Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 64
Filter
2.
Neurol Sci ; 45(4): 1447-1454, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37991640

ABSTRACT

Neurolymphomatosis (NL) is an uncommon malignant lymphoma characterized by selective infiltration of the central and peripheral nervous system. In this case report, we present a patient diagnosed with diffuse large B-cell lymphoma who initially manifested with peripheral neuropathy, primarily characterized by weakness of the left lower limb. By exploring its clinical manifestations, ancillary tests, and reviewing the relevant literature, we aim to deepen our understanding, diagnosis, and treatment of this disease. A 48-year-old male patient presented to the Department of Neurology, Hematology, and Neurosurgery with complaint of left lower limb weakness that had persisted for over 11 months. Initial laboratory tests and cerebrospinal fluid analysis yielded negative results. Electromyography examination indicated damage to the left lumbar plexus and iliac plexus nerves raising suspicions of nerve root involvement. Enhanced MRI of the lumbosacral plexus nerves revealed thickening and enhanced signals in left nerve roots at T12-L1, L1-2, and L3-4 levels. Additionally, local thickening and enhancement of signals were observed in the left erector spine muscle, psoas major, and iliopsoas muscles compared to the contralateral side. PEC/CT imaging displayed multiple soft tissue density shadows in the left foraminal area at the T12-1 and L1-2 levels. Bone marrow examination excluded hematological disease. Subsequent biopsy of the left foraminal nerve root at T12-L1 and the vertebral muscle at L3 level confirmed a diagnosis of diffuse large B-cell malignant lymphoma, indicating PNSL due to the involvement of multiple nerve roots. Following diagnosis, the patient underwent chemotherapy, resulting in the alleviation of his symptoms. Diagnosing PNSL can be challenging due to the nonspecific clinical manifestations and often inconclusive laboratory test results. Misdiagnosis and delayed diagnosis are common pitfalls. Electromyography may reveal damage to the affected peripheral nerves, while MR imaging might show nerve root thickening, and PET/CT can demonstrate increased lesion uptake. However, the definitive diagnosis relies on a biopsy of the lesion. Treatment for PNSL typically involves chemotherapy.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Peripheral Nervous System Neoplasms , Male , Humans , Middle Aged , Positron Emission Tomography Computed Tomography , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Peripheral Nervous System/pathology , Peripheral Nervous System Neoplasms/diagnosis , Peripheral Nerves
3.
Life Sci ; 338: 122392, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38160788

ABSTRACT

AIMS: The serine/arginine-rich splicing factor (SRSF) protein family members are essential mediators of the alternative splicing (AS) regulatory network, which is tightly implicated in cancer progression. However, the expression, clinical correlation, immune infiltration, and prognostic value of SRSFs in gliomas remain unclear. MATERIALS AND METHODS: Glioma samples were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Several databases, such as HPA, DAVID, UALCAN were used to comprehensively explore the roles of SRSFs. In addition, experimental validation of SRSF10 was also conducted. KEY FINDINGS: Here, we found the expression alterations of the SRSF family in glioma samples using data from the TCGA and CGGA_325 datasets. Among the 12 genes, most were found to be closely associated with glioma clinical features, which linked to poor prognosis in glioma patients. Interestingly, survival analysis identified only SRSF10 as a potential independent risk prognostic biomarker for glioma patients. Immune analysis indicated that glioma patients with high SRSF10 expression may respond well to immunotherapies targeting immune checkpoint (ICP) genes. Finally, knocking down SRSF10 reduced glioma cell viability, induced G1 cell cycle arrest, and induced the exclusion of bcl-2-associated transcription factor 1 (BCLAF1) exon 5a. SIGNIFICANCE: Overall, this study uncovers the oncogenic roles of most SRSF family members in glioma, with the exception of SRSF5, while highlighting SRSF10 as a potential novel independent prognostic biomarker for glioma.


Subject(s)
Glioma , Serine-Arginine Splicing Factors , Humans , Arginine , Biomarkers , Cell Cycle Proteins , Exons , Glioma/diagnosis , Glioma/genetics , Prognosis , Repressor Proteins , Serine-Arginine Splicing Factors/genetics
4.
Case Rep Oncol ; 16(1): 919-929, 2023.
Article in English | MEDLINE | ID: mdl-37900808

ABSTRACT

Collision tumors are rarely reported in patients with von Hippel-Lindau (VHL) disease, even though VHL patients often present with multi-organ tumor syndromes, like hemangioblastoma and renal cell carcinoma (RCC). Hemangioblastoma is rarely located in a supratentorial location, and intracranial lateral ventricular is also not a common site of metastasis for RCC. It is extremely rare for the two tumors to collide in the supratentorial area. We report a 64-year-old man with a history of clear cell RCC who presented with a sudden headache. The brain magnetic resonance imaging revealed that there was a cystic-solid mass in the intracranial lateral ventricular trigone. Histopathologically, the tumor consisted of two distinct components, most of which showed the typical morphology of hemangioblastoma. However, there were a few acinar structures composed of clear cells scattered in hemangioblastoma, and these acinar structures were subsequently confirmed as clear cell RCC. The genetic testing confirmed that the patient had VHL disease with de novo somatic mutation. Based on our case report, we systematically reviewed the characteristics of collision tumor composed of hemangioblastoma and metastatic RCC in VHL patients. The special growth site of our case is the first report of this kind of collision tumor, and can also help enrich our understanding of VHL disease and collision tumor.

5.
Eur J Clin Invest ; 53(6): e13964, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36727260

ABSTRACT

BACKGROUND: Emerging evidence has shown that miR-29 is a promising biomarker and therapeutic target for malignancies. The roles of miR-29a/b/c in glioma pathogenesis remain need further investigation. METHODS: The expression levels of miR-29a/b/c and CDC42 were systematically analysed, and prognostic significance was evaluated by Kaplan-Meier survival and Cox regression analyses. The roles of miR-29a/b/c in apoptosis and the underlying mechanisms were explored via an alkaline single-cell gel electrophoresis assay, caspase 3/7 activity assays and Western blotting. RESULTS: miR-29a/b/c expression decreased progressively with the elevation of the WHO grade in our 147 human glioma specimens, compared with 20 non-tumour control brain tissues, and decreased miR-29a/b/c expression was associated with more aggressive phenotypes. Kaplan-Meier and Cox regression analyses demonstrated that lower miR-29a/b/c expression was correlated with worse prognosis, which was confirmed by analysis of 198 glioma patients from the CGGA cohort. These all indicate that miR-29a/b/c were independent predictors of prognosis in glioma patients. miR-29a/b/c induced apoptosis in GBM cells by silencing CDC42. Further detailed mechanistic investigation revealed that miR-29a/b/c promoted apoptosis in a p53-dependent manner by suppressing the CDC42/PAK/AKT/MDM2 pathway. CONCLUSIONS: miR-29a/b/c are independent predictors of prognosis in glioma patients. They induce glioblastoma cell apoptosis via silencing of CDC42 and suppression of downstream PAK/AKT/MDM2 signalling in a p53-dependent manner.


Subject(s)
Glioblastoma , Glioma , MicroRNAs , Humans , Glioblastoma/genetics , Glioblastoma/metabolism , Glioblastoma/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Tumor Suppressor Protein p53 , Proto-Oncogene Proteins c-akt/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Glioma/genetics , Glioma/metabolism , Glioma/pathology , Apoptosis/genetics , Cell Cycle
6.
Cell Death Dis ; 13(9): 818, 2022 09 24.
Article in English | MEDLINE | ID: mdl-36153326

ABSTRACT

Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFß/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFß/SMAD signalling. Intriguingly, we found that Pontin amplified TGFßR2 gene transcription by recruiting LEF1, thereby activating TGFß/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFßR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFßR2 gene transcription, which could be exploited to target TGFß/SMAD signalling for anti-glioma therapy.


Subject(s)
ATPases Associated with Diverse Cellular Activities , Carrier Proteins , DNA Helicases , Glioma , Lymphoid Enhancer-Binding Factor 1 , Transcription Factors , ATPases Associated with Diverse Cellular Activities/metabolism , Carrier Proteins/metabolism , Cell Proliferation , Chromatin , DNA Helicases/metabolism , Glioma/genetics , Humans , Lymphoid Enhancer-Binding Factor 1/metabolism , Receptor, Transforming Growth Factor-beta Type II/genetics , Transcription Factors/metabolism , Transforming Growth Factor beta/metabolism
8.
Cell Death Dis ; 12(2): 141, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33542204

ABSTRACT

Pontin (RUVBL1) is a highly conserved ATPase of the AAA + (ATPases Associated with various cellular Activities) superfamily and is implicated in various biological processes crucial for oncogenesis. Its overexpression is observed in multiple human cancers, whereas the relevance of Pontin to gliomagenesis remains obscure. To gain insights into Pontin involvement in glioma, we performed bioinformatics analyses of Pontin co-expressed genes, Pontin-affected genes, and carried out experimental studies. The results verified that Pontin was upregulated in gliomas. Its higher levels might predict the worse prognosis of glioma patients. The Pontin co-expressed genes were functionally enriched in cell cycle progression and RNA processing. In the nucleus, Pontin promoted cell growth via facilitating cell cycle progression. Using RNA-seq, we found that Pontin knockdown resulted in altered expression of multiple genes, among which the E2F1 targets accounted for a large proportion. Mechanistic studies found that Pontin interacted with E2F1 and markedly amplified the E2F1 transcription response in an ATPase domain-dependent manner. By analyzing the RNA-seq data, we also found that Pontin could impact on the alternative splicing (AS). Both differential expressed genes and AS events affected by Pontin were associated with cell cycle regulation. Taken together, our findings provide novel insights of the importance of Pontin in gliomagenesis by regulating cell cycle and AS, and shed light on the possible application of Pontin as an antineoplastic target in glioma.


Subject(s)
ATPases Associated with Diverse Cellular Activities/metabolism , Brain Neoplasms/metabolism , Carrier Proteins/metabolism , DNA Helicases/metabolism , E2F1 Transcription Factor/metabolism , Brain Neoplasms/genetics , Glioma/genetics , Glioma/pathology , Humans , Transfection
9.
Adv Sci (Weinh) ; 8(3): 2001960, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33552853

ABSTRACT

In order to solve the problems of receptor promiscuity and poor blood-brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual-functional nanocomplex drug delivery system is developed based on the strategy of peptide-drug conjugates. In this study, SynB3-PVGLIG-PTX is designed and screened out by matrix metalloproteinase-2 (MMP-2), to which it exhibits the best affinity. The MMP-2-sensitive peptide (PVGLIG) and a cell-penetration peptide (SynB3) are combined to form a dual-functional peptide. Moreover, as a drug-peptide nanocomplex, SynB3-PVGLIG-PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP-2. From a functional perspective, it is found that SynB3-PVGLIG-PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP-2, in contrast to that observed in MMP-2 siRNA transfected cells. Further investigation in vivo shows that SynB3-PVGLIG-PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3-PVGLIG-PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3-PVGLIG-PTX can be used as a novel drug-loading delivery system to treat GBM due to its specificity and BBB permeability.

10.
Eur J Pharmacol ; 890: 173669, 2021 Jan 05.
Article in English | MEDLINE | ID: mdl-33098832

ABSTRACT

Glioma is the most common primary intracranial tumor, in which glioblastoma (GBM) is the most malignant and lethal. However, the current chemotherapy drugs are still unsatisfactory for GBM therapy. As the natural products mainly extracted from Eucalyptus species, phloroglucinol-terpene adducts have the potential to be anti-cancer lead compounds that attracted increasing attention. In order to discover the new lead compounds with the anti-GBM ability, we isolated Eucalyptal A with a phloroglucinol-terpene skeleton from the fruit of E. globulus and investigated its anti-GBM activity in vitro and in vivo. Functionally, we verified that Eucalyptal A could inhibit the proliferation, growth and invasiveness of GBM cells in vitro. Moreover, Eucalyptal A had the same anti-GBM activity in tumor-bearing mice as in vitro and prolonged the overall survival time by maintaining mice body weight. Further mechanism research revealed that Eucalyptal A downregulated SRSF1 expression and rectified SRSF1-guided abnormal alternative splicing of MYO1B mRNA, which led to anti-GBM activity through the PDK1/AKT/c-Myc and PAK/Cofilin axes. Taken together, we identified Eucalyptal A as an important anti-GBM lead compound, which represents a novel direction for glioma therapy.


Subject(s)
Brain Neoplasms/metabolism , Carcinogenesis/drug effects , Eucalyptol/therapeutic use , Glioma/metabolism , Myosin Type I/metabolism , Protein Splicing/drug effects , Serine-Arginine Splicing Factors/biosynthesis , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/therapeutic use , Brain Neoplasms/genetics , Brain Neoplasms/prevention & control , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Line, Tumor , Drugs, Chinese Herbal/isolation & purification , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Eucalyptol/isolation & purification , Eucalyptol/pharmacology , Gene Expression Regulation, Neoplastic , Glioma/genetics , Glioma/prevention & control , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Myosin Type I/genetics , Protein Splicing/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Serine-Arginine Splicing Factors/antagonists & inhibitors , Serine-Arginine Splicing Factors/genetics , Xenograft Model Antitumor Assays/methods
11.
Int J Biochem Cell Biol ; 113: 75-86, 2019 08.
Article in English | MEDLINE | ID: mdl-31200124

ABSTRACT

The relevance of RNA processing has been increasingly recognized in a variety of diseases. We previously identified serine/arginine-rich splicing factor 1 (SRSF1) as an oncodriver in glioma via splicing control. However, its splicing-independent roles and mechanisms are poorly defined in glioma. In this study, by integrating the data mining of SRSF1-co-expressed genes, SRSF1-affected genes and experimental studies, we demonstrated that SRSF1 was the most highly expressed SRSF in the 9 tumor types tested, and it was a crucial cell cycle regulator in glioma. Importantly, we identified nuclear paraspeckle assembly transcript1 (NEAT1), an upregulated long non-coding RNA (lncRNA) in glioma, as a target of SRSF1. Endogenous NEAT1 inhibition resembled the effect of SRSF1 knockdown on glioma cell proliferation by retarding cell cycle. Mechanistically, we proved that SRSF1 bound to NEAT1 and facilitated its RNA stability. The positive correlation between SRSF1 and NEAT1 levels in cancers further supported the positive regulation of NEAT1 by SRSF1. Collectively, our results provide novel insights on the splicing-independent mechanisms of SRSF1 in glioma, and confirm that NEAT1, whose stability maintained by SRSF1, implicates gliomagenesis by regulating cell cycle. Both SRSF1 and NEAT1 may serve as promising targets for antineoplastic therapies.


Subject(s)
Brain Neoplasms/genetics , Glioma/genetics , RNA, Long Noncoding/genetics , Serine-Arginine Splicing Factors/genetics , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cattle , Cell Cycle/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Female , Gene Knockdown Techniques , Gene Regulatory Networks , Glioma/metabolism , Glioma/pathology , Heterografts , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , RNA Stability , RNA, Long Noncoding/metabolism , Serine-Arginine Splicing Factors/biosynthesis , Serine-Arginine Splicing Factors/metabolism , Transcriptome , Up-Regulation
12.
Cancer Biol Med ; 16(1): 55-70, 2019 Feb.
Article in English | MEDLINE | ID: mdl-31119046

ABSTRACT

OBJECTIVE: Despite evidence that estrogens and insulin are involved in the development and progression of many cancers, their synergistic role in endometrial carcinoma (EC) has not been analyzed yet. METHODS: Here, we investigated how estrogens act synergistically with insulin to promote EC progression. Cell growth in vitro and in vivo, effects of estradiol and insulin on apoptosis and cell cycle distribution, and expression and activation of estrogen receptor (ER), insulin receptor (InsR), and key proteins in the PI3K and MAPK pathways were examined after combined stimulation with estradiol and insulin. RESULTS: Compared to EC cells treated with estradiol or insulin alone, those treated with both estradiol and insulin exhibited stronger stimulation. Estradiol significantly induced phosphorylation of InsR-ß and IRS-1, whereas insulin significantly induced phosphorylation of ER-α. In addition, treatment with both insulin and estradiol together significantly increased the expression and phosphorylation of Akt, MAPK, and ERK. Notably, InsR-ß inhibition had a limited effect on estradiol-dependent proliferation, cell cycle, and apoptosis, whereas ER-α inhibition had a limited insulin-dependent effect, in EC cell lines. Insulin and estradiol individually and synergistically promoted EC xenograft growth in mice. CONCLUSIONS: Estrogen and insulin play synergistic roles in EC carcinogenesis and progression by activating InsR-ß and ER-α, promoting a crosstalk between them, and thereby resulting in the activation of downstream PI3K/Akt and MAPK/ERK signaling pathways.

13.
Neuro Oncol ; 21(6): 742-754, 2019 06 10.
Article in English | MEDLINE | ID: mdl-30753603

ABSTRACT

BACKGROUND: Upregulation of staphylococcal nuclease domain-containing protein 1 (SND1) is a common phenomenon in different human malignant tissues. However, little information is available on the underlying mechanisms through which SND1 affects glioma cell proliferation and invasion. METHODS: SND1, Ras homolog family member A (RhoA), and marker of proliferation Ki-67 (MKI67) were analyzed in 187 gliomas by immunostaining. The correlation between those markers and patients' prognoses was assessed using the Kaplan-Meier estimator. Gene Ontology, chromatin immunoprecipitation, electrophoretic mobility shift assay, and chromosome conformation capture were applied to identify SND1-activated target genes. We also used MTT, colony formation, transwell and orthotopic implantation assays to investigate SND1 function in glioma cell proliferative and invasive activity. RESULTS: We identified SND1 and RhoA as independent predictors of poor prognosis in glioma patients. SND1 knockdown significantly suppressed the proliferation and invasion of glioma cells. Mechanistically, we discovered that SND1 facilitated malignant glioma phenotypes by epigenetically inducing chromatin topological interaction, which activated downstream RhoA transcription. RhoA sequentially regulated expression of CCND1, CCNE1, CDK4, and CDKN1B and accelerated G1/S phase transition in glioma cell proliferation. CONCLUSIONS: Our findings identify SND1 as a novel chromatin architectural modifier and promising prognostic indicator for glioma classification and treatment.


Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/pathology , Cell Proliferation , Endonucleases/metabolism , Gene Expression Regulation, Neoplastic , Glioma/pathology , rhoA GTP-Binding Protein/genetics , Animals , Apoptosis , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Case-Control Studies , Cell Cycle , Endonucleases/genetics , Glioma/genetics , Glioma/metabolism , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness , Prognosis , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
14.
Am J Pathol ; 189(1): 162-176, 2019 01.
Article in English | MEDLINE | ID: mdl-30312580

ABSTRACT

miR-135a-5p has been reported as a tumor suppressor in several extracranial tumors. However, its exact roles in gliomagenesis and relevance to the patients' prognoses are largely unknown. Herein, we detected the miR-135a-5p and tumor necrosis factor receptor-associated factor 5 (TRAF5) levels in 120 human glioma specimens and 20 nontumoral brain tissues; we found the miR-135a-5p level decreased, whereas the TRAF5 level increased, with the elevation of glioma grade. Their labeling indexes were inversely correlated with each other and showed strong negative (miR-135a-5p) and positive (TRAF5) correlation with the Ki-67 index. Cox regression demonstrated that both of their expression levels were independent survival predictors, whereas Kaplan-Meier analysis showed that subgrouping the glioma patients according to their levels could perfectly reflect the patients' prognoses regardless of the similarities in pathologic, molecular, and clinical features. In the following in vitro and in vivo studies, it was demonstrated that miR-135a-5p induced G1 arrest and inhibited the proliferation of glioma cells by targeting TRAF5 and subsequently blocking AKT phosphorylation as well as c-Myc and cyclin D1 expression. These effects could be reversed by TRAF5 overexpression and simulated by specific TRAF5 silencing. This study highlights the importance of miR-135a-5p and TRAF5 in gliomagenesis and progression and implies their potential prognostic and therapeutic values in malignant glioma.


Subject(s)
Brain Neoplasms/metabolism , Genes, Tumor Suppressor , Glioblastoma/metabolism , MicroRNAs/metabolism , RNA, Neoplasm/metabolism , TNF Receptor-Associated Factor 5/metabolism , Animals , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Cell Line, Tumor , Cyclin D1/genetics , Cyclin D1/metabolism , Glioblastoma/genetics , Glioblastoma/mortality , Glioblastoma/pathology , Humans , Kaplan-Meier Estimate , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Neoplasm Staging , Neoplasm Transplantation , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA, Neoplasm/genetics , TNF Receptor-Associated Factor 5/genetics , Transplantation, Heterologous
15.
J Clin Invest ; 129(2): 676-693, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30481162

ABSTRACT

Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Serine/arginine splicing factor 1 (SRSF1) has emerged as a key oncodriver in numerous solid tumors, leaving its roles and mechanisms largely obscure in glioma. Here, we demonstrate that SRSF1 is increased in glioma tissues and cell lines. Moreover, its expression was correlated positively with tumor grade and Ki-67 index, but inversely with patient survival. Using RNA-Seq, we comprehensively screened and identified multiple SRSF1-affected AS events. Motif analysis revealed a position-dependent modulation of AS by SRSF1 in glioma. Functionally, we verified that SRSF1 promoted cell proliferation, survival, and invasion by specifically switching the AS of the myosin IB (MYO1B) gene and facilitating the expression of the oncogenic and membrane-localized isoform, MYO1B-fl. Strikingly, MYO1B splicing was dysregulated in parallel with SRSF1 expression in gliomas and predicted the poor prognosis of the patients. Further investigation revealed that SRSF1-guided AS of the MYO1B gene increased the tumorigenic potential of glioma cells through the PDK1/AKT and PAK/LIMK pathways. Taken together, we identify SRSF1 as an important oncodriver that integrates AS control of MYO1B into promotion of gliomagenesis and represents a potential prognostic biomarker and target for glioma therapy.


Subject(s)
Alternative Splicing , Brain Neoplasms/metabolism , Cell Transformation, Neoplastic/metabolism , Glioma/metabolism , Myosin Type I/biosynthesis , Neoplasm Proteins , Serine-Arginine Splicing Factors/metabolism , Animals , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Glioma/genetics , Glioma/pathology , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Myosin Type I/genetics , Serine-Arginine Splicing Factors/genetics , Signal Transduction/genetics
16.
Cell Death Dis ; 9(11): 1078, 2018 10 22.
Article in English | MEDLINE | ID: mdl-30348972

ABSTRACT

Robust proliferation and apoptosis inhibition of tumor cells are responsible for the high mortality and poor outcome of patients with high-grade gliomas. miR-29a/b/c have been reported to be important suppressors in several human tumor types. However, their exact roles in gliomagenesis and their relevance to patient prognosis remain unclear. In this study, using 187 human glioma specimens and 20 nontumoral brain tissues, we demonstrated that the expression of miR-29a/b/c decreased progressively as the grade of glioma and the Ki-67 index increased. However, the expression of TRAF4, the functional target of miR-29a/b/c, exhibited the inverse trend, and its level was inversely correlated with the levels of miR-29a/b/c. A Kaplan-Meier analysis demonstrated that the miR-29a/b/c and TRAF4 levels were closely associated with patient survival even in patients with the same tumor grade and identical IDH gene status. A functional study verified that miR-29a/b/c induced apoptosis and suppressed the proliferation of glioma cells by directly targeting TRAF4. An investigation of the mechanism revealed that miR-29a/b/c promoted apoptosis through the TRAF4/AKT/MDM2 pathway in a p53-dependent manner, while miR-29a/b/c induced G1 arrest and inhibited tumor cell proliferation by blocking the phosphorylation of AKT and GSK-3ß, and the expression of cyclin D1 and c-Myc. Furthermore, TRAF4-knockdown perfectly simulated the anti-glioma effects of miR-29a/b/c. These findings enrich our understanding of gliomagenesis, highlight the prognostic value of miR-29a/b/c and TRAF4, and imply their potential therapeutic roles in malignant gliomas.


Subject(s)
Glioma/genetics , Glioma/pathology , MicroRNAs/genetics , TNF Receptor-Associated Factor 4/genetics , Tumor Suppressor Proteins/genetics , Apoptosis/genetics , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Neoplasm Grading/methods , Prognosis , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/genetics
17.
Onco Targets Ther ; 11: 5239-5252, 2018.
Article in English | MEDLINE | ID: mdl-30214229

ABSTRACT

BACKGROUND: Downregulation of miR-361-5p contributes to epithelial-mesenchymal transition of glioma cells. However, the relevance of miR-361-5p to migration and invasion of gliomas remains unknown. MATERIALS AND METHODS: The relationship between miR-361-5p and SND1 expression was analyzed in 120 human gliomas and 8 glioma cell lines by in situ hybridization, immunohistochemistry, and Western blot. Dual-luciferase reporter assay was used to identify SND1 as a target of miR-361-5p. The mechanisms through which miR-361-5p inhibits glioma cell migration and invasion were studied by in vitro assays. RESULTS: miR-361-5p expression was significantly downregulated in glioma tissues and glioma cell lines, and was inversely correlated with glioma grades. However, SND1 expression was positively correlated with glioma grades and inversely correlated with miR-361-5p expression. miR-361-5p overexpression suppressed glioma cell migration and invasion through targeting SND1 and subsequently decreasing MMP-2 expression. In glioma cell lines, SND1 overexpression could partly reverse the antitumor effects of miR-361-5p. CONCLUSION: The findings provide evidence that miR-361-5p directly targets SND1 to degradation and then reduces MMP-2 gene transcription, thus inhibiting glioma migration and invasion. miR-361-5p is an important tumor suppressor and a novel diagnostic biomarker of glioma, and miR-361-5p and SND1 are potential therapeutic candidates for malignant gliomas.

18.
Oncotarget ; 8(47): 82174-82184, 2017 Oct 10.
Article in English | MEDLINE | ID: mdl-29137254

ABSTRACT

Quaking-5 (QKI-5) belongs to the STAR (signal transduction and activation of RNA) family of RNA binding proteins and functions as a tumor suppressor in several human malignancies. In this study, we attempt to elucidate the role of QKI-5 in the pro-metastasis processes of lung cancer (LC) cells and the underlying mechanisms. We confirmed that QKI-5 was decreased in human LC tissues and cell lines, especially in high-metastatic cells. Moreover, QKI expression was positively correlated with LC patients' survival. Functional studies verified that QKI-5 suppressed migration, invasion and TGF-ß1-induced epithelial-mesenchymal transition (EMT) of LC cells. Mechanistically, we affirmed that QKI-5 reduced ß-catenin level in LC cells via suppressing its translation and promoting its degradation, whereas QKI-5 promoter hypermethylation suppressed QKI-5 expression. Our findings indicate that QKI-5 inhibits pro-metastasis processes of LC cells through interdicting ß-catenin signaling pathway, and that QKI-5 promoter hypermethylation is a crucial epigenetic regulation reducing QKI-5 expression in LC cells, and reveal that QKI-5 is a potential prognostic biomarker for LC patients.

19.
Cancer Biol Ther ; 18(12): 1000-1010, 2017 Dec 02.
Article in English | MEDLINE | ID: mdl-29172956

ABSTRACT

Despite evidence that estrogens and insulin are related to type 1 endometrial carcinoma (EC), their synergistic role has not been analyzed. Here, we investigated how estrogens cooperate with insulin to promote type 1 EC progression. We examined the clinical significance of serum estrogen and insulin levels using type 1 EC patients and control subjects. Univariate and multivariate logistic regression analyses for total, premenopausal, and postmenopausal subjects were performed. Type 1 EC risk was evaluated with respect to estrone, estradiol, and insulin levels based on odds ratios (ORs) using stratified data. Cell growth in vitro and in vivo, effects of insulin and estradiol on apoptosis and cell cycle distribution were measured after estradiol and insulin stimulation. Estrone and insulin concentrations were significantly high in type 1 EC patients and retained positive associations with type 1 EC after adjustment for BMI, WHR, diabetes, and hypertension. The odds ratio was significantly high for type 1 EC patients with higher levels of estrone/estradiol and insulin than for patients with higher levels of either estrone/estradiol or insulin, suggesting that estrogen and insulin play a synergistic role in type 1 EC carcinogenesis and progression. Compared to EC cells and cell-based xenografts treated with estradiol or insulin alone, those treated with estradiol and insulin exhibited stronger stimulation. Estrogen and insulin play synergistic roles in type 1 EC carcinogenesis and progression, extending our understanding of EC risks.


Subject(s)
Carcinogenesis/genetics , Endometrial Neoplasms/blood , Estrogens/blood , Insulin/blood , Aged , Apoptosis/genetics , Cell Cycle/genetics , Cell Proliferation/genetics , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Endometrium/metabolism , Endometrium/pathology , Estradiol/blood , Estrogens/genetics , Estrone/blood , Female , Humans , Insulin/genetics , Middle Aged , Premenopause , Xenograft Model Antitumor Assays
20.
Br J Cancer ; 117(7): 1036-1047, 2017 Sep 26.
Article in English | MEDLINE | ID: mdl-28787434

ABSTRACT

BACKGROUND: The lethality and poor outcome of high-grade gliomas result from the tumour relentless invasion. miR-29a/b/c downexpressions contribute to several human tumourigenesis. However, their relevance to prognosis and invasion in gliomas remains unclear. METHODS: Relationships of miR-29a/b/c and CDC42 expressions to grade and survival-time in 147 human gliomas were analysed by in situ hybridisation and immunohistochemistry. Dual-luciferase reporter assay was used to identify CDC42 as a target of miR-29a/b/c. Underlining mechanisms by which miR-29a/b/c inhibited glioma cell migration and invasion were studied by in vitro and in vivo assays. RESULTS: miR-29a/b/c expressions were inversely correlated with glioma grades, but positively correlated with patients' survival. Two distinct subgroups of grade I-IV glioma patients with different prognoses were identified according to miR-29a/b/c expressions. miR-29a/b/c overexpressions suppressed glioma cell migration and invasion through targeting CDC42 and subsequently decreasing phosphorylated PAK1/2/3, LIMK1/2 and cofilin, the pivotal downstream effectors of CDC42. Moreover, CDC42 expression was positively correlated with glioma grades, but inversely correlated with miR-29a/b/c expressions and patients' survival. In glioblastoma cell lines, CDC42-knockdown could mimic the anti-tumour effects of miR-29a/b/c. CONCLUSIONS: miR-29a/b/c are important tumour suppressors and novel prognostic biomarkers of gliomas, and miR-29a/b/c and CDC42 are potential therapeutic candidates for malignant gliomas.


Subject(s)
Brain Neoplasms/genetics , Glioma/genetics , MicroRNAs/analysis , MicroRNAs/genetics , cdc42 GTP-Binding Protein/analysis , cdc42 GTP-Binding Protein/genetics , Actin Depolymerizing Factors/metabolism , Animals , Brain Chemistry , Brain Neoplasms/chemistry , Brain Neoplasms/metabolism , Cell Line, Tumor , Cell Movement/genetics , Disease-Free Survival , Gene Expression , Gene Silencing , Glioma/chemistry , Glioma/metabolism , Humans , Lim Kinases/metabolism , Mice , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Transplantation , Survival Rate , Transfection , p21-Activated Kinases/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...