Long non coding RNAs lncRNAs are mRNA

Long non-coding RNAs (lncRNAs) are mRNA-like transcripts of greater than 200 nucleotides (nt), with little or no protein-coding potential [13,14]. LncRNAs have been suggested to participate in transcription and post-transcription regulation as scaffolds, guides, decoys or repressors, activators, and sponges [15]. It has been shown that lncRNAs play a key role in diverse cancer initiation, development and progression [16]. For example, Hou et al. [17] demonstrated that lncRNA-ROR contributed to breast cancer tumorigenesis and metastasis by inducing the epithelial-to-mesenchymal transition. Ma et al. [18] found that lncRNA XIST regulated the miR-497/MACC1 axis in gastric cancer, thus promoted the growth and invasion of gastric cancer cells. Nevertheless, few studies have been conducted to explore the role and mechanism of lncRNAs in cancer glycolysis-mediated metastasis. In the current study, we identified a lncRNA named lnc-p23154, which was upregulated in OSCC. Then, we determined the role of lnc-p23154 in promoting OSCC metastasis in vitro and in vivo and demonstrated that lnc-p23154 participated in glycolysis by regulating Glut1 expression. In addition, we found that miR-378a-3p targeted to 3ʹUTR of Glut1 and inhibited Glut1-mediated OSCC metastasis. Importantly, we found that lnc-p23154 interacted with miR-378a-3p promoter to repress its transcription, and then increased Glut1 expression. These findings suggested that the lnc-p23154-miR-378a/Glut1 pathway participated in OSCC metastasis, and it may provide a new potential biomarker for OSCC diagnosis and therapeutic target.
Materials and methods
Results
Discussion It has been demonstrated that several genes are involved in glycolysis and regulate the biological characteristics of tumor cells, such as drug resistance, cell growth, and metastasis [[20], [21], [22]]. LncRNAs are considered to be emerging regulators of glycolysis by regulating glycolysis-related genes [23,24]. For example, by binding to c-Myc directly, the lncRNA PCGEM1 modulated the expression of critical Cy7.5 NHS ester (non-sulfonated) involved in glycolysis and promoted glucose uptake in prostate cancer [25]. In addition, in bladder cancer, UCA1 contributed to the regulation of HK2, a rate-limiting enzyme, via mTOR–STAT3 signaling and then enhanced glycolysis [26]. However, few studies have focused on the function and mechanism of lncRNAs in OSCC glycolysis. Here, we identified an upregulated lncRNA, lnc-p23154, which was co-expressed with numerous metabolism-related genes in OSCC tissues. Furthermore, our data suggested that lnc-p23154 promoted glycolysis by increasing Glut1 expression and contributed to OSCC metastasis. To our knowledge, this is the first report to reveal the effect of lncRNA on Glut1-mediated glycolysis in OSCC. Glut1 was a member of glucose transporter (GLUT) proteins and suggested to play a role as the basal switch in tumor cell glycolysis [27]. Many studies reported that high level of Glut1 expression was correlated with poor survival outcomes in human cancer, probably because it was involved in the status of metastasis [28]. Glut1 overexpression accelerated tumor cell glycolysis and provided energy for cells metastasizing to distant locations. Therefore, knockdown Glut1 significantly inhibit the migration and invasion of tumor cells [29,30]. Similarly, we found that Glut1 was up-regulated in OSCC and related with the node metastasis in OSCC patients. Our results also indicated that Glut1 contributed in the OSCC cell glycolysis and then manipulate the cell migrative and invasive ability. Through an RNA-seq assay, we found that downregulation of lnc-p23154 could significantly influence the expression of cell movement-related genes, including MMP1 and CTGF. As an oncogene, MMP1 has been suggested to participate in cancer metastasis [[31], [32], [33]]. Numerous studies have shown that CTGF promotes migration and invasion by inducing EMT-related gene expression [[34], [35], [36]]. We found that knockdown of Glut1 in OSCC cells repressed MMP and CTGF expression, and lnc-p23154 could reverse this effect. Moreover, transwell assay demonstrated that lnc-p23154 restored the inhibition of Glut1 downregulation during metastasis. Thus, we suggested that lnc-p23154 regulates OSCC metastasis through Glut1.