LINC00152 expression level in glioma subtypes and association with patient outcome in different cancers. A-B) LINC00152 is not differentially expressed in LGGs globally or between GBM subtypes. A) Boxplot of LINC00152 expression in normal brain tissue, G2 (grade 2 glioma) and G3 (grade 3 glioma). B) Boxplot of LINC00152 expression in GBM subtypes. C-E) High levels of LINC00152 expression is associated with negative patient outcomes in three more cancers. C-D) Kaplan Meier plots of the top third of LINC00152 expressing patients and the bottom third of LINC00152 expressing patients in renal papillary tumor and pancreatic adenocarcinoma, respectively. E) Kaplan Meier plots of the top quarter of LINC00152 expressing patients and the bottom quarter of LINC00152 expressing patients in acute myeloid leukemia. Hazard ratio is indicated as "HR" and the 95% confidence interval is indicated as "CI".
ARTICLE ABSTRACT
Long noncoding RNAs (lncRNA) are increasingly implicated in oncogenesis. Here, it is determined that LINC00152/CYTOR is upregulated in glioblastoma multiforme (GBM) and aggressive wild-type IDH1/2 grade 2/3 gliomas and upregulation associates with poor patient outcomes. LINC00152 is similarly upregulated in over 10 other cancer types and associates with a poor prognosis in 7 other cancer types. Inhibition of the mostly cytoplasmic LINC00152 decreases, and overexpression increases cellular invasion. LINC00152 knockdown alters the transcription of genes important to epithelial-to-mesenchymal transition (EMT). PARIS and Ribo-seq data, together with secondary structure prediction, identified a protein-bound 121-bp stem-loop structure at the 3′ end of LINC00152 whose overexpression is sufficient to increase invasion of GBM cells. Point mutations in the stem-loop suggest that stem formation in the hairpin is essential for LINC00152 function. LINC00152 has a nearly identical homolog, MIR4435-2HG, which encodes a near identical hairpin, is equally expressed in low-grade glioma (LGG) and GBM, predicts poor patient survival in these tumors, and is also reduced by LINC00152 knockdown. Together, these data reveal that LINC00152 and its homolog MIR4435-2HG associate with aggressive tumors and promote cellular invasion through a mechanism that requires the structural integrity of a hairpin structure.Implications: Frequent upregulation of the lncRNA, LINC00152, in glioblastoma and other tumor types combined with its prognostic potential and ability to promote invasion suggests LINC00152 as a potential biomarker and therapeutic target. Mol Cancer Res; 16(10); 1470–82. ©2018 AACR.
