system tumors, including cervical carcinoma, ovarian cancer and osteosarcoma. Song et al. suggested that high PVT1 expression predicted poor prognosis. PVT1 over expression increased glucose uptake, lactate production, and the expression of HK2 in osteosarcoma cells. PVT1 could act as molecular sponge to repress the expression of miR-497 and promote the development of osteosarcoma [30].

To summarize, although mechanisms of PVT1 acted were not the same in various cancers, many similarities were still existed. First, PVT1 played a key role in cancers by interacting with miRNAs. An inverse association was observed between PVT1 and miR-186 expression levels which was observed in gastric cancer and hepatocellular cancer, while PVT1 functions as an endogenous ‘sponge’ by competing for miR-448 in pancreatic cancer. Second, PVT1 could also alter the expression of certain genes, including bind to EZH2 in non-small cell lung cancer and gastric cancer. PVT1 could interact with FOXM1 directly and increase its protein expression in gastric cancer and increased glucose uptake, lactate production, and the expression of HK2 in osteosarcoma cancer. Finally, PVT1 also affected cell cycle progression, such as promoted cell proliferation, migration and invasion and inhibited cell apoptosis in various cancers. In general, PVT1 expression was significantly associated with metastasis, clinical stage, and poor prognosis in various types of cancer in different systems.

Otherwise, as with other meta-analysis, it should be acknowledged that some limitations existed in this meta-analysis. First, the cutoff values of PVT1 high expression and low expression were lack of uniform standard in different types of cancer, which may result in some heterogeneity and affect the results of the study. Second, different studies have different postoperative regimens that may have a significant impact on OS, DFS, PFS and RFS. Third, since most studies report positive results and negative results are rarely published, the results of this study may overestimate the effect of PVT1 on cancers to a certain extent. Although there are some limitations, but this meta-analysis still has its noteworthy advantages. First, 24 literatures including a total of 2212 cases were included in this meta-analysis. The sample size included was the largest, which significantly improved the statistical efficiency and accuracy of the test. Second, the search databases were the most and cancer types were the most comprehensive in this meta-analysis compared with the previous reports. Third, lymph node metastasis and distant metastasis, OS、DFS、PFS and RFS were included in this study, which made the results more complete and comprehensive. Finally, the inclusion and exclusion criteria were more stringent and the quality of the literatures incorporated was higher.

In conclusion, despite the limitations described above, our meta-analysis reveals that upregulated PVT1 is significantly correlated with more metastasis, advanced clinical stage and poor prognosis in patients with various cancers. Furthermore, the significance of PVT1 in the metastasis, clinical stage and prognosis of respiratory system tumors is more obvious and can be used as a potential molecular marker to evaluate the prognosis of cancer. Nevertheless, the indication in the urinary system is relatively weak as the fewer samples; suggesting that we need to incorporate more studies in the urinary system tumors to validate this result.