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1.
Nat Commun ; 11(1): 5105, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037191

RESUMO

RB1 mutational inactivation is a cancer driver in various types of cancer including lung cancer, making it an important target for therapeutic exploitation. We performed chemical and genetic vulnerability screens in RB1-isogenic lung cancer pair and herein report that aurora kinase A (AURKA) inhibition is synthetic lethal in RB1-deficient lung cancer. Mechanistically, RB1-/- cells show unbalanced microtubule dynamics through E2F-mediated upregulation of the microtubule destabilizer stathmin and are hypersensitive to agents targeting microtubule stability. Inhibition of AURKA activity activates stathmin function via reduced phosphorylation and facilitates microtubule destabilization in RB1-/- cells, heavily impacting the bipolar spindle formation and inducing mitotic cell death selectively in RB1-/- cells. This study shows that stathmin-mediated disruption of microtubule dynamics is critical to induce synthetic lethality in RB1-deficient cancer and suggests that upstream factors regulating microtubule dynamics, such as AURKA, can be potential therapeutic targets in RB1-deficient cancer.


Assuntos
Aurora Quinase A/genética , Neoplasias Pulmonares/genética , Microtúbulos/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Estatmina/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Nus , Microtúbulos/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteínas de Ligação a Retinoblastoma/metabolismo , Estatmina/genética , Mutações Sintéticas Letais , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
PLoS One ; 15(7): e0229193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614890

RESUMO

BACKGROUND: Urine-based diagnostics indicated involvement of oncoprotein 18 (OP18) in bladder cancer. In cell culture models we investigated the role of OP18 for malignant cell growth. METHODS: We analyzed 113 urine samples and investigated two human BCa cell lines as a dual model: RT-4 and ECV-304, which represented differentiated (G1) and poorly differentiated (G3) BCa. We designed specific siRNA for down-regulation of OP18 in both cell lines. Phenotypes were characterized by cell viability, proliferation, and expression of apoptosis-related genes. Besides, sensitivity to cisplatin treatment was evaluated. RESULTS: Analysis of urine samples from patients with urothelial BCa revealed a significant correlation of the RNA-ratio OP18:uroplakin 1A with bladder cancer. High urinary ratios were mainly found in moderately to poorly differentiated tumors (grade G2-3) that were muscle invasive (stage T2-3), whereas samples from patients with more differentiated non-invasive BCa (G1) showed low OP18:UPK1A RNA ratios. Down-regulation of OP18 expression in ECV-304 shifted its phenotype towards G1 state. Further, OP18-directed siRNA induced apoptosis and increased chemo-sensitivity to cisplatin. CONCLUSIONS: This study provides conclusive experimental evidence for the link between OP18-derived RNA as a diagnostic marker for molecular staging of BCa in non-invasive urine-based diagnostics and the patho-mechanistic role of OP18 suggesting this gene as a therapeutic target.


Assuntos
Biomarcadores Tumorais/urina , RNA/urina , Estatmina/genética , Neoplasias da Bexiga Urinária/diagnóstico , Idoso , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/secundário , Gradação de Tumores , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Estatmina/antagonistas & inibidores , Estatmina/metabolismo , Estatmina/urina , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Uroplaquina Ia/genética
3.
J Gastroenterol Hepatol ; 35(10): 1668-1675, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32250469

RESUMO

BACKGROUND AND AIM: The role of STMN1 in the development and progression of esophageal carcinoma is not yet determined. The present study aimed to systematically evaluate the correlation between STMN1 and prognosis of patients with esophageal carcinoma. METHODS: Electronic databases including PubMed, Embase, the Cochrane library, and Chinese Biomedical Literature Database (CBM) were searched to identify studies evaluating the impact of STMN1 on the survival of esophageal cancer patients, without the language limitation. Two investigators screened the literature according to the inclusion and exclusion criteria and evaluated the quality of the included studies. The combined analysis was performed using RevMan 5.3 software. RESULTS: A total of eight studies, involving 1240 esophageal carcinoma patients, were included in this retrospective design. Meta-analysis showed that esophageal carcinoma patients with low STMN1 had a superior overall survival and disease-free survival than those with high expression of STMN1. Compared with the high expression of STMN1, the 5-year survival rate was significantly higher in patients with low level of STMN1. Patients with high STMN1 expression had a higher risk of experiencing clinical grade III-IV disease, lymph node metastasis, and tumor invasion than those with low STMN1. CONCLUSION: STMN1 is an indicator for the prognosis of esophageal carcinoma patients.


Assuntos
Carcinoma/genética , Neoplasias Esofágicas/genética , Regulação da Expressão Gênica , Expressão Gênica , Estudos de Associação Genética , Estatmina/genética , Estatmina/metabolismo , Grupo com Ancestrais do Continente Asiático , Carcinoma/mortalidade , Carcinoma/patologia , Intervalo Livre de Doença , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
4.
Sci Rep ; 10(1): 2914, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076022

RESUMO

Studies indicate that stathmin expression associates with PI3K activation in breast cancer, suggesting stathmin as a marker for targetable patient subgroups. Here we assessed stathmin in relation to tumour proliferation, vascular and immune responses, BRCA1 germline status, basal-like differentiation, clinico-pathologic features, and survival. Immunohistochemical staining was performed on breast cancers from two series (cohort 1, n = 187; cohort 2, n = 198), and mass spectrometry data from 24 cases and 12 breast cancer cell lines was examined for proteomic profiles. Open databases were also explored (TCGA, METABRIC, Oslo2 Landscape cohort, Cancer Cell Line Encyclopedia). High stathmin expression associated with tumour proliferation, p53 status, basal-like differentiation, BRCA1 genotype, and high-grade histology. These patterns were confirmed using mRNA data. Stathmin mRNA further associated with tumour angiogenesis, immune responses and reduced survival. By logistic regression, stathmin protein independently predicted a BRCA1 genotype (OR 10.0, p = 0.015) among ER negative tumours. Cell line analysis (Connectivity Map) implied PI3K inhibition in tumours with high stathmin. Altogether, our findings indicate that stathmin might be involved in the regulation of tumour angiogenesis and immune responses in breast cancer, in addition to tumour proliferation. Cell data point to potential effects of PI3K inhibition in tumours with high stathmin expression.


Assuntos
Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/imunologia , Estatmina/genética , Proteína BRCA1/genética , Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mutação em Linhagem Germinativa/genética , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Invasividade Neoplásica , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Estrogênicos/metabolismo , Estatmina/metabolismo
5.
Cancer Sci ; 111(4): 1303-1313, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31994271

RESUMO

The survival benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy in oral squamous cell carcinoma (OSCC) patients is not satisfactory. Previously, we identified that stathmin, a microtubule-destabilizing protein, is overexpressed in OSCC. Here, we further investigated its role as a biomarker that impacts on OSCC chemosensitivity. We analyzed the predictive value of stathmin on TPF induction chemotherapy and its impact on OSCC cell chemosensitivity. Then, we further investigated the therapeutic effects of the combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors in vitro and in vivo. We found that OSCC patients with low stathmin expression benefited from TPF induction chemotherapy, while OSCC patients with high stathmin expression could not benefit from TPF induction chemotherapy. Stathmin overexpression promoted cellular proliferation and decreased OSCC cell sensitivity to TPF treatment. In addition, inhibition of the PI3K-AKT-mTOR signaling pathway decreased stathmin expression and phosphorylation. The combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors exhibited a potent antitumor effect both in vitro and in vivo. Therefore, stathmin can be used as a predictive biomarker for TPF induction chemotherapy and a combination therapy regimen based on stathmin expression might improve the survival of OSCC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Estatmina/genética , Idoso , Animais , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Medicina de Precisão , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Taxoides/administração & dosagem
6.
Lab Invest ; 100(6): 812-823, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31949244

RESUMO

Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Invasividade Neoplásica/patologia , Zixina , Animais , Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Silenciamento de Genes , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Camundongos , Camundongos Endogâmicos NOD , Prognóstico , Estatmina/análise , Estatmina/genética , Estatmina/metabolismo , Zixina/análise , Zixina/genética , Zixina/metabolismo
7.
Br J Cancer ; 122(3): 434-444, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31806880

RESUMO

BACKGROUND: Stathmin mediates cell migration and invasion in vitro, and metastasis in vivo. To investigate stathmin's role on the metastatic process, we performed integrated mRNA-miRNA expression analysis to identify pathways regulated by stathmin. METHODS: MiRNA and gene arrays followed by miRNA-target-gene integration were performed on stathmin-depleted neuroblastoma cells (CtrlshRNA vs. Stmn Seq2shRNA). The expression of the predicted target PTPN14 was evaluated by RT-qPCR, western blot and immunohistochemistry. Gene-silencing technology was used to assess the role of PTPN14 on proliferation, migration, invasion and signalling pathway. RESULTS: Stathmin levels modulated the expression of genes and miRNA in neuroblastoma cells, leading to a deregulation of migration and invasion pathways. Consistent with gene array data, PTPN14 mRNA and protein expression were downregulated in stathmin- depleted neuroblastoma cells and xenografts. In two independent neuroblastoma cells, suppression of PTPN14 expression led to an increase in cell migration and invasion. PTPN14 and stathmin expression did not act in a feedback regulatory loop in PTPN14- depleted cells, suggesting a complex interplay of signalling pathways. The effect of PTPN14 on YAP pathway activation was cell-type dependent. CONCLUSIONS: Our findings demonstrate that stathmin levels can regulate PTPN14 expression, which can modulate neuroblastoma cell migration and invasion.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neuroblastoma/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Estatmina/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Camundongos , Camundongos SCID , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Transplante de Neoplasias , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Estatmina/metabolismo
8.
Cancer Sci ; 111(2): 406-417, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785057

RESUMO

STMN1 has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. However, the detailed functions and underlying mechanisms of STMN1 are still largely unknown in hepatocellular carcinoma (HCC) development. Herein, we analyzed STMN1 expression and the related clinical significance in HCC by using well-established Protein Atlas, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cancer databases. Analysis indicated that STMN1 was highly expressed in HCC and closely associated with vascular invasion, higher histological grade, advanced clinical grade and shorter survival time in HCC patients. Overexpressing and silencing STMN1 in HCC cell lines showed that STMN1 could regulate cell proliferation, migration, drug resistance, cancer stem cell properties in vitro as well as tumor growth in vivo. Further experiments showed that STMN1 mediated intricate crosstalk between HCC and hepatic stellate cells (HSC) by triggering the hepatocyte growth factor (HGF)/MET signal pathway. When HSC were cocultured with HCC cells, HSC secreted more HGF to stimulate the expression of STMN1 in HCC cells. Mutually, STMN1 upregulation in HCC cells facilitated HSC activation to acquire cancer-associated fibroblast (CAF) features. The MET inhibitor crizotinib significantly blocked this crosstalk and slowed tumor growth in vivo. In conclusion, our findings shed new insight on STMN1 function, and suggest that STMN1 may be used as a potential marker to identify patients who may benefit from MET inhibitor treatment.


Assuntos
Carcinoma Hepatocelular/patologia , Células Estreladas do Fígado/citologia , Neoplasias Hepáticas/patologia , Transdução de Sinais , Estatmina/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Gradação de Tumores , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Regulação para Cima
9.
Cell Commun Signal ; 17(1): 159, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783876

RESUMO

BACKGROUND: Members of the karyopherin superfamily serve as nuclear transport receptors/adaptor proteins and provide exchange of macromolecules between the nucleo- and cytoplasm. Emerging evidence suggests a subset of karyopherins to be dysregulated in hepatocarcinogenesis including karyopherin-α2 (KPNA2). However, the functional and regulatory role of KPNA2 in liver cancer remains incompletely understood. METHODS: Quantitative proteomics (LC-MS/MS, ~ 1750 proteins in total) was used to study changes in global protein abundance upon siRNA-mediated KPNA2 knockdown in HCC cells. Functional and mechanistic analyses included colony formation and 2D migration assays, co-immunoprecipitation (CoIP), chromatin immunoprecipitation (ChIP), qRT-PCR, immmunblotting, and subcellular fractionation. In vitro results were correlated with data derived from a murine HCC model and HCC patient samples (3 cohorts, n > 600 in total). RESULTS: The proteomic approach revealed the pro-tumorigenic, microtubule (MT) interacting protein stathmin (STMN1) among the most downregulated proteins upon KPNA2 depletion in HCC cells. We further observed that KPNA2 knockdown leads to reduced tumor cell migration and colony formation of HCC cells, which could be phenocopied by direct knockdown of stathmin. As the underlying regulatory mechanism, we uncovered E2F1 and TFDP1 as transport substrates of KPNA2 being retained in the cytoplasm upon KPNA2 ablation, thereby resulting in reduced STMN1 expression. Finally, murine and human HCC data indicate significant correlations of STMN1 expression with E2F1/TFPD1 and with KPNA2 expression and their association with poor prognosis in HCC patients. CONCLUSION: Our data suggest that KPNA2 regulates STMN1 by import of E2F1/TFDP1 and thereby provide a novel link between nuclear transport and MT-interacting proteins in HCC with functional and prognostic significance.


Assuntos
Fator de Transcrição E2F1/metabolismo , Neoplasias Hepáticas/genética , Estatmina/genética , Fator de Transcrição DP1/metabolismo , alfa Carioferinas/metabolismo , Fator de Transcrição E2F1/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Transdução de Sinais/genética , Estatmina/metabolismo , Fator de Transcrição DP1/genética , Células Tumorais Cultivadas , alfa Carioferinas/genética
10.
Nat Commun ; 10(1): 5234, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748532

RESUMO

Genetic and genomic studies have advanced our knowledge of inherited Parkinson's disease (PD), however, the etiology and pathophysiology of idiopathic PD remain unclear. Herein, we perform a meta-analysis of 8 PD postmortem brain transcriptome studies by employing a multiscale network biology approach to delineate the gene-gene regulatory structures in the substantia nigra and determine key regulators of the PD transcriptomic networks. We identify STMN2, which encodes a stathmin family protein and is down-regulated in PD brains, as a key regulator functionally connected to known PD risk genes. Our network analysis predicts a function of human STMN2 in synaptic trafficking, which is validated in Stmn2-knockdown mouse dopaminergic neurons. Stmn2 reduction in the mouse midbrain causes dopaminergic neuron degeneration, phosphorylated α-synuclein elevation, and locomotor deficits. Our integrative analysis not only begins to elucidate the global landscape of PD transcriptomic networks but also pinpoints potential key regulators of PD pathogenic pathways.


Assuntos
Redes Reguladoras de Genes/genética , Doença de Parkinson/genética , Estatmina/genética , Substância Negra/metabolismo , Animais , Neurônios Dopaminérgicos , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Locomoção , Camundongos , Fosforilação , Transcriptoma , alfa-Sinucleína/metabolismo
11.
Hum Mol Genet ; 28(22): 3742-3754, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31363739

RESUMO

Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.


Assuntos
Atrofia Muscular Espinal/genética , Estatmina/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Animais , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos/genética , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microtúbulos/metabolismo , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/fisiopatologia , Fenótipo , Estatmina/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo
12.
Cell Syst ; 9(2): 167-186.e12, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31302154

RESUMO

Neuroepithelial stem cells (NSC) from different anatomical regions of the embryonic neural tube's rostrocaudal axis can differentiate into diverse central nervous system tissues, but the transcriptional regulatory networks governing these processes are incompletely understood. Here, we measure region-specific NSC gene expression along the rostrocaudal axis in a human pluripotent stem cell model of early central nervous system development over a 72-h time course, spanning the hindbrain to cervical spinal cord. We introduce Escarole, a probabilistic clustering algorithm for non-stationary time series, and combine it with prior-based regulatory network inference to identify genes that are regulated dynamically and predict their upstream regulators. We identify known regulators of patterning and neural development, including the HOX genes, and predict a direct regulatory connection between the transcription factor POU3F2 and target gene STMN2. We demonstrate that POU3F2 is required for expression of STMN2, suggesting that this regulatory connection is important for region specificity of NSCs.


Assuntos
Células-Tronco Neurais/metabolismo , Rombencéfalo/embriologia , Medula Espinal/embriologia , Diferenciação Celular/genética , Linhagem Celular , Regulação da Expressão Gênica no Desenvolvimento/genética , Redes Reguladoras de Genes/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células-Tronco Neurais/fisiologia , Células Neuroepiteliais , Neurogênese , Neurônios/metabolismo , Fatores do Domínio POU/genética , Fatores do Domínio POU/metabolismo , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/fisiologia , Estatmina/genética , Estatmina/metabolismo , Transcriptoma/genética
13.
J Clin Psychiatry ; 80(3)2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087825

RESUMO

OBJECTIVE: To investigate how the combination of clinical and molecular biomarkers can predict worsening of suicidal ideation during antidepressant treatment. METHODS: Samples were obtained from 237 patients with major depressive disorder (DSM-IV criteria) treated with either duloxetine or placebo in an 8-week randomized controlled trial. Data were collected between 2007 and 2011. The relationship between treatment-worsening suicidal ideation (TWSI) and a number of clinical variables, as well as peripheral expression of messenger RNA (mRNA) and microRNA (miRNA), was assessed at baseline. We generated 4 predictive models for TWSI: clinical, mRNA, miRNA, and a combined model comprising the best predictive variables from clinical, mRNA, and miRNA data. RESULTS: Eleven patients (9.8%) presented with TWSI in the duloxetine group. Among the clinical variables, only baseline depressive severity was found to be mildly predictive of TWSI. Two mRNAs (stathmin 1 [STMN1] and protein phosphatase 1 regulatory subunit 9B [PPP1R9B]) and 2 miRNAs (miR-3688 and miR-5695) were identified that were significantly predictive of TWSI when mRNA and miRNA were assessed separately (P = .002, .044, .004, and .005, respectively). The best model included baseline depression severity and expression of STMN1 and miR-5695 and predicted TWSI with area under the curve = 0.94 (P < .001). Additionally, the combined model did not significantly predict TWSI in the placebo group. CONCLUSIONS: This study generated a predictive tool for TWSI that combines both biological and clinical variables. These biological variables can be easily quantified in peripheral tissues, thus rendering them viable targets to be used in both clinical practice and future studies of suicidal behaviors. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00635219, NCT00599911, and NCT01140906.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Cloridrato de Duloxetina/uso terapêutico , MicroRNAs/genética , RNA Mensageiro/genética , Ideação Suicida , Adolescente , Adulto , Idoso , Animais , Método Duplo-Cego , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Prognóstico , Estatmina/genética , Adulto Jovem
14.
Ann Thorac Surg ; 108(1): 235-243, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910656

RESUMO

BACKGROUND: Stathmin-1 regulates microtubule dynamics and is associated with malignant phenotypes in non-small cell lung cancer (NSCLC). This study evaluated its diagnostic value for differentiating between NSCLC and high-grade lung neuroendocrine tumor (HGNET). METHODS: Stathmin-1 protein expression was assessed by immunohistochemistry in 414 NSCLC (305 adenocarcinoma [AD], 102 squamous cell carcinoma [SCC], 7 large-cell carcinoma), 5 typical carcinoid (low-grade lung neuroendocrine tumor), and 34 HGNET (17 small-cell carcinoma [SCLC] and 17 large-cell neuroendocrine carcinoma [LCNEC]) surgical specimens and 57 NSCLC (29 AD and 28 SCC) and 42 HGNET (17 LCNEC and 25 SCLC) biopsy specimens. We also analyzed stathmin-1 mRNA levels in 81 NSCLCs and 26 HGNETs with the use of reverse transcription-polymerase chain reaction. RESULTS: Among NSCLC samples, we saw high stathmin-1 protein expression in only three ADs, one SCC, and one large-cell carcinoma surgical samples, all five of which showed neuroendocrine characteristics in pathologic re-review; and low or intermediate expression in all five typical carcinoid surgical samples and all 57 NSCLC biopsy samples. In contrast, all HGNET surgical (n = 34) and biopsy (n = 42) samples showed high stathmin-1 expression. In reverse transcription-polymerase chain reaction, stathmin-1 expression was significantly higher in HGNET tissues than in NSCLC tissues (p < 0.001). CONCLUSIONS: Stathmin-1 expression can help in differentiating NSCLC from HGNET.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Estatmina/metabolismo , Biópsia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatmina/genética
15.
Int J Oncol ; 54(3): 1086-1098, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628664

RESUMO

Globally, gastric cancer is the fifth most common malignancy, with high rates of incidence and mortality. The high mortality rate and poor prognosis of gastric cancer are closely associated with its profound invasiveness, high incidence of metastasis, rapid proliferation, and high rate of recurrence. Previous studies have confirmed that stathmin (STMN) has an important role in the occurrence, development and prognosis of gastric cancer. However, the detailed mechanisms by which STMN affects these processes remain unclear. The aim of the present study was to determine how STMN promotes invasion, migration and proliferation in gastric cancer tumor cells. The results of immunohistochemistry indicated that STMN is overexpressed in stomach neoplasm tissues, and that it is associated with migration, invasion, proliferation and anti­apoptotic states of gastric cancer cells. The secretory proteins of gastric cancer cells with or without STMN knockdown were further analyzed using the isobaric tags for relative and absolute quantitation method to identify differentially expressed proteins verified by reverse transcription­quantitative polymerase chain reaction and western blot analysis. Inhibition of STMN decreases the levels of clusterin, cystatin C and matrix metalloproteinases, followed by inhibiting the protein kinase B and signal transducer and activation of transcription activation. These findings suggest that STMN could be a promising therapeutic target for gastric cancer.


Assuntos
Clusterina/metabolismo , Inativação Gênica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Estatmina/genética , Neoplasias Gástricas/patologia , Idoso , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Clusterina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fator de Transcrição STAT3/genética , Estatmina/metabolismo , Neoplasias Gástricas/metabolismo
16.
J BUON ; 24(6): 2523-2530, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31983128

RESUMO

PURPOSE: To investigate the expression of Stathmin and vascular endothelial growth factor C (VEGF-C) in the serum of patients with esophageal cancer (EC) and the diagnostic value of the combined two factors. METHODS: 88 EC patients (the EC Group) treated in Shaanxi Provincial People's Hospital and 50 healthy people (the Control Group) were selected as subjects of this study. After detecting the levels of Stathmin mRNA and VEGF-C mRNA using real-time quantitative PCR (qRT-PCR) and the expression levels of Stathmin protein and VEGF-C protein using enzyme-linked immunosorbent assay (ELISA), analysis of the relationship between the expression levels of Stathmin mRNA and VEGF-C mRNA in the serum and the clinicopathological features of EC were analyzed. RESULTS: The levels of Stathmin mRNA and VEGF-C mRNA, Stathmin protein and VEGF-C protein in the serum of the Control Group were lower than those in the EC group (p<0.001). The mRNA and protein expressions of Stathmin and VEGF-C in the serum of EC group were related to lymph node metastasis, clinical stage, grade of differentiation and degree of infiltration (p<0.05). Compared with the combined detection of mRNA, the sensitivity of separate detection of Stathmin mRNA and VEGF-C mRNA was lower, but the specificity of the separate detection of Stathmin mRNA was higher (p<0.05). Compared with the sensitivity of the combined detection of protein, the sensitivity of the separate test of Stathmin protein and VEGF-C protein was lower (p<0.05). CONCLUSION: Stathmin and VEGF-C could be used as markers for early diagnosis of EC, and the combined detection of the two factors could improve the sensitivity of diagnosis since the expression levels of mRNAs and proteins of Stathmin and VEGFC in the serum of EC patients were proved to be higher than those of healthy volunteers.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas do Esôfago/diagnóstico , RNA Mensageiro/sangue , Estatmina/sangue , Fator C de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/genética , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética , Curva ROC , Estudos Retrospectivos , Estatmina/genética , Fator C de Crescimento do Endotélio Vascular/genética , Adulto Jovem
17.
FASEB J ; 33(2): 1565-1577, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30183377

RESUMO

Hypoxia plays an important role in the development of renal fibrosis. G2/M arrest in renal tubular cells is an important pathway in the development of chronic kidney disease. It is unknown whether hypoxia leads to renal fibrosis via the regulation of G2/M arrest in renal tubular epithelial cells. For the first time, to our knowledge, we showed that hypoxia induces G2/M arrest in renal tubular cells leading to renal fibrosis, and microRNAs are involved in this regulation. We compared microRNA expression between hypoxia and normoxia in HK2 cells and found microRNA (miR)-493 to be highly expressed at 24 and 48 h after hypoxia. The overexpression of miR-493 reduced the expression of the cell cycle regulator, Stathmin (STMN)-1, and increased the percentage of G2/M phase cells and profibrotic factors in HK2 cells. Targeting STMN-1 with short hairpin RNA produced an effect similar to that of miR-493 overexpression. On contrast, the miR-493 inhibitor reversed these effects in vitro. Consistent with these results, miR-493 sponge adeno-associated virus reduced the expression of profibrotic factors and increased STMN-1 in vivo. In summary, these results suggest that the miR-493-STMN-1 pathway contributes to hypoxia-induced tubular epithelial cell G2/M arrest and renal fibrosis. Abrogating G2/M arrest and blocking the miR-493-STMN-1 pathway will provide further insight for the development of antifibrosis therapy.-Liu, T., Liu, L., Liu, M., Du, R., Dang, Y., Bai, M., Zhang, L., Ma, F., Yang, X., Ning, X., Sun, S. MicroRNA-493 targets STMN-1 and promotes hypoxia-induced epithelial cell cycle arrest In G2/M and renal fibrosis.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Divisão Celular , Fase G2 , Hipóxia/metabolismo , Nefropatias/patologia , MicroRNAs/genética , Estatmina/genética , Adulto , Animais , Linhagem Celular , Feminino , Fibrose/patologia , Fibrose/prevenção & controle , Humanos , Nefropatias/prevenção & controle , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Adulto Jovem
18.
Oncogene ; 38(7): 935-949, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30202098

RESUMO

Tumor metastasis is the main cause of death in advanced colorectal cancer. Our previous research showed that upregulation of KIAA1199 predicted poorer outcomes, and promoted cell motility and tumor metastasis in colorectal cancer, with the mechanisms not being fully elucidated. Here, we demonstrate that silencing of KIAA1199 results in reduced tumor metastasis in the orthotopic transplantation tumor model of colorectal cancer. Importantly, we find that KIAA1199 interacts with protein phosphatase 2A (PP2A) through the C-terminal domain and increases phosphatase activity of PP2A, which is essential for KIAA1199-mediated cell motility. Moreover, we identify stathmin, a microtubule-destabilizing protein, as a downstream of KIAA1199-PP2A complex. KIAA1199-induced dephosphorylation of stathmin results in microtubule destabilization and leads to enhanced cell motility. Furthermore, a microtubule-stabilizing drug paclitaxel could prevent KIAA1199-induced microtubule destabilization, and inhibit cell migration and invasion in vitro and tumor metastasis in vivo in colorectal cancer. Collectively, our study reveals that KIAA1199 promotes metastasis of colorectal cancer cells via microtubule destabilization regulated by a PP2A/stathmin pathway, and suggests that KIAA1199 may be a promising target for preventing metastasis in colorectal cancer.


Assuntos
Movimento Celular , Neoplasias Colorretais/metabolismo , Microtúbulos/metabolismo , Proteína Fosfatase 2/metabolismo , Proteínas/metabolismo , Estatmina/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Hialuronoglucosaminidase , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microtúbulos/patologia , Invasividade Neoplásica , Metástase Neoplásica , Proteína Fosfatase 2/genética , Proteínas/genética , Estatmina/genética
19.
Cancer Res ; 79(2): 397-409, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30478213

RESUMO

Postnatal development of the mammary gland relies on the maintenance of oriented cell division and apicobasal polarity, both of which are often deregulated in cancer. The microtubule (MT) network contributes to control these processes; however, very little is known about the impact of altered MT dynamics in the development of a complex organ and on the role played by MT-interacting proteins such as stathmin. In this study, we report that female stathmin knock-out (STM KO) mice are unable to nurse their litters due to frank impairment of mammary gland development. In mouse mammary epithelial cells, loss of stathmin compromised the trafficking of polarized proteins and the achievement of proper apicobasal polarity. In particular, prolactin receptor internalization and localization was altered in STM KO mammary epithelial cells, leading to decreased protein stability and downmodulation of the Prl/PrlR/STAT5 signaling pathway. Absence of stathmin induced alterations in mitotic spindle orientation, accumulation of mitotic defects, and apoptosis, overall contributing to tissue disorganization and further decreasing the expansion of the mammary epithelial compartment. Loss of stathmin in MMTV-Δ16HER2 transgenic mice decreased the incidence and increased the latency of these very aggressive mammary carcinomas. Collectively, these data identify the essential mammary protein stathmin as protumorigenic and suggest it may serve as a potential therapeutic target in breast cancer. SIGNIFICANCE: Stathmin expression is critical to maintain oriented cell division and apicobasal polarity in normal mammary glands and to establish a protumorigenic program that eventually sustains HER2-positive breast cancer formation in mice.


Assuntos
Glândulas Mamárias Animais/crescimento & desenvolvimento , Neoplasias Mamárias Experimentais/metabolismo , Receptor ErbB-2/metabolismo , Estatmina/metabolismo , Animais , Carcinogênese , Feminino , Células HEK293 , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Prolactina/metabolismo , Receptor ErbB-2/genética , Receptores da Prolactina/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Estatmina/deficiência , Estatmina/genética
20.
Cell Physiol Biochem ; 50(6): 2249-2259, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30423576

RESUMO

BACKGROUND/AIMS: Increasing evidences suggest that dysregulated expression of miRNAs contributes to the progression of various tumors. However, the underlying function of miR-423-5p in osteosarcoma remains unexplored. METHODS: The expression of miR-423-5p and STMN1 were determined in osteosarcoma samples and cell lines via quantitative real-time PCR. Colony formation and Cell Counting Kit-8 (CCK-8) assays were performed to measure cell proliferation ability and transwell analysis was used to detect cell invasion, and dual luciferase reporter assay was perform to analysis the interaction between the miR-423-5p and STMN1. RESULTS: The expression levels of miR-423-5p and STMN1 in the osteosarcoma tissues and cell lines were measured by qRT-PCR. Cell viability was determined using the clone formation and CCK-8 assays. A dual-luciferase reporter and Western blot were performed to stdudy the target gene of miR-423-5p. Here, we showed that miR-423-5p expression was downregulated in osteosarcoma tissues and cell lines. However, the expression of stathmin1 (STMN1) was downregulated in osteosarcoma tissues and cell lines. Moreover, STMN1 expression level was negatively correlated with the miR-423-5p expression in the osteosarcoma tissues. We identified STMN1 was a direct target gene of miR-423-5p in osteosarcoma cell. Overexpression of miR-423-5p inhibited osteosarcoma cell proliferation, colony formation and invasion. Furthermore, we demonstrated that STMN1 was involved in miR-423-5p-mediated cell behavior such as cell proliferation, colony formation and invasion in the osteosarcoma cell. CONCLUSION: Our present study indicated that miR-423-5p acted as a tumor suppressor gene in osteosarcoma partly through inhibiting STMN1 expression.


Assuntos
Neoplasias Ósseas/patologia , Proliferação de Células , MicroRNAs/metabolismo , Osteossarcoma/patologia , Estatmina/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Sequência de Bases , Sítios de Ligação , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Mutagênese , Osteossarcoma/genética , Osteossarcoma/metabolismo , Alinhamento de Sequência , Estatmina/química , Estatmina/genética
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