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Objective: Radiotherapy (RT) is a cornerstone of the glioblastoma (GBM) treatment. However, the resistance of tumour cells to radiation results in early recurrence. The mechanisms underlying GBM radioresistance remain unclear. Screening for differentially expressed genes (DEGs) related to radiation might be a potential solution to this problem. Method: RT‐associated DEGs were screened based on the RNA sequencing of 15 paired primary and recurrent GBMs. The mRNA and protein expression of candidate genes were validated in RNA sequencing of The Chinese Genome Atlas (CGGA) dataset and 18 cases of GBM samples. The relationship between the candidate gene and radiation was confirmed in irradiated GBM cells. The association of candidate gene with clinical characteristics and survival was investigated in the CGGA and TCGA dataset. Biological function and pathway analysis were explored by gene ontology analysis. The association of the candidate gene with radiosensitivity was verified using cell counting Kit‐8, comet, and colony formation assays in vitro and subcutaneous tumour xenograft experiments in vivo. Results: Gelsolin (GSN) was selected for further study. GSN expression was significant elevated in recurrent GBM and up‐regulated in irradiated GBM cell lines. High expression of GSN was enriched in malignant phenotype of glioma. Moreover, high expression of GSN was associated with poor prognosis. Further investigation demonstrated that GSN‐knockdown (GSN‐KD) combined with RT significantly inhibited cell proliferation and enhanced radiosensitivity in vivo and in vitro. Mechanistically, GSN‐KD could lead to more serious DNA damage and promotes apoptosis after RT. Conclusion: Radiation induced up‐regulated of GSN. GSN‐KD could enhance the radiosensitivity of GBM. [ABSTRACT FROM AUTHOR]

Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β‐catenin, c‐Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β‐catenin pathway. [ABSTRACT FROM AUTHOR]

Polymerase I and transcript release factor (PTRF) plays a role in the regulation of gene expression and the release of RNA transcripts during transcription, which have been associated with various human diseases. However, the role of PTRF in glioma remains unclear. In this study, RNA sequencing (RNA-seq) data (n = 1022 cases) and whole-exome sequencing (WES) data (n = 286 cases) were used to characterize the PTRF expression features. Gene ontology (GO) functional enrichment analysis was used to assess the biological implication of changes in PTRF expression. As a result, the expression of PTRF was associated with malignant progression in gliomas. Meanwhile, somatic mutational profiles and copy number variations (CNV) revealed the glioma subtypes classified by PTRF expression showed distinct genomic alteration. Furthermore, GO functional enrichment analysis suggested that PTRF expression was associated with cell migration and angiogenesis, particularly during an immune response. Survival analysis confirmed that a high expression of PTRF is associated with a poor prognosis. In summary, PTRF may be a valuable factor for the diagnosis and treatment target of glioma. [ABSTRACT FROM AUTHOR]

Glioma is the most common primary intracranial tumor and is associated with very low survival rates. The development of reliable biomarkers can help to elucidate the molecular mechanisms involved in glioma development. Here the expression of ABCC8 mRNA, clinical characteristics, and survival information based on 1893 glioma samples from four independent databases were analyzed. The expression patterns of ABCC8 mRNA were compared by a Chi square test. The overall survival rate of gliomas was evaluated according to the expression level of ABCC8 mRNA. The prognostic value of this marker in gliomas was tested using Cox single factor and multi factor regression analyses. We found patients with low WHO grade, oligodendrocytoma, low molecular grade, IDH mutation, and 1p19q combined deletion had high ABCC8 mRNA expression. The patients with high expression of ABCC8 mRNA had longer survival. ABCC8 mRNA expression was a new independent prognostic index for glioma. Temozolomide chemotherapy was an independent index to prolong overall survival in high ABCC8 mRNA expression glioma patients, whereas in patients with low expression, there was no significant difference. So ABCC8 mRNA expression could be an independent prognostic indicator for glioma patients and could predict the sensitivity of glioma to temozolomide. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common and malignant type of glioma, with a poor prognosis for patients. The survival time of patients varies greatly due to the complexity of the human genome, which harbors diverse oncogenic drivers. In order to identify the specific driving factors, 325 glioma samples from the Chinese Glioma Genome Atlas (CGGA) database were analyzed in the present study. The level of RELB proto-oncogene, NF-κβ subunit (RELB) expression increased with the pathological grade progression of the gliomas, and higher expression levels were present in the mesenchymal subtype and isocitrate dehydrogenase 1 (IDH1) wild-type gliomas. This RELB expression pattern was identified in the CGGA database and observed in three large independent databases. In patients with GBM from the CGGA database, a higher RELB expression level was associated with a shorter survival time, a mesenchymal subtype and IDH1 wild-type gliomas. Kaplan-Meier survival analysis, survival nomograms and Cox analysis demonstrated an independent prognostic value for RELB expression. Moreover, biological function analysis indicated the association of RELB with the 'immune response', 'cell activation' and the 'apoptotic process'. In addition, RELB expression levels exhibited a negative correlation with the levels of microRNA (miR)-139-5p and miR-139-3p. The present study identified the pathological and biological roles of RELB in glioma and revealed its independent prognostic effect. These results suggested that RELB may be used as a prognostic biomarker and potential therapeutic target in glioma. [ABSTRACT FROM AUTHOR]

Background: Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Methods: We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. Results: TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. Conclusion: Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC. [ABSTRACT FROM AUTHOR]

Aberrant expression of microRNAs contributes to the initiation and progression of numerous human cancers. The underlying effects and molecular mechanisms of microRNA-187 (miR-187) in gastric cancer (GC) remain unclear. The present study reports that miR-187 was significantly overexpressed in GC tissues compared to that in non-tumor tissues and was associated with malignant clinical factors such as depth of invasion (P = 0.005), tumor size (P = 0.024), lymph node metastasis (P = 0.048), and TNM stage (P = 0.035). Additionally, miR-187 promoted tumor growth in vivo , and significantly increased migration, invasion, and proliferation, but inhibited apoptosis in GC cells. It was found that collapsin response mediator protein 1 (CRMP1), a tumor suppressor, was a direct downstream target of miR-187 in GC. Furthermore, CRMP1 silencing resulted in similar effects on cell proliferation, migration, and apoptosis as those of miR-187 overexpressing GC cells. Additionally, the effects of miR-187 inhibitor on cell migration and cell apoptosis were reversed by CRMP1 downregulation. In summary, miR-187 promotes tumor progression by regulating CRMP1 expression in GC and may thus be a potential prognostic marker and a therapeutic target in GC. [ABSTRACT FROM AUTHOR]

Abstract: To date, the aberrations in the DNA methylation patterns that are associated with different prognoses of G-CIMP− primary GBMs remain to be elucidated. Here, DNA methylation profiling of primary GBM tissues from 13 long-term survivors (LTS; overall survival ⩾18months) and 20 short-term survivors (STS; overall survival ⩽9months) was performed. Then G-CIMP+ samples were excluded. The differentially expressed CpG loci were identified between residual 18 STS and 9 LTS G-CIMP− samples. Methylation levels of 11 CpG loci (10genes) were statistically significantly lower, and 43 CpG loci (40genes) were statistically significantly higher in the tumor tissues of LTS than those of STS G-CIMP− samples (P <0.01). Of the 43 CpG loci that were hypermethylated in LTS G-CIMP− samples, 3 CpG loci localized in the promoter of ALDH1A3. Furthermore, using an independent validation cohort containing 37 primary GBM samples without IDH1 mutation and MGMT promoter methylation, the hypermethylation status of ALDH1A3 promoter predicted a better prognosis with an accompanied low expression of ALDH1A3 protein. Taken together, our results defined prognosis-related methylation signatures systematically for the first time in G-CIMP− primary GBMs. ALDH1A3 promoter methylation conferred a favorable prognosis in G-CIMP− primary GBMs. [Copyright &y& Elsevier]

Abstract: The poor prognosis of glioblastoma multiforme (GBM) is largely attributed to their highly invasive nature and MMP-9 plays a pivotal role in regulating invasiveness of malignant glioma cells. MicroRNAs (miRNAs) are small non-coding RNAs that have been shown to regulate a wide range of biological processes via targeting messenger RNA. Previous reports have shown many oncogenes regulate survival and invasion via targeting MMP-9 in GBM. But no literature indicates that miRNAs regulate glioma cell invasion through targeting MMP-9. Here, we show MMP-9 overexpression conferred a poor prognosis in 163 GBM patients. Furthermore, MMP-9 specific miRNA expression profile (14 positively and 31 negatively correlated miRNAs with MMP-9) was established via miRNA microarrays in 60 GBM samples. Among them, two miRNAs: miR-885-5p and miR-491-5p, were chosen for functional validation for their high positive correlation with MMP-9 expression. And upregulation of miR-885-5p and miR-491-5p were demonstrated to reduce the levels of MMP-9 expression and inhibit cellular invasion in U251 and U87 glioma cells. Furthermore, we found that miR-491-5p suppressed glioma cell invasion via targeting MMP-9 directly. To our knowledge, this is the first study to identify the MMP-9 specific microRNA signature which may provide potential targets for anti-invasion therapy in GBM. [Copyright &y& Elsevier]