EID3 Promotes Glioma Cell Proliferation and Survival by Inactivating AMPKα1

Xiang, Yaoxian,Zhu, Lei,He, Zijian,Xu, Lei,Mao, Yuhang,Jiang, Junjian,Xu, Jianguang The Korean Neurosurgical Society 2022 Journal of Korean neurosurgical society Vol.65 No.6

Objective : EID3 (EP300-interacting inhibitor of differentiation) was identified as a novel member of EID family and plays a pivotal role in colorectal cancer development. However, its role in glioma remained elusive. In current study, we identified EID3 as a novel oncogenic molecule in human glioma and is critical for glioma cell survival, proliferation and invasion. Methods : A total of five patients with glioma were recruited in present study and fresh glioma samples were removed from patients. Four weeks old male non-obese diabetic severe combined immune deficiency (NOD/SCID) mice were used as transplant recipient models. The subcutaneous tumor size was calculated and recorded every week with vernier caliper. EID3 and AMP-activated protein kinase α1 (AMPKα1) expression levels were confirmed by real-time polymerase chain reaction and Western blot assays. Colony formation assays were performed to evaluate cell proliferation. Methyl thiazolyl tetrazolium (MTT) assays were performed for cell viability assessment. Trypan blue staining approach was applied for cell death assessment. Cell Apoptosis DNA ELISA Detection Kit was used for apoptosis assessment. Results : EID3 was preferentially expressed in glioma tissues/cells, while undetectable in astrocytes, neuronal cells, or normal brain tissues. EID3 knocking down significantly hindered glioma cell proliferation and invasion, as well as induced reduction of cell viability, apoptosis and cell death. EID3 knocking down also greatly inhibited tumor growth in SCID mice. Knocking down of AMPKα1 could effectively rescue glioma cells from apoptosis and cell death caused by EID3 absence, indicating that AMPKα1 acted as a key downstream regulator of EID3 and mediated suppression effects caused by EID3 knocking down inhibition. These findings were confirmed in glioma cells generated patient-derived xenograft models. AMPKα1 protein levels were affected by MG132 treatment in glioma, which suggested EID3 might down regulate AMPKα1 through protein degradation. Conclusion : Collectively, our study demonstrated that EID3 promoted glioma cell proliferation and survival by inhibiting AMPKα1 expression. Targeting EID3 might represent a promising strategy for treating glioma.

Experience Profiling of Fluorescence-Guided Surgery I: Gliomas

( So Young Ji ),( Jin Wook Kim ),( Chul-kee Park ) 대한뇌종양학회·대한신경종양학회·대한소아뇌종양학회 2019 Brain Tumor Research and Treatment Vol.7 No.2

Background Numerous studies reported a usefulness of 5-aminolevulinic acid (5-ALA) fluorescence- guided surgery (FGS) in high grade gliomas. However, fluorescence patterns and intensities are variable among gliomas. In this study, we report our extensive experience with FGS in various gliomas, focusing on epidemiological data of fluorescence patterns. Methods A total of 827 histologically proven glioma patients out of 900 brain tumor patients who had undergone FGS using 5-ALA during the period of 8.5 years between July 2010 and January 2019 were analyzed. Indications of FGS in glioma surgery are evidence for possible high-grade foci in putative gliomas in preoperative MRI. Results Among the 827 gliomas, the number of cases corresponding to 2016 World Health Organization (WHO) grade IV, III, II, and I are 528 (58.7%), 193 (21.4%), 87 (9.7%) and 19 (2.1%), respectively. In terms of fluorescence rate, grade IV gliomas showed positive fluorescence in 95.4% of cases including strong intensity in 85.6%. Grade III gliomas showed fluorescence in about half of cases (55.0%), but 45.0% of the cases showed no fluorescence at all. Anaplastic oligodendroglioma had a higher positive rate (63.9%) than anaplastic astrocytoma (46.2%). Both grade II and I gliomas still showed positive fluorescence in about one-fourth of cases (24.1% and 26.3% respectively). Among them ependymoma and pilocytic astrocytoma were fluorescence-prone tumors. Conclusion This epidemiological data of 5-ALA fluorescence in various grades of glioma provides a basic reference to the clinical application of FGS with 5-ALA in glioma surgery.

Deregulated Expression of Cry1 and Cry2 in Human Gliomas

Luo, Yong,Wang, Fan,Chen, Lv-An,Chen, Xiao-Wei,Chen, Zhi-Jun,Liu, Ping-Fei,Li, Fen-Fen,Li, Cai-Yan,Liang, Wu Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.11

Growing evidence shows that deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of gene chnages controlling circadian rhythm in glioma cells have not been explored. Using real time polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, cry1 and cry2, in 69 gliomas. In this study, out of 69 gliomas, 38 were cry1-positive, and 51 were cry2-positive. The expression levels of cry1 and cry2 in glioma cells were significantly different from the surrounding non-glioma cells (P<0.01). The difference in the expression rate of cry1 and cry 2 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was non-significant (P>0.05) but there was a difference in the intensity of immunoactivity for cry 2 between high-grade gliomas and low-grade gliomas (r=-0.384, P=0.021). In this study, we found that the expression of cry1 and cry2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in cry1 and cry2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.

Comparison of Genetic Profiles and Prognosis of High-Grade Gliomas Using Quantitative and Qualitative MRI Features: A Focus on G3 Gliomas

Hong Eun Kyoung,Choi Seung Hong,Shin Dong Jae,Jo Sang Won,Yoo Roh-Eul,Kang Koung Mi,Yun Tae Jin,김지훈,Sohn Chul-Ho,Park Sung-Hye,Won Jae-Kyoung,Kim Tae Min,Park Chul-Kee,Kim Il Han,Lee Soon-Tae 대한영상의학회 2021 Korean Journal of Radiology Vol.22 No.2

Objective: To evaluate the association of MRI features with the major genomic profiles and prognosis of World Health Organization grade III (G3) gliomas compared with those of glioblastomas (GBMs). Materials and Methods: We enrolled 76 G3 glioma and 155 GBM patients with pathologically confirmed disease who had pretreatment brain MRI and major genetic information of tumors. Qualitative and quantitative imaging features, including volumetrics and histogram parameters, such as normalized cerebral blood volume (nCBV), cerebral blood flow (nCBF), and apparent diffusion coefficient (nADC) were evaluated. The G3 gliomas were divided into three groups for the analysis: with this isocitrate dehydrogenase (IDH)-mutation, IDH mutation and a chromosome arm 1p/19q-codeleted (IDHmut1p/19qdel), IDH mutation, 1p/19q-nondeleted (IDHmut1p/19qnondel), and IDH wildtype (IDHwt). A prediction model for the genetic profiles of G3 gliomas was developed and validated on a separate cohort. Both the quantitative and qualitative imaging parameters and progression-free survival (PFS) of G3 gliomas were compared and survival analysis was performed. Moreover, the imaging parameters and PFS between IDHwt G3 gliomas and GBMs were compared. Results: IDHmut G3 gliomas showed a larger volume (p = 0.017), lower nCBF (p = 0.048), and higher nADC (p = 0.007) than IDHwt. Between the IDHmut tumors, IDHmut1p/19qdel G3 gliomas had higher nCBV (p = 0.024) and lower nADC (p = 0.002) than IDHmut1p/19qnondel G3 gliomas. Moreover, IDHmut1p/19qdel tumors had the best prognosis and IDHwt tumors had the worst prognosis among G3 gliomas (p < 0.001). PFS was significantly associated with the 95th percentile values of nCBV and nCBF in G3 gliomas. There was no significant difference in neither PFS nor imaging features between IDHwt G3 gliomas and IDHwt GBMs. Conclusion: We found significant differences in MRI features, including volumetrics, CBV, and ADC, in G3 gliomas, according to IDH mutation and 1p/19q codeletion status, which can be utilized for the prediction of genomic profiles and the prognosis of G3 glioma patients. The MRI signatures and prognosis of IDHwt G3 gliomas tend to follow those of IDHwt GBMs.

White Matter Change Revealed by Diffusion Tensor Imaging in Gliomas

( Young Il Won ),( Chun Kee Chung ),( Chi Heon Kim ),( Chul-kee Park ),( Bang-bon Koo ),( Jong-min Lee ),( Hee-won Jung ) 대한뇌종양학회·대한신경종양학회·대한소아뇌종양학회 2016 Brain Tumor Research and Treatment Vol.4 No.2

Background Tumor-related white matter change is detected at late stages with magnetic resonance imaging (MRI), when mass effect or prominent edema is present. We analyzed if diffusion tensor imaging (DTI) white matter change earlier than conventional MRI. Methods Twenty-six patients with gliomas (World Health Organization grade II, 5; grade III, 12; and grade IV, 9) within 2 cm from the posterior limb of the internal capsule (IC) were studied. Fifteen normal adults were enrolled as controls. Fluid attenuation inversion recovery MRI showed a high signal change at the posterior limb of the IC (HSIC) in 9 patients with grade III or IV gliomas. We classified the gliomas as WHO grade II (gliomas II), grade III or IV without HSIC [gliomas III/IV(-)] and grade III or IV with HSIC [gliomas III/IV(+)], as an indicator of the increase in the severity of the white matter changes. Fractional anisotropy (FA) and apparent diffusion coefficients (ADC) were calculated for the pyramidal tract. Tumor progression along pyramidal tract was evaluated by follow-up MRI in 16 patients at 40±18 months. Results FA showed no significant difference between gliomas II and control (p=0.694), but was lower in gliomas III/IV(-) and gliomas III/IV(+) (p<0.001). ADCs were higher in gliomas II, gliomas III/IV(-) and gliomas III/IV(+) than control (p<0.001). Tumor progression was detected in 2/16 patients. Conclusion DTI detected white matter changes that appeared to be normal in MRI. ADC changed even in low grade glioma, indicating ADC may be a better parameter for the early detection of white matter change.

Proteomic Analysis of Glioma Chemoresistance

Bentham Science Publishers 2012 Current neuropharmacology Vol.10 No.1

<P>Malignant glioma is the most common and destructive form of primary brain tumor. Along with surgery and radiation, chemotherapy remains as the major treatment modality. The emergence of drug resistance, however, often leads to a therapeutic failure in the treatment of glioma, precluding long-term survival of the patients. A proteomic approach has recently been adapted for the mechanistic analysis of glioma drug resistance. The proteomic analysis of drug-resistant glioma led to the discovery of novel biomarkers that can be used for the prognosis of glioma as well as for monitoring the drug response or resistance of glioma. These proteomics-based biomarkers can also be a druggable target that one can exploit for successful glioma chemotherapy. In this review, recent reports on proteomic analysis of glioma from the perspective of chemoresistance are discussed with a focus on the proteome profiles of glioma cells that are resistant to the alkylating agent, 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU), as a prime example. Among numerous proteins that were up- or down-regulated in drug-resistant glioma cells, lipocalin 2 (LCN2) and integrin β3 (ITGB3) were identified as key proteins that determine the survival and death of glioma cells. LCN2, ITGB3, and other proteins identified by proteomic analysis could be utilized to overcome glioma chemoresistance.</P>

Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

Guo, Yan,Wang, Gan,Gao, Wen-Wei,Cheng, Shi-Wen,Wang, Ren,Ju, Shi-Ming,Cao, He-Li,Tian, Heng-Li Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.6

We investigated whether IFN-${\beta}$ inhibits the growth of human malignant glioma and induces glioma cell apoptosis using the human IFN-${\beta}$ gene transfected into glioma cells. A eukaryonic expression vector ($pSV2IFN{\beta}$) for IFN-${\beta}$ was transfected into the glioma cell line SHG44 using liposome transfection. Stable transfection and IFN-${\beta}$ expression were confirmed using an enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was also assessed by Hoechst staining and electron microscopy. In vivo experiments were used to establish a SHG44 glioma model in nude mice. Liposomes containing the human IFN-${\beta}$ gene were injected into the SHG44 glioma of nude mice to observe glioma growth and calculate tumor size. Fas expression was evaluated using immunohistochemistry. The IFN-${\beta}$ gene was successfully transfected and expressed in the SHG44 glioma cells in vitro. A significant difference in the number of apoptotic cells was observed between transfected and non-transfected cells. Glioma growth in nude mice was inhibited in vivo, with significant induction of apoptosis. Fas expression was also elevated. The IFN-${\beta}$ gene induces apoptosis in glioma cells, possibly through upregulation of Fas. The IFN-${\beta}$ gene modulation in the Fas pathway and apoptosis in glioma cells may be important for the treatment of gliomas.

Identification and validation of an ECM organization-related gene signature as a prognostic biomarker and therapeutic target for glioma patients

Zhong Qiong,Zhong Qiuxia,Cai Xiaolong,Wu Renrui 한국유전학회 2023 Genes & Genomics Vol.45 No.9

Background Glioma is the most common and devastating form of malignant brain tumor, with a poor prognosis. Extracellular matrix (ECM) organization is a crucial determinant of glioma invasion and progression. However, the clinical significance of ECM organization in glioma patients remains unclear. Objective To evaluate the prognostic value of ECM organization-related genes in glioma patients and identify potential therapeutic targets. Methods Bulk RNA-sequencing and corresponding clinical data for patients with glioma were downloaded from TCGA and GEO databases. Differentially expressed ECM organization genes were identified, and an ECM organization-related gene prognostic model was then generated. Furthermore, the prognostic model has validated in the Chinese Glioma Genome Atlas (CGGA) dataset. The role of TIMP1 in glioma cells by using various functional assays revealed their underlying mechanism in vitro. Results We identified and validated a nine-gene signature (TIMP1, SERPINE1, PTX3, POSTN, PLOD3, PDPN, LOXL1, ITGA2, and COL8A1) related to ECM organization as a robust prognostic biomarker for glioma. Time-dependent ROC curve analysis confirmed the specificity and sensitivity of the signature. The signature was closely related to an immunosuppressive phenotype, and its combination with immune checkpoints served as a good predictor for patients' clinical outcomes. Notably, single-cell RNA sequencing analysis revealed high expression of TIMP1 in astrocytes and oligodendrocyte progenitor cells in glioma patients. Last, we show that TIMP1 regulates glioma cell growth and invasion via the AKT/GSK3β signaling pathway. Conclusion This study provides promising insights into predicting glioma prognosis and identifying a potential therapeutic target in TIMP1.

ceRNA network of lncRNA MIR210HG/miR-377-3p/LMX1A in malignant proliferation of glioma cells

Yu Zhikuan,Che Ningwei,He Yeting,Zhang Bo 한국유전학회 2022 Genes & Genomics Vol.44 No.12

Background: Glioma represents the most heterogeneous and malignant form of brain tumor with a poor prognosis. The long non-coding RNA (LncRNA)-mediated competing endogenous RNA (ceRNA) network plays a regulatory role in cancer progression. Objectives: The present study was conducted to expound on the role of lncRNA MIR210 host gene (MIR210HG)-mediated ceRNA mechanism in the malignant proliferation of glioma cells and provide a novel theoretical basis for the treatment of glioma. Methods: Expression levels of lncRNA MIR210HG, microRNA (miR)-377-3p, and LIM homeobox transcription factor 1 alpha (LMX1A) in glioma tissues and cells were determined by reverse-transcription quantitative polymerase chain reaction. Then, cell proliferation was assessed by cell counting kit-8 and colony formation assays. After that, the subcellular localization of lncRNA MIR210HG was analyzed by subcellular fractionation assay and the bindings of miR-377-3p to lncRNA MIR210HG and LMX1A were analyzed by the dual-luciferase assay. Glioma cells were transfected with si-MIR210HG, miR-377-3p inhibitor, or overexpressed-LMX1A vectors to evaluate their effects on the malignant proliferation of glioma cells. Results: LncRNA MIR210HG was elevated in glioma tissues and cells and inhibition of lncRNA MIR210HG reduced the proliferation potential of glioma cells. LncRNA MIR210HG targeted and inhibited miR-377-3p and miR-377-3p targeted and inhibited LMX1A transcription. miR-377-3p downregulation or LMX1A overexpression reversed the inhibition of silencing lncRNA MIR210HG on glioma cell proliferation. Conclusion: LncRNA MIR210HG was upregulated in glioma tissues and cells and inhibition of lncRNA MIR210HG suppressed glioma cell proliferation through promoting miR-377-3p and repressing LMX1A.

뇌 신경교종에서의 증식능과 세포고사

김영철,박명수,양정원 조선대학교 2001 The Medical Journal of Chosun University Vol.26 No.1

Background and Objectives : Proliferating cell nuclear antigen (PCNA) correlated with the rates of cellular proliferation and DNA synthesis. It is 36-kD nuclear acidic protein, and present throughout the cell cycle. Apoptosis also correlates with tumor development. The purpose of this study is the investigate of the relationshipal PCNA and apoptotic rates in gliomas. Materials and Methods : This study analyzed 50 paraffin-embedded glioma, including 15 cases of low grade, 20 cases of high grade, and 15 cases of maligant glioma (glioblastoma multiforme), for the status of proliferating index and apoptotic rates. The evaluation of immunostaining result was based on the percentage of positive neoplastic cells. Results : Average positive cell rates of PCNA were 14.3%, 45.2% and 62.0% in low grade glioma, high grade glioma and glioblastoma multiforme, respectively. Apoptotic rates were 52.3%, 41.0% and 25.2% in low grade glioma, high grade glioma and glioblastoma multiforme, respectively. Conclusion : This results suggest that PCNA positivity was correlated with histologic grade of glial tumors. And high grade glioma and glioblastoma multiforme showed higher positive cell rate rather than low grade glioma. Apoptotic rates were higher in low grade glioma than high grade or malignant glioma. So, the PCNA and the apoptosis rates is great useful parameter for a patient’ s prognosis.