Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor. Despite surgical resection followed by radiotherapy and chemotherapy, the median survival rate is approximately 14 months. Although experimental therapies are in clinical trials for GBM, there is an urgent need for a peripheral GBM biomarker for measuring treatment response. As we have previously demonstrated that the long noncoding RNA HOX Transcript Antisense Intergenic RNA, or HOTAIR, is dysregulated in GBM and required for GBM cell proliferation, we hypothesized that HOTAIR expression may be utilized as a peripheral biomarker for GBM. HOTAIR expression was measured in serum from 43 GBM and 40 controls using quantitative real-time PCR (qRT-PCR). The PCR products were subsequently subcloned into pCR™4-TOPO®TA vectors for DNA sequencing. A ROC curve was also generated to examine HOTAIR’s prognostic value. The amount of HOTAIR in serum exosomes and exosome-depleted supernatant was calculated by qRT-PCR. The relative HOTAIR expression was also investigated in 15 pairs of GBM serum and tumors. We detected HOTAIR in serum from GBM patients. HOTAIR levels in serum samples from GBM patients was significantly higher than in the corresponding controls (P < 0.0001). The area under the ROC curve distinguishing GBM patients from controls was 0.913 (95% CI: 0.845–0.982, P < 0.0001), with 86.1% sensitivity and 87.5% specificity at the cut-off value of 10.8. HOTAIR expression was significantly correlated with high grade brain tumors. In addition, Pearson correlation analysis indicated a medium correlation of serum HOTAIR levels and the corresponding tumor HOTAIR levels (r = 0.734, P < 0.01). We confirmed via sequencing that the amplified HOTAIR from serum contained the HOTAIR sequence and maps to the known HOTAIR locus at 12q13. The serum-derived exosomes contain HOTAIR and the purified exosomes were validated by western blot and nanoparticle tracking analysis. Importantly, our results demonstrate that serum HOTAIR can be used as a novel prognostic and diagnostic biomarker for GBM.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor [1]
HOX transcrpt antisense intergenic ribonucleic acid (HOTAIR) expression is higher in serum isolated from GBM patients relative to controls HOTAIR expression has been shown to be greater in tumors from GBM patients relative to lower grade glioma
Our findings suggest that serum HOTAIR levels was higher in serum from all brain tumor patients relative to control serum and HOTAIR expression in GBM serum is significantly higher than in normal control serum (Fig. 1a, b and Methods are explained in Additional file 1: Materials and Methods)
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive malignant adult primary brain tumor [1]. In this study we demonstrate that HOTAIR levels is a serum biomarker in GBM. Serum HOTAIR levels can be potentially be monitored in GBM patients during treatment to detect treatment response and tumor recurrence.
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