Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme

Tan, Sze Kiat; Pastori, Chiara; Penas, Clara; Komotar, Ricardo J.; Ivan, Michael E.; Wahlestedt, Claes; Ayad, Nagi G.

doi:10.1186/s12943-018-0822-0

Cited by 223 publications

(173 citation statements)

References 18 publications

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“…In recent years, the roles of lncRNAs in cancer have been widely studied. Many reports have shown that lncRNAs participate in several cancer-associated processes including chemoresistance [26,27], and abnormal expression of lncRNAs have been shown to be involved in the malignant process of glioma [28][29][30]. However, lncRNAmediated TMZ-resistant mechanisms have rarely been studied.…”

Section: Discussionmentioning

confidence: 99%

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

et al. 2020

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Background: Accumulating evidence shows that long noncoding RNAs (lncRNAs) are important regulator molecules involved in diverse biological processes. Acquired drug resistance is a major challenge in the clinical treatment of glioblastoma (GBM), and lncRNAs have been shown to play a role in chemotherapy resistance. However, the underlying mechanisms by which lncRNA mediates TMZ resistance in GBM remain poorly characterized. Methods: Quantitative reverse transcription PCR (qRT-PCR) and fluorescence in situ hybridization assays were used to detect small nucleolar RNA host gene 12 (SNHG12) levels in TMZ-sensitive and TMZ-resistant GBM cells and tissues. The effects of SNHG12 on TMZ resistance were investigated through in vitro assays (western blots, colony formation assays, flow cytometry assays, and TUNEL assays). The mechanism mediating the high expression of SNHG12 in TMZ-resistant cells and its relationships with miR-129-5p, mitogen-activated protein kinase 1 (MAPK1), and E2F transcription factor 7 (E2F7) were determined by bioinformatic analysis, bisulfite amplicon sequencing, methylation-specific PCR, dual luciferase reporter assays, chromatin immunoprecipitation assays, RNA immunoprecipitation assays, immunofluorescence, qRT-PCR, and western blot. For in vivo experiments, an intracranial xenograft tumor mouse model was used to investigate SNHG12 function. Results: SNHG12 was upregulated in TMZ-resistant cells and tissues. Overexpression of SNHG12 led to the development of acquired TMZ resistance, while knockdown of SNHG12 restored TMZ sensitivity. An abnormally low level of DNA methylation was detected within the promoter region of SNHG12, and loss of DNA methylation made this region more accessible to the Sp1 transcription factor (SP1); this indicated that methylation and SP1 work together to regulate SNHG12 expression. In the cytoplasm, SNHG12 served as a sponge for miR-129-5p, leading to upregulation of MAPK1 and E2F7 and endowing the GBM cells with TMZ resistance. Disinhibition of MAPK1 regulated TMZ-induced cell apoptosis and the G1/S cell cycle transition by activating the MAPK/ERK pathway, while E2F7 dysregulation was primarily associated with G1/S cell cycle transition. Clinically, SNHG12 overexpression was associated with poor survival of GBM patients undergoing TMZ treatment. Conclusion: Our results suggest that SNHG12 could serve as a promising therapeutic target to surmount TMZ resistance, thereby improving the clinical efficacy of TMZ chemotherapy.

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Section: Discussionmentioning

confidence: 99%

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

et al. 2020

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“…Genome‐wide lncRNA expression profiles in glioma patients have revealed that dysregulated lncRNA expression plays important roles in the tumorigenesis and malignant progression of this cancer, and several lncRNAs are related to the prognosis of patients with GBM 45. Circulating levels of HOTAIR are significantly correlated with high‐grade brain tumours, and one study demonstrated that this lncRNA could be considered a novel prognostic and diagnostic biomarker for GBM 97. Moreover, in vitro and in vivo studies have demonstrated that aberrant expression of lncRNAs is correlated with response to therapy in gliomas.…”

Section: Epigenetic Alterations Induced By Lncrnasmentioning

confidence: 99%

“…72 45 Circulating levels of HOTAIR are significantly correlated with high-grade brain tumours, and one study demonstrated that this lncRNA could be considered a novel prognostic and diagnostic biomarker for GBM. 97 Moreover, in vitro and in vivo studies have demonstrated that aberrant expression of lncRNAs is correlated with response to therapy in gliomas. For example, knockdown of MALAT1 increases permeability of the blood-tumour barrier, which might contribute to the improvement of therapeutic strategies, 98 while restoration of CASC2 expression upregulates PTEN and can increase glioma sensitivity to temozolomidebased chemotherapy.…”

Section: Tumour-suppressor Lncrnasmentioning

confidence: 99%

Long non‐coding RNAs in brain tumours: Focus on recent epigenetic findings in glioma

Pop

Enciu

Necula

et al. 2018

J Cellular Molecular Medi

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Glioma biology is a major focus in tumour research, primarily due to the aggressiveness and high mortality rate of its most aggressive form, glioblastoma. Progress in understanding the molecular mechanisms behind poor prognosis of glioblastoma, regardless of treatment approaches, has changed the classification of brain tumours after nearly 100 years of relying on anatomopathological criteria. Expanding knowledge in genetic, epigenetic and translational medicine is also beginning to contribute to further elucidating molecular dysregulation in glioma. Long non‐coding RNAs (lncRNAs) and their main representatives, large intergenic non‐coding RNAs (lincRNAs), have recently been under scrutiny in glioma research, revealing novel mechanisms of pathogenesis and reinforcing others. Among those confirmed was the reactivation of events significant for foetal brain development and neuronal commitment. Novel mechanisms of tumour suppression and activation of stem‐like behaviour in tumour cells have also been examined. Interestingly, these processes involve lncRNAs that are present both during normal brain development and in brain malignancies and their reactivation might be explained by epigenetic mechanisms, which we discuss in detail in the present review. In addition, the review discusses the lncRNAs‐induced changes, as well as epigenetic changes that are consequential for tumour formation, affecting, in turn, the expression of various types of lncRNAs.

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“…These discoveries suggested that lncRNAs could be excellent prognostic biomarkers and potential therapeutic targets for GBM. Although recent studies have identified some lncRNAs that exert regulatory activities during the development of GBM, these have mainly focused on the expression pattern of lncRNAs (9,10). At present, the regulatory mechanism of the vast majority of lncRNAs in GBM, especially dNA methylation, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Genome‑wide DNA methylation regulation analysis of long non‑coding RNAs in glioblastoma

Zhao

et al. 2020

Int J Mol Med

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Glioblastoma (GBM) is a malignant brain tumor associated with high mortality. Long non-coding RNAs (lncRNAs) are increasingly being recognized as its modulators. However, it remains mostly unexplored how lncRNAs are mediated by dNA methylation in GBM. The present study integrated multi-omics data to analyze the epigenetic dysregulation of lncRNAs in GBM. Widely aberrant methylation in the lncRNA promoters was observed, and the lncRNA promoters exhibited a more hypomethylated pattern in GBM. By combining transcriptional datasets, it was possible identify the lncRNAs whose transcriptional changes might be associated with the aberrant promoter methylation. Then, a methylation-mediated lncRNA regulatory network and functional enrichment analysis of aberrantly methylated lncRNAs showed that lncRNAs with different methylation patterns were involved in diverse GBM progression-related biological functions and pathways. Specifically, four lncRNAs whose increased expression may be regulated by the corresponding promoter hypomethylation were evaluated to have an excellent diagnostic effect and clinical prognostic value. Finally, through the construction of drug-target association networks, the present study identified potential therapeutic targets and small-molecule drugs for GBM treatment. The present study provides novel insights for understanding the regulation of lncRNAs by dNA methylation and developing cancer biomarkers in GBM.

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Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme

Cited by 223 publications

References 18 publications

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

Long non‐coding RNAs in brain tumours: Focus on recent epigenetic findings in glioma

Genome‑wide DNA methylation regulation analysis of long non‑coding RNAs in glioblastoma

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