RESUMO
BACKGROUND: PVT1, a previously uncharacterized lncRNA, was identified as a critical regulator involved in multiple functions in tumor, including cell proliferation, cell motility, angiogenesis and so on. However, the clinical significance and underlying mechanism of PVT1 was not be fully explored in glioma. METHODS: In this study, 1210 glioma samples with transcriptome data from three independent databases (CGGA RNA-seq, TCGA RNA-seq and GSE16011 cohorts) were enrolled in this study. Clinical information and genomic profiles containing somatic mutations and DNA copy numbers were collected from TCGA cohort. The R software was performed for statistical calculations and graphics. Furthermore, we validated the function of PVT1 in vitro. RESULTS: The results indicated that higher PVT1 expression was associated with aggressive progression of glioma. Cases with higher PVT1 expression always accompanied by PTEN and EGFR alteration. In addition, functional analyses and western blot results suggested that PVT1 inhibited the sensitivity of TMZ chemotherapy via JAK/STAT signaling. Meanwhile, knockdown of PVT1 increased the sensitivity of TZM chemotherapy in vitro. Finally, high PVT1 expression was associated with reduced survival time and may serve as a strong prognostic indicator for gliomas. CONCLUSIONS: This study demonstrated that PVT1 expression strongly correlated with tumor progression and chemo-resistance. PVT1 may become a potential biomarker for the diagnosis and treatment in glioma.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Glioma , RNA Longo não Codificante , Temozolomida , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Silenciamento de Genes , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioma/tratamento farmacológico , Glioma/genética , Glioma/fisiopatologia , Análise de Sobrevida , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismoRESUMO
Background: Isocitrate dehydrogenase (IDH) mutant is one of the most robust and important genetic aberrations in glioma. However, the underlying regulation mechanism of long non-coding RNA (lncRNA) in IDH mutant glioma has not been systematically portrayed. Methods:In this work, 775 IDH mutant glioma samples with transcriptome data, including 167 samples from the Chinese Glioma Genome Atlas (CGGA) RNAseq dataset, 390 samples from The Cancer Genome Atlas (TCGA) dataset, 79 samples from GSE16011 dataset, and 139 samples from CGGA microarray dataset, were enrolled. R language and GraphPad Prism software were applied for the statistical analysis and graphical work. Results: By comparing the differentially lncRNA genes between IDH mutant and IDH wild-type glioma samples, a four-lncRNA (JAG1, PVT1, H19, and HAR1A) signature was identified in IDH mutant glioma patients. The signature model was established based on the expression level and the regression coefficient of the four lncRNA genes. IDH mutant glioma samples could be successfully stratified into low-risk and high-risk groups in CGGA RNAseq, TCGA, GSE16011, and CGGA microarray databases. Meanwhile, multivariate Cox analysis showed that the four-lncRNA signature was an independent prognostic biomarker after adjusting for other clinicopathologic factors. Moreover, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the immune response and cellular metabolism were significantly associated with the four-lncRNA risk signature. Conclusion: Taken together, the four-lncRNA risk signature was identified as a novel prognostic marker for IDH mutant glioma patients and may potentially lead to improvements in the lives of glioma patients.
