Recently, large numbers of lncRNAs were found to be aberrantly expressed and involved in tumor initiation and progression in various cancers. Such lncRNAs could function as oncogenes and tumor suppressor genes and their expression could correlate with good or poor prognosis, making them valuable prognostic biomarkers. lncRNA HOTAIR has been used as a prognostic marker in different cancer types. High HOTAIR expression was significantly associated with poor overall survival and could serve as an independent prognostic factor [
17]. It had been shown that MALAT1 was upregulated in many cancers and might act as a biomarker to predict survival in lung cancer [
18]. lncRNA MEG3 was downregulated in a variety of primary cancers and found to be a prognostic factor for patients with glioma [
19]. It was reported that lncRNA GAS5 expression was significantly reduced in liver cancer and could be an independent prognostic factor for patients [
20]. In our study, we profiled differentially expressed antisense lncRNAs in glioma and identified a new antisense lncRNA WDFY3-AS2. Univariate and multivariate COX regression analysis found that WDFY3-AS2 downregulation was independently correlated with overall survival in patients, which indicated that WDFY3-AS2 could be a valuable prognostic biomarker for glioma.
As we known, increasing evidence has demonstrated that antisense lncRNAs are involved in regulation of a large range of biological processes through various mechanisms, such as transcriptional, post-transcriptional regulation and epigenetic modification. For example, antisense lncRNAs may regulate gene transcription in cis or trans through recruiting chromatin-modifying enzymes. Zhang et al. reported that lncRNA EZR-AS1 could enhance EZR transcription and expression by recruiting SMYD3 (a histone H3K4-methyltransferase) to its promoter region in esophageal squamous cell carcinoma [
21]. lncRNA AGAP2-AS1 could bind with EZH2 and LSD1 and recruit them to KLF2 and LATS2 promoter regions to repress their transcription in non-small-cell lung cancer [
22]. Antisense lncRNAs could function as competing endogenous RNAs (ceRNAs) to regulate targeted genes by binding with miRNAs. Wang et al. found lncRNA HOXD-AS1 promoted tumor progression by regulating the expression of frizzled family receptor 4 (FZD4) through competitively binding to miR-608 in ovarian cancer [
23]. lncRNA TP73-As1 modulated cell proliferation through miR-200a dependent HMGB1/RAGE regulation in hepatocellular carcinoma [
24]. In addition, antisense lncRNAs could also act as a molecular partner. Ding et al. reported that HNF1A-AS1 functioned as phosphatase activator through direct interaction with SHP-1 in hepatocellular carcinoma [
25]. WDFY3, known as ALFY, encodes a phosphatidylinositol 3-phosphate-binding protein that function as a master conductor for aggregate clearance by autophagy [
26]. Tschan reported that WDFY3 is critical for the granulocytic differentiation of AML cells [
27]. Since antisense lncRNAs generally function as regulators of their complementary protein-coding genes [
21], we first detected the expression correlation between WDFY3-AS2 and WDFY3 to evaluate the possible function and mechanism of WDFY3-AS2 in glioma. As shown in Additional file
1: Figure S1, WDFY3-AS2 expression was positively correlated with WDFY3 level in glioma (Pearson correlation coefficient r
2 = 0.6418,
P < 0.001), indicating a possible regulatory relationship between WDFY3-AS2 and WDFY3. Moreover, we also predicted the miRNAs that may interact with WDFY3-AS2 using LncBase v2 (
https://omictools.com/lncrna2target-tool). mir-221, mir-26a, mir-135a, mir-9 and mir-139 showed the potential interaction with WDFY3-AS2. Among these miRNAs, mir-221 and mir-26a were overexpressed and could promote the malignant progression in glioma [
28‐
30]. Therefore, we speculated that WDFY3-AS2 might modulate glioma cell malignant phenotype through interacting with mir-221 or mir-26a. GO and GSEA revealed that gene sets correlated with WDFY-AS2 expression were involved in regulation of synaptic transmission, glutamate receptor and TNF signaling pathways. Glutamate receptor signaling pathway plays important role in regulating glioma cell proliferation and invasion [
31,
32]. Ciceroni found that type-3 glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with gliomas [
33]. TNF signaling pathway is also an important regulator of the progression of glioma. Glioma cells tend to develop a resistance mechanism opposing to the TRAIL-induced apoptosis by overexpressing a wide variety of antiapoptotic proteins [
34]. Deshayes reported that abnormal production of the TNF-homologue APRIL increases the proliferation of human malignant glioblastoma cell lines via a specific receptor [
35]. Therefore, we proposed to determine whether WDFY-AS2 affected glioma cell behaviors through regulating glutamate receptor or TNF signaling pathway. Overall, further studies are required to clarify the function and molecular mechanism of WDFY3-AS2 in glioma.