Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
Add more filters










Publication year range
1.
World Neurosurg ; 183: e825-e837, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38216032

ABSTRACT

BACKGROUND: The main treatment of low-grade glioma (LGG) is still surgical resection followed by radiotherapy and/or chemotherapy, which has certain limitations, including side effects and drug resistance. Immunotherapy is a promising treatment for LGG, but it is generally hindered by the tumor microenvironment with the limited expression of tumor antigens. METHODS: We integrated RNA sequencing data sets and clinical information and conducted consistent cluster analysis to explore the most suitable patients for immune checkpoint therapy. Gene set enrichment analysis, UMAP analysis, mutation correlation analysis, TIMER analysis, and TIDE analysis were used to identify the immune characteristics of 3 immune subtypes and the feasibility of 5 antigens as immune checkpoint markers. RESULTS: We analyzed the isolation and mutation of homologous recombination repair genes (HRR) of the 3 immune subtypes, and the HRR genes of the 3 subtypes were obviously segregated. Among them, the IS2 subtype has a large number of HRR gene mutations, which increases the immunogenicity of tumors-this is consistent with the results of tumor mutation load analysis of 3 immune subtypes. Then we evaluated the immune cell infiltration of immune subtypes and found that IS2 and IS3 subtypes were rich in immune cells. It is worth noting that there are many Treg cells and NK cells in the IS1 subtype. In addition, when analyzing the immune checkpoint gene expression of the 3 subtypes, we found that they were upregulated most in IS2 subtypes compared with other subtypes. Then when we further confirmed the role of immune-related genes in LGG; through TIDE analysis and TISIDB analysis, we obtained 5 markers that can predict the efficacy of ICB in patients with LGG. In addition, we confirmed that they were associated with poor prognosis through survival analysis. CONCLUSIONS: We obtained 3 reliable immune subtypes, and patients with the IS2 subtype are suitable for immunotherapy, in which NAMPT, SLC11A1, TNC, VIM, and SPP1 are predictive panel markers for ICB in the LGG group. Our findings provide a rationale for immunotherapy selection and prediction of patient prognosis in LGG patients.


Subject(s)
Glioma , Immunotherapy , Humans , Glioma/genetics , Glioma/therapy , Mutation/genetics , Prognosis , Tumor Microenvironment/genetics
2.
Int J Biol Macromol ; 246: 125590, 2023 Aug 15.
Article in English | MEDLINE | ID: mdl-37385320

ABSTRACT

Membrane-bound transcription factors (MTFs) have been observed in many types of organisms, such as plants, animals and microorganisms. However, the routes of MTF nuclear translocation are not well understood. Here, we reported that LRRC4 is a novel MTF that translocates to the nucleus as a full-length protein via endoplasmic reticulum-Golgi transport, which is different from the previously described nuclear entry mechanism. A ChIP-seq assay showed that LRRC4 target genes were mainly involved in cell motility. We confirmed that LRRC4 bound to the enhancer element of the RAP1GAP gene to activate its transcription and inhibited glioblastoma cell movement by affecting cell contraction and polarization. Furthermore, atomic force microscopy (AFM) confirmed that LRRC4 or RAP1GAP altered cellular biophysical properties, such as the surface morphology, adhesion force and cell stiffness. Thus, we propose that LRRC4 is an MTF with a novel route of nuclear translocation. Our observations demonstrate that LRRC4-null glioblastoma led to disordered RAP1GAP gene expression, which increased cellular movement. Re-expression of LRRC4 enabled it to suppress tumors, and this is a potential for targeted treatment in glioblastoma.


Subject(s)
Glioblastoma , Animals , Glioblastoma/metabolism , Transcription Factors/genetics , Cell Line, Tumor , Nerve Tissue Proteins/metabolism , Cell Movement/genetics
3.
Front Oncol ; 12: 817737, 2022.
Article in English | MEDLINE | ID: mdl-35574340

ABSTRACT

PELATON is a long noncoding RNA also known as long intergenic nonprotein coding RNA 1272 (LINC01272). The known reports showed that PELATON functions as an onco-lncRNA or a suppressor lncRNA by suppressing miRNA in colorectal cancer, gastric cancer and lung cancer. In this study, we first found that PELATON, as an onco-lncRNA, alleviates the ferroptosis driven by mutant p53 and promotes mutant p53-mediated GBM proliferation. We also first confirmed that PELATON is a new ferroptosis suppressor lncRNA that functions as a ferroptosis inhibitor mainly by mutant P53 mediating the ROS ferroptosis pathway, which inhibits the production of ROS, reduces the levels of divalent iron ions, promotes the expression of SLC7A11, and inhibits the expression of ACSL4 and COX2.PELATON can inhibit the expression of p53 in p53 wild-type GBM cells and regulate the expression of BACH1 and CD44, but it has no effect on p53, BACH1 and CD44 in p53 mutant GBM cells. PELATON and p53 can form a complex through the RNA binding protein EIF4A3. Knockdown of PELATON resulted in smaller mitochondria, increased mitochondrial membrane density, and enhanced sensitivity to ferroptosis inducers to inhibit GBM cell proliferation and invasion. In addition, we established a favourite prognostic model with NCOA4 and PELATON. PELATON is a promising target for the prognosis and treatment of GBM.

4.
Clin Chem ; 68(2): 332-343, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34942001

ABSTRACT

BACKGROUND: Although major advances have been made in the histopathological diagnosis of high-grade astrocytoma (HGA), methods for effective and noninvasive diagnosis remain largely unknown. Exosomes can cross the blood-brain barrier and are readily accessible in human biofluids, making them promising biomarkers for HGA. Circular RNAs (circRNAs) have potential as tumor biomarkers owing to their stability, conservation, and tissue specificity. However, the landscape and characteristics of exosome circRNAs in HGA remain to be studied. METHODS: CircRNA deep sequencing and bioinformatics approaches were used to generate a circRNA profiling database and analyze the features of HGA cell circRNAs and HGA cell-derived exosome circRNAs. Exosome circRNA expression in the serum and tissues of healthy individuals and patients with HGA was detected using reverse transcription-quantitative PCR. Additionally, the receiver operating characteristic curve and overall survival curves were analyzed. RESULTS: By investigating the characteristics of HGA cell-derived exosome circRNAs and HGA cell circRNAs, we observed that exosomes were more likely to enrich short-exon and suppressor circRNAs than HGA cells. Moreover, a serum exosome circRNA panel including hsa_circ_0075828, hsa_circ_0003828, and hsa_circ_0002976 could be used to screen for HGA, whereas a good prognosis panel comprised high concentrations of hsa_circ_0005019, hsa_circ_0000880, hsa_circ_0051680, and hsa_circ_0006365. CONCLUSIONS: This study revealed a comprehensive circRNA landscape in HGA exosomes and cells. The serum exosome circexosome circRNA panel and tissue circRNAs are potentially useful for HGA liquid biopsy and prognosis monitoring. Exosome circRNAs as novel targets should facilitate further biomarker discovery and aid in HGA diagnosis and therapy monitoring.


Subject(s)
Astrocytoma , Exosomes , Astrocytoma/diagnosis , Astrocytoma/genetics , Biomarkers, Tumor/genetics , Exosomes/genetics , Humans , RNA/genetics , RNA, Circular/genetics , Sequence Analysis, RNA
5.
Mol Ther Nucleic Acids ; 26: 473-487, 2021 Dec 03.
Article in English | MEDLINE | ID: mdl-34631278

ABSTRACT

Mounting evidence reveals that dysregulation of circular RNAs (circRNAs) is involved in the development of glioblastoma. Leucine-rich repeat-containing 4 (LRRC4) has been shown to suppress tumors in glioblastoma. However, whether LRRC4 can regulate the formation of circRNA is not yet understood. In this study, LRRC4 was found to interact with SAM68. LRRC4 promoted the generation of circCD44 by inhibiting the binding between SAM68 and CD44 pre-mRNA. Moreover, downregulated expression of circCD44 was found in glioblastoma multiforme (GBM) tissues and GBM primary cells. Re-expression of circCD44 significantly suppressed the proliferation, colony formation, and invasion of GBM cells and inhibited tumor growth in vivo. Mechanistically, circCD44 could regulate the expression of SMAD6 via sponging miR-326 and miR-330-5p involved in the progression of GBM. Thus, the LRRC4/SAM68/circCD44/miR-326/miR-330-5p/SMAD6 signaling axis could be a potential target for GBM treatment.

6.
Mol Cancer Res ; 19(10): 1651-1665, 2021 10.
Article in English | MEDLINE | ID: mdl-34158391

ABSTRACT

Nestin, a class IV intermediate filament protein, is generally considered as a putative marker of neural stem and progenitor cells in the central nervous system. Glioma is a common type of adult brain tumors, and glioblastoma (GBM) represents the most aggressive form of glioma. Here, we report that Nestin expression is significantly upregulated in human GBM, compared with other types of glioma. Nestin knockdown or deletion in U251 cells and tumor cells from GBM patients derived xenografts resulted in G2-M arrest, finally leading to apoptosis in tumor cells. Using proximity-dependent biotin identification method, we identified ßII-tubulin as an interacting protein of Nestin in U251 cells. Nestin stabilized ßII-tubulin in U251 cells through physical interaction. Knockdown of Nestin or ßII-tubulin disrupted spindle morphology in tumor cells. Our studies further revealed that Nestin deficiency in U251 cells and GBM PDX cells repressed tumor growth upon transplantation. Finally, we found that Nestin deficiency sensitized GBM cells to microtubule-destabilizing drugs such as vinblastine and vincristine. Our studies demonstrate the essential functions and underlying mechanisms of Nestin in the growth and drug response of GBM cells. IMPLICATIONS: Through interaction with ßII-tubulin, Nestin facilitates cell-cycle progression and spindle assembly of tumor cells in glioblastoma.


Subject(s)
Brain Neoplasms/metabolism , Cell Cycle/physiology , Glioblastoma/metabolism , Nestin/metabolism , Spindle Apparatus/metabolism , Animals , Apoptosis/physiology , Cell Line , Cell Line, Tumor , Glioma/metabolism , HEK293 Cells , Humans , Mice, Nude , Mice, SCID , Tubulin/metabolism
7.
Mol Med ; 27(1): 44, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33932995

ABSTRACT

BACKGROUND: Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), belongs to the superfamily of LRR proteins and serves as a receptor for netrin-G2. LRRC4 regulates the formation of excitatory synapses and promotes axon differentiation. Mutations in LRRC4 occur in Autism Spectrum Disorder (ASD) and intellectual disability. Multiple sclerosis (MS) is a chronic neuroinflammatory disease with spinal cords demyelination and neurodegeneration. Here, we sought to investigate whether LRRC4 is involved in spinal cords neuron-associated diseases. METHODS: LRRC4 was detected in the CNS of experimental autoimmune encephalomyelitis (EAE) mice by the use of real-time PCR and western blotting. LRRC4-/- mice were created and immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35-55. Pathological changes in spinal cords of LRRC4-/- and WT mice 15 days after immunization were examined by using hematoxylin and eosin (H&E), Luxol Fast Blue (LFB) staining and immunohistochemistry. The number of Th1/Th2/Th17/Treg cells in spleens and blood were measured with flow cytometry. Differential gene expression in the spinal cords from WT and LRRC4-/- mice was analyzed by using RNA sequencing (RNA-seq). Adeno-associated virus (AAV) vectors were used to overexpress LRRC4 (AAV-LRRC4) and were injected into EAE mice to assess the therapeutic effect of AAV-LRRC4 ectopic expression on EAE. RESULTS: We report that LRRC4 is mainly expressed in neuron of spinal cords, and is decreased in the spinal cords of the EAE mice. Knockout of LRRC4 have a disease progression quickened and exacerbated with more severe myelin degeneration and infiltration of leukocytes into the spinal cords. We also first found that Rab7b is high expressed in EAE mice, and the deficiency of LRRC4 induces the elevated NF-κB p65 by up-regulating Rab7b, and up-regulation of IL-6, IFN-γ and down-regulation of TNF-α, results in more severe Th1 immune response in LRRC4-/- mice. Ectopic expression of LRRC4 alleviates the clinical symptoms of EAE mice and protects the neurons from immune damages. CONCLUSIONS: We identified a neuroprotective role of LRRC4 in the progression of EAE, which may be used as a potential target for auxiliary support therapeutic treatment of MS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/genetics , Nerve Tissue Proteins/genetics , Animals , Cytokines/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , HEK293 Cells , Humans , Mice, Inbred C57BL , Mice, Knockout , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Neuroprotection , Proto-Oncogene Proteins c-akt/metabolism , Spinal Cord/metabolism
9.
Oncogene ; 39(23): 4551-4566, 2020 06.
Article in English | MEDLINE | ID: mdl-32372061

ABSTRACT

Temozolomide (TMZ) insensitivity and resistance are major causes of treatment failure and poor prognosis for GBM patients. Here, we identify LRRC4 as a novel autophagy inhibitor that restores the sensitivity of GBMs to TMZ. LRRC4 was associated with the DEPTOR/mTOR complex, and this interaction resulted in autophagy inhibition. Further investigation demonstrated that the PDZ binding domain of LRRC4 binds to the PDZ domain of DEPTOR. This binding decreases the half-life of DEPTOR via ubiquitination, thus inhibiting GBM cell autophagy and increasing the TMZ treatment response of GBM. Combined LRRC4 expression and TMZ treatment prolonged the survival of mice with tumour xenografts. Furthermore, the levels of LRRC4, DEPTOR and autophagy are clinically relevant for GBM, indicating that LRRC4 is likely to have significant potential as a therapeutic marker and target for TMZ treatment in glioma patients.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Autophagy/genetics , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Temozolomide/pharmacology , Animals , Brain Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Glioblastoma/pathology , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Knockout , Protein Domains/physiology , TOR Serine-Threonine Kinases/metabolism , Ubiquitination , Xenograft Model Antitumor Assays
10.
Mol Ther Nucleic Acids ; 19: 1198-1208, 2020 Mar 06.
Article in English | MEDLINE | ID: mdl-32069702

ABSTRACT

Long non-coding RNAs (lncRNAs) play a significant role in post-translational modifications of proteins, yet the importance of lncRNAs for SUMOylation is unknown. rhabdomyosarcoma 2 associated transcript (RMST) expression in glioma tissues and normal brain tissues was measured by quantitative real-time PCR and in situ hybridization. The functional roles of RMST in astrocytomas were demonstrated by a series of in vitro experiments. The potential mechanisms of RMST for SUMOylation were investigated by RNA immunoprecipitation, RNA pull-down, western blotting, and coimmunoprecipitation assays. We first demonstrated the oncogenic activity of lncRNA RMST by inhibiting glioma cells mitophagy. We also first determined that RMST is an enhancer of FUS SUMOylation, especially boosting SUMO1 modification at K333. SUMOylation induced by RMST contributes to the interaction between FUS and heterogeneous nuclear ribonucleoprotein D (hnRNPD) and stabilized their expression and cells mitophagy. Importantly, lncRNA RMST could serve as a promising prognostic factor for glioma patients. Our results demonstrated a previously unknown function of lncRNAs worked as an enhancer in FUS SUMOylation, and RMST will be a significant guide for the development of medications targeting gliomas.

11.
Oncogene ; 38(1): 103-119, 2019 01.
Article in English | MEDLINE | ID: mdl-30082910

ABSTRACT

Ectopic epigenetic mechanisms play important roles in facilitating tumorigenesis. Here, we first demonstrated that ANKDD1A is a functional tumor suppressor gene, especially in the hypoxia microenvironment. ANKDD1A directly interacts with FIH1 and inhibits the transcriptional activity of HIF1α by upregulating FIH1. In addition, ANKDD1A decreases the half-life of HIF1α by upregulating FIH1, decreases glucose uptake and lactate production, inhibits glioblastoma multiforme (GBM) autophagy, and induces apoptosis in GBM cells under hypoxia. Moreover, ANKDD1A is highly frequently methylated in GBM. The tumor-specific methylation of ANKDD1A indicates that it could be used as a potential epigenetic biomarker as well as a possible therapeutic target.


Subject(s)
Autophagy , DNA Methylation , Glioblastoma/pathology , Intracellular Signaling Peptides and Proteins/physiology , Mixed Function Oxygenases/metabolism , Neoplasm Proteins/metabolism , Repressor Proteins/metabolism , Tumor Hypoxia , Tumor Suppressor Proteins/physiology , Ankyrin Repeat , Apoptosis , Cell Line, Tumor , Chromosomes, Human, Pair 15/genetics , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Glioblastoma/metabolism , Glucose/metabolism , Half-Life , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lactates/metabolism , Mixed Function Oxygenases/genetics , Neoplasm Proteins/genetics , Protein Stability , Recombinant Proteins/metabolism , Repressor Proteins/genetics , Transcription, Genetic , Tumor Hypoxia/physiology , Tumor Microenvironment , Up-Regulation , Von Hippel-Lindau Tumor Suppressor Protein/metabolism
12.
Mol Ther ; 26(9): 2267-2281, 2018 09 05.
Article in English | MEDLINE | ID: mdl-30037656

ABSTRACT

The epigenetics and genomics of glioblastoma (GBM) are complicated. Previous reports indicate that ELFN2 is widely distributed in the cerebral cortex neurons, striatum, and hippocampus cone and in granular cells. However, the function and mechanism of ELFN2, particularly in GBM, have rarely been explored. In this study, we identified ELFN2 as a new hypomethylation gene that acts as an oncogene in GBM. ELFN2 promoted cell autophagy by interacting with AurkA and eIF2α and inhibiting the activation of AurkA. We also demonstrated that aberrantly high ELFN2 expression is obtained due to hypomethylation of its promoter and abnormal miR-101 and LINC00470 expression in GBM. LINC00470 not only enhanced the expression of ELFN2 through adsorption of miR-101 but also affected the methylation level of ELFN2 by decreasing H3K27me3 occupancy. In addition, LINC00470 played a dominant role in the regulation of GBM cell autophagy, even though it upregulated ELFN2 expression. The results indicate that the combination of LINC00470 and ELFN2 has important significance for evaluating the prognosis of astrocytoma patients.


Subject(s)
Epigenesis, Genetic/genetics , Glioblastoma/metabolism , RNA, Long Noncoding/metabolism , Aurora Kinase A/genetics , Aurora Kinase A/metabolism , Autophagy/drug effects , Autophagy/genetics , Cell Line, Tumor , DNA Methylation/genetics , DNA Methylation/physiology , Epigenesis, Genetic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Glioblastoma/genetics , Glioblastoma/pathology , Humans , In Vitro Techniques , MicroRNAs/genetics , MicroRNAs/metabolism , Promoter Regions, Genetic/genetics , RNA, Long Noncoding/genetics
13.
Front Immunol ; 9: 1557, 2018.
Article in English | MEDLINE | ID: mdl-30034397

ABSTRACT

Tumor-associated macrophages (TAMs) constitute a major component of inflammatory cells in the glioblastoma multiforme (GBM) tumor microenvironment. TAMs have been implicated in GBM angiogenesis, invasion, local tumor recurrence, and immunosuppression. Coagulation factor X (FX) is a vitamin K-dependent plasma protein that plays a role in the regulation of blood coagulation. In this study, we first found that FX was highly expressed and positively correlated with TAM density in human GBM. FX exhibited a potent chemotactic capacity to recruit macrophages and promoted macrophages toward M2 subtype polarization, accelerating GBM growth. FX bound to extracellular signal-related kinase (ERK)1/2 and inhibited p-ERK1/2 in GBM cells. FX was secreted in the tumor microenvironment and increased the phosphorylation and activation of ERK1/2 and AKT in macrophages, which may have been responsible for the M2 subtype macrophage polarization. Moreover, although the lncRNA CASC2c has been verified to function as a miR-101 competing endogenous RNA (ceRNA) to promote miR-101 target genes in GBM cells, we first confirmed that CASC2c did not function as a miR-338-3p ceRNA to promote FX expression, and that FX was a target gene of miR-338-3p. CASC2c interacted with and reciprocally repressed miR-338-3p. Both CASC2c and miR-388-3p bound to FX and commonly inhibited its expression and secretion. CASC2c repressed M2 subtype macrophage polarization. Taken together, our findings revealed a novel mechanism highlighting CASC2c and FX as potential therapeutic targets to improve GBM patients by altering the GBM microenvironment.

14.
J Hematol Oncol ; 11(1): 77, 2018 06 04.
Article in English | MEDLINE | ID: mdl-29866190

ABSTRACT

BACKGROUND: Despite the overwhelming number of investigations on AKT, little is known about lncRNA on AKT regulation, especially in GBM cells. METHODS: RNA-binding protein immunoprecipitation assay (RIP) and RNA pulldown were used to confirm the binding of LINC00470 and fused in sarcoma (FUS). Confocal imaging, co-immunoprecipitation (Co-IP) and GST pulldown assays were used to detect the interaction between FUS and AKT. EdU assay, CCK-8 assay, and intracranial xenograft assays were performed to demonstrate the effect of LINC00470 on the malignant phenotype of GBM cells. RT-qPCR and Western blotting were performed to test the effect of LINC00470 on AKT and pAKT. RESULTS: In this study, we demonstrated that LINC00470 was a positive regulator for AKT activation in GBM. LINC00470 bound to FUS and AKT to form a ternary complex, anchoring FUS in the cytoplasm to increase AKT activity. Higher pAKT activated by LINC00470 inhibited ubiquitination of HK1, which affected glycolysis, and inhibited cell autophagy. Furthermore, higher LINC00470 expression was associated with GBM tumorigenesis and poor patient prognosis. CONCLUSIONS: Our findings revealed a noncanonical AKT activation signaling pathway, i.e., LINC00470 directly interacts with FUS, serving as an AKT activator to promote GBM progression. LINC00470 has an important referential significance to evaluate the prognosis of patients.


Subject(s)
Autophagy , Glioblastoma/pathology , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/physiology , Cell Line, Tumor , Cytoplasm/genetics , Cytoplasm/metabolism , Disease Progression , Humans , Prognosis , Protein Binding , RNA-Binding Protein FUS/metabolism , RNA-Binding Protein FUS/physiology , Signal Transduction
15.
J Hematol Oncol ; 10(1): 115, 2017 06 08.
Article in English | MEDLINE | ID: mdl-28595628

ABSTRACT

BACKGROUND: SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. METHODS: Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. RESULTS: SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. CONCLUSION: SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.


Subject(s)
Astrocytoma/genetics , Aurora Kinase A/genetics , Aurora Kinase B/genetics , Brain Neoplasms/genetics , Carcinogenesis/genetics , Eye Proteins/metabolism , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/metabolism , Nerve Tissue Proteins/metabolism , Animals , Astrocytoma/metabolism , Aurora Kinase A/metabolism , Aurora Kinase B/metabolism , Brain Neoplasms/metabolism , Carcinogenesis/metabolism , Cell Line, Tumor , Eye Proteins/genetics , Genes, Tumor Suppressor , Homeodomain Proteins/genetics , Humans , Male , Mice, Inbred BALB C , Mice, Nude , Nerve Tissue Proteins/genetics , Signal Transduction , Transcriptional Activation , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism , Homeobox Protein SIX3
16.
Oncotarget ; 7(42): 68585-68596, 2016 Oct 18.
Article in English | MEDLINE | ID: mdl-27612424

ABSTRACT

Osteosarcoma (OS) is the most common primary bone malignancy with a poor prognosis for all races and both sexes. In this study, we found that miR-381 is a positive prognosis factor for OS patients that OS patients with a low expression of miR-381 had a longer survival time after surgical intervention, and miR-381 expression promotes MG-63 cell proliferation and cell invasion ability. Our results also showed a strong negative correlation between the expression of miR-381 and LRRC4 (brain relative specific expression gene) in OS tissues. This demonstrated that LRRC4 is a direct target gene of miR-381, and suppressing the expression of miR-381 increases the sensitivity of OS cells to chemotherapeutic drugs through the LRRC4-mediated mTOR pathway. In summary, miR-381 is an important biomarker in directing therapeutic intervention and predicting prognosis in OS patients.


Subject(s)
Bone Neoplasms/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Osteosarcoma/genetics , 3' Untranslated Regions/genetics , Adolescent , Adult , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/metabolism , Cell Survival/drug effects , Cell Survival/genetics , Female , Humans , Kaplan-Meier Estimate , Male , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Osteosarcoma/drug therapy , Osteosarcoma/metabolism , Prognosis , Young Adult
17.
Oncotarget ; 7(4): 5007-22, 2016 Jan 26.
Article in English | MEDLINE | ID: mdl-26701852

ABSTRACT

Our previous report identified PR domain containing 16 (PRDM16), a member of the PR-domain gene family, as a new methylation associated gene in astrocytoma cells. This previous study also reported that miR-101 is a tumor suppressor in glioma. The present study confirms that PRDM16 is a hypomethylated gene that can be overexpressed in astrocytoma patients and demonstrates that the hypomethylation status of the PRDM16 promoter can predict poor prognoses for astrocytoma patients. The results reported herein show that PRDM16 was inhibited by miR-101 directly and also through epigenetic regulation. PRDM16 was confirmed as a new target of miR-101 and shown to be directly inhibited by miR-101. miR-101 also decreased the expression of PRDM16 by altering the methylation status of the PRDM16 promoter. miR-101 was associated with a decrease in the methylation-related histones H3K4me2 and H3K27me3 and an increase in H3K9me3 and H4K20me3 on the PRDM16 promoter. In addition, EZH2, EED and DNMT3A were identified as direct targets of miR-101, and miR-101 suppressed PRDM16 expression by targeting DNMT3A which decreases histone H3K27me3 and H3K4me2 at the PRDM16 core promoter. The results reported here demonstrate that miR-101 disrupted cellular mitochondrial function and induced cellular apoptosis via the mitochondrial pathway; for example, MMP and ATP levels decreased, while there was an increase in ADP/ATP ratios and ROS levels, levels of cleaved Caspase-9 and cleaved-PARP, the Bax/Bcl-2 ratios, and Smac release from the mitochondria to the cytoplasm. Knockdown of PRDM16 reversed the anti-apoptotic effect of miR-101 inhibition. In summary, miR-101 reversed the hypomethylation of the PRDM16 promoter which suppressed the expression of PRDM16, disrupted cellular mitochondrial function, and induced cellular apoptosis.


Subject(s)
Astrocytoma/genetics , Astrocytoma/pathology , DNA Methylation , DNA-Binding Proteins/genetics , MicroRNAs/genetics , Promoter Regions, Genetic/genetics , Transcription Factors/genetics , Adolescent , Adult , Aged , Astrocytoma/metabolism , Blotting, Western , Epigenesis, Genetic , Female , Humans , Immunoenzyme Techniques , Male , Membrane Potential, Mitochondrial , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Neoplasm Staging , Prognosis , RNA, Messenger/genetics , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL
...