<p>A protein-bound stem loop in LINC00152. A and B) The two lowest free-energy structures of LINC00152, predicted by mfold. Boxed areas show overlapping stem-loop regions between the structures which also overlaps with the PARIS reads and Ribo-seq reads. C) IGV view of PARIS reads (two separate experiments) generated from HeLa cells. The boxed areas overlap with the beige area in A. The darker shaded areas show the reads obtained from PARIS with 2-bp gap where indicated. D) Top three tracks: IGV view of Ribo-seq reads from the brain showing sites bound by RNPs as darker shaded areas in the top five tracks. Boxed area is the same as the boxed area in A. Bottom three tracks: RNA-seq reads from the brain that map to exon 2 of LINC00152. The different tracks represent three biological samples. If there is >20% of reads at a position is different from the reference genome (due to mutation, polymorphism, cross-link site), the nucleotide is colored as follows: A: green; T: red; C: blue; G: orange.</p>
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.
