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1.
J Cancer Res Clin Oncol ; 145(9): 2293-2301, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401673

RESUMO

PURPOSE: Androgen receptors (ARs) are expressed on a variety of cell types, and AR signaling plays an important role in tumor development and progression in several cancers. This in vitro study evaluated the effect of dihydrotestosterone (DHT) on the proliferation of renal cell carcinoma (RCC) cells in relation to AR status. METHODS: Steroid hormone receptor expression was evaluated using RT-PCR and Western blotting. The effect of DHT on cell proliferation and STAT5 phosphorylation was evaluated in RCC cell lines (Caki-2, A498, and SN12C) and primary RCC cells using cell viability assays and Western blotting. ARs and glucocorticoid receptors (GRs) were knocked down with small interfering RNAs before assessing changes in cell proliferation and STAT5 activation. RESULTS: DHT treatment promoted cell proliferation and increased STAT5 phosphorylation regardless of AR status. The AR antagonist bicalutamide reduced kidney cancer cell proliferation, regardless of AR status. AR and GR knockdown blocked STAT5 activation and reduced cell proliferation in all RCC cell lines. In patient-derived primary cells, DHT enhanced cell proliferation and this effect was diminished by treatment with the AR antagonists bicalutamide and enzalutamide and the GR antagonist mifepristone. CONCLUSION: DHT promotes cell proliferation through STAT5 activation in RCC cells, regardless of AR status. DHT appears to utilize the AR and GR pathways to activate STAT5, and the inhibition of AR and GR showed antitumor activity in RCC cells. These data suggest that targeting AR and GR may be a promising new approach to the treatment of RCC.


Assuntos
Carcinoma de Células Renais/patologia , Proliferação de Células/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Neoplasias Renais/patologia , Receptores Androgênicos/fisiologia , Receptores de Glucocorticoides/fisiologia , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Fator de Transcrição STAT5/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Supressoras de Tumor/genética
2.
Gene ; 715: 144015, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357025

RESUMO

Tripartite Motif Containing 13 (TRIM13), a member of TRIM proteins, is deleted in multiple tumor types, especially in B-cell chronic lymphocytic leukemia and multiple myeloma. The present study explored the expression and potential role of TRIM13 in non-small-cell lung carcinoma (NSCLC). We found that TRIM13 mRNA and protein expression was reduced in NSCLC tissues and cell lines in comparison to paired non-cancerous tissues and a human normal bronchial epithelial cell line, respectively. Overexpression of TRIM13 in NCI-H1975 and SPC-A-1 cells hampered cell proliferation. Additionally, TRIM13 overexpression increased the levels of cleaved caspase-3. TRIM13-induced NSCLC cell apoptosis was attenuated by a caspase-3 inhibitor Ac-DEVD-CHO, suggesting that TRIM13 induced cell apoptosis partially through a caspase-3-dependent pathway. Moreover, it has been reported that TRIM13 can regulate nuclear factor kappaB (NF-κB) activity. Our data showed that TRIM13 overexpression inactivated NF-κB as indicated by the increased cytosolic NF-κB and decreased nuclear NF-κB. Exposure to an NF-κB inhibitor PDTC significantly blocked the impact of TRIM13 knockdown on cell proliferation and apoptosis, indicating the functions of TRIM13 in NSCLC cells were mediated by the NF-κB pathway. Finally, we demonstrated that TRIM13 overexpression suppressed tumor growth and induced cell apoptosis in vivo by using a xenograft mouse model. Collectively, our results indicate that TRIM13 behaves as a tumor suppressor in NSCLC through regulating NF-κB pathway. Our findings may offer a promising therapeutic target for NSCLC.


Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ligação a DNA/genética , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , NF-kappa B/genética , Transplante de Neoplasias , Transdução de Sinais , Proteínas Supressoras de Tumor/genética
3.
Gene ; 712: 143963, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279706

RESUMO

BACKGROUND: The aim of this study was to identify the expression of LIM and calponin-homology domains 1 (LIMCH1) in lung cancer and normal tissues, to determine the interaction between LIMCH1 and HUWE1 in regulating p53 stability. METHODS: The expression of LIMCH1 was detected by the Oncomine and Cancer Genome Atlas databases. Expression of LIMCH1 mRNA was identified using qRT-PCR. In transfected human lung cancer cells, co-immunoprecipitation experiments were performed. The mechanism that HUWE1 sustained lung cancer malignancy was verified by western blotting. The proliferation of tranfected cells was assessed by CCK-8 assay and colony formation. RESULTS: Bioinformatic data and e TCGA database suggested LIMCH1 mRNA levels in tumor tissues were down-regulated compared to tumor adjacent tissues. We found low expression of LIMCH1 mRNA in tumor sites and tumor cell line. Exogenous expression of LIMCH1 interacts with HUWE1 promotes expression of p53. Use of siRNA or shRNA against LIMCH1 resulted in decreased p53 protein levels. LIMCH1 deletion lead to enhance of p53 ubiquitination and protein expression of p53 and substrate p21, puma. Growth curve showed that LIMCH1 deletion significantly promoted the proliferation of A549 cells. CONCLUSIONS: LIMCH1 was a negative regulator and indicated a new molecular mechanism for the pathogenesis of lung cancer via modulating HUWE1 and p53.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio LIM/metabolismo , Neoplasias Pulmonares/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células A549 , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Humanos , Proteínas com Domínio LIM/genética , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Processamento de Proteína Pós-Traducional , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
4.
Life Sci ; 232: 116626, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276688

RESUMO

PURPOSE: The aim of this study was to investigate the role of the suppressor of activator protein-1 regulated by interferon (SARI), in the development and progression of prostate cancer. METHODS: Sixty-seven prostate cancer tissue specimens and 20 benign prostatic hyperplasia specimens were used to investigate the correlation between SARI expression and clinicopathologic parameters. Immunohistochemistry was used to detect the SARI and E-cadherin protein expression in the prostate cancer and benign prostatic hyperplasia specimens, and their correlation was established. Quantitative PCR (qPCR) was used to determine the SARI mRNA expression in a normal prostate cell line (RWPE-1) and prostate cancer cell lines (LNCaP and PC3). Western blotting was used to detect the SARI protein expression in the RWPE-1, LNCaP, and PC3 cell lines. RESULTS: SARI protein expression did not correlate with the prostate cancer patients' age or serum Prostate-Specific Antigen value but did show a correlation with the tumor stage of prostate cancer and Gleason score. SARI and E-cadherin expression in the prostate cancer tissue was significantly lower than in the benign prostatic hyperplasia specimens, suggesting a positive correlation between the SARI and E-cadherin expression. SARI mRNA and protein were highly expressed in RWPE-1, the normal prostate cell line, but SARI mRNA and protein expression were reduced in the prostate cancer cell lines, LNCaP and PC3. Significant differences in the expression were found between the prostate cancer cell lines and the normal prostate cell line. CONCLUSION: In this study, high SARI expression was found to be negatively correlated with the development and progression of prostate cancer.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Idoso , Western Blotting , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Imuno-Histoquímica , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fosfatidilinositol 3-Quinases/metabolismo , Próstata/citologia , Próstata/patologia , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Fator de Transcrição AP-1/metabolismo , beta Catenina/metabolismo
5.
Life Sci ; 232: 116649, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301415

RESUMO

AIMS: To investigate the potential biological role of E2F6 and its underlying molecular mechanism in gastric carcinoma (GC) progression. MAIN METHODS: The expressions of cancer susceptibility candidate 2 (CASC2), E2F6 and matrix metalloprotein-2 (MMP-2) were measured by quantitative real-time polymerase chain reaction and western blotting. The inhibitory effect of E2F6 on CASC2 was evaluated using luciferase reporter assay. Cell growth was assessed by colony formation assay and cell counting kit-8. Cell invasion and apoptosis were measured by transwell assay and flow cytometry assay, respectively. In vivo tumorigenicity was assessed by tumor xenografts in nude mice. KEY FINDINGS: Our data revealed that CASC2 was downregulated while E2F6 was upregulated in GC tissues and cell lines. Remarkably, lower expression of CASC2 was associated with poor survival in GC patients. E2F6 inhibited the expression of CASC2. Subsequently, reliable data showed that downregulation of E2F6 suppressed the proliferation and invasion, and promoted the apoptosis of GC cells. Furthermore, downregulation of E2F6 decreased the expression of MMP-2 and increased the activity of caspase-3. However, these changes triggered by E2F6 knockdown could be reversed by inhibition of CASC2. Moreover, we also proved that downregulation of CASC2 reverses the effect of E2F6 knockdown on tumor growth in vivo. SIGNIFICANCE: Our data demonstrated that E2F6 could regulate the proliferation, invasion and apoptosis of GC cells via inhibiting the expression of CASC2, suggesting that E2F6/CASC2 axis is another regulator of GC progression.


Assuntos
Regulação para Baixo/fisiologia , Fator de Transcrição E2F6/fisiologia , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Proteínas Supressoras de Tumor/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Progressão da Doença , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
7.
Chem Commun (Camb) ; 55(52): 7466-7469, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31184647
8.
Nat Commun ; 10(1): 2854, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253781

RESUMO

SETD1A, a Set1/COMPASS family member maintaining histone-H3-lysine-4 (H3K4) methylation on transcriptionally active promoters, is overexpressed in breast cancer. Here, we show that SETD1A supports mitotic processes and consequentially, its knockdown induces senescence. SETD1A, through promoter H3K4 methylation, regulates several genes orchestrating mitosis and DNA-damage responses, and its depletion causes chromosome misalignment and segregation defects. Cell cycle arrest in SETD1A knockdown senescent cells is independent of mutations in p53, RB and p16, known senescence mediators; instead, it is sustained through transcriptional suppression of SKP2, which degrades p27 and p21. Rare cells escaping senescence by restoring SKP2 expression display genomic instability. In > 200 cancer cell lines and in primary circulating tumor cells, SETD1A expression correlates with genes promoting mitosis and cell cycle suggesting a broad role in suppressing senescence induced by aberrant mitosis. Thus, SETD1A is essential to maintain mitosis and proliferation and its suppression unleashes the tumor suppressive effects of senescence.


Assuntos
Senescência Celular/fisiologia , Regulação da Expressão Gênica/fisiologia , Histona-Lisina N-Metiltransferase/metabolismo , Mitose/fisiologia , Linhagem Celular Tumoral , Histona-Lisina N-Metiltransferase/genética , Histonas , Humanos , Metilação , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
9.
Nat Commun ; 10(1): 2625, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201299

RESUMO

Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.


Assuntos
Hexoquinase/metabolismo , Células-Tronco Neoplásicas/fisiologia , Neoplasias da Próstata/patologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Glicólise , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Próstata/patologia , RNA Interferente Pequeno , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Biochem ; 166(3): 271-279, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31157375

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. miR-484 is previously reported to be a crucial modulator during the process from precancerous lesion to cancer. Tumour suppressor candidate 5 (TUSC5) is a potential tumour suppressor, but its expression and function in HCC are obscure. In this study, we aimed to explore the roles of miR-484 and TUSC5 in HCC, and clarify the relationship between them. We demonstrated that miR-484 was significantly up-regulated in HCC, while TUSC5 was down-regulated. TUSC5 was validated as the target gene of miR-484 and both of them were associated with the prognosis of HCC patients. miR-484 mimics markedly promoted the malignant phenotypes while TUSC5 plasmid had the opposite effect. In conclusion, miR-484/TUSC5 is potential diagnostic biomarkers and therapy targets for HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Proteínas de Membrana/análise , Proteínas de Membrana/genética , MicroRNAs/análise , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/genética
11.
Nat Commun ; 10(1): 2780, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239441

RESUMO

In the developing central nervous system, cell departure from the apical surface is the initial and fundamental step to form the 3D, organized architecture. Both delamination of differentiating cells and repositioning of progenitors to generate outer radial glial cells (oRGs) contribute to mammalian neocortical expansion; however, a comprehensive understanding of their mechanisms is lacking. Here, we demonstrate that Lzts1, a molecule associated with microtubule components, promotes both cell departure events. In neuronally committed cells, Lzts1 functions in apical delamination by altering apical junctional organization. In apical RGs (aRGs), Lzts1 expression is variable, depending on Hes1 expression levels. According to its differential levels, Lzts1 induces diverse RG behaviors: planar division, oblique divisions of aRGs that generate oRGs, and their mitotic somal translocation. Loss-of-function of lzts1 impairs all these cell departure processes. Thus, Lzts1 functions as a master modulator of cellular dynamics, contributing to increasing complexity of the cerebral architecture during evolution.


Assuntos
Cérebro/crescimento & desenvolvimento , Cérebro/metabolismo , Células Ependimogliais/metabolismo , Neurogênese , Neurônios/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Movimento Celular , Cérebro/citologia , Células Ependimogliais/citologia , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Proteínas Supressoras de Tumor/genética
12.
Gene ; 710: 333-340, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31202904

RESUMO

Gene promoter methylation is a common epigenetic event, taking place in the early phase of tumorigenesis, which has a great potential as a diagnostic and prognostic cancer biomarker. In this umbrella review, we provide an overview on the association between gene-promoter methylation of protein-coding genes and cancer risk based on currently available meta-analyses data on gene promoter methylation. We searched MEDLINE via PubMed and the Cochrane Database of Systematic Reviews for meta-analyses that examine the association between gene-promoter methylation and cancer, published until January 2019 in English. We used AMSTAR to assess the quality of the included studies and applied a set of pre-specified criteria to evaluate the magnitude of each association. We provide a comprehensive overview of 80 unique combinations between 22 different genes and 18 cancer outcomes, all of which indicated a positive association between promoter hypermethylation and cancer. In total, the 70 meta-analyses produced significant results under a random-effects model with odds ratios that ranged from 1.94 to 26.60, with the summary effect being in favor of the unmethylated group in all cases. Three of the strong evidence associations involve RASSF1 methylation on bladder cancer risk (OR = 18.46; 95% CI: 12.69-26.85; I2 = 0%), MGMT methylation on NSCLC (OR = 4.25; 95% CI: 2.83-6.38; I2 = 22.4%) and RARB methylation on prostate cancer (OR = 6.87; 95% CI: 4.68-10.08; I2 = 0%). Meta-analyses showed a moderate quality, AMSTAR score ranging from 4 to 9 (Mdn = 8; IQR: 7.0 to 8.0). As primary studies and meta-analyses on the subject accumulate, more genetic loci may be found to be highly associated with specific cancer types and hence the biomarker sets will become wider.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Neoplasias/genética , Receptores do Ácido Retinoico/genética , Proteínas Supressoras de Tumor/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Masculino , Metanálise como Assunto , Razão de Chances , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Bexiga Urinária/genética
13.
Anticancer Res ; 39(5): 2289-2298, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092420

RESUMO

BACKGROUND/AIM: We previously identified that promoter DNA methylation of cysteine dioxygenase type 1 (CDO1) and homeobox only protein homeobox (HOPX) were both cancer specific, and have a clinical potential as prognostic biomarkers in breast cancer (BC). The present study compared the differential prognostic relevance of methylation status of the CDO1 and HOPX genes in BC. MATERIALS AND METHODS: Methylation levels (TaqMethVs) were quantified in 7 BC cell lines and 133 BC patients by TaqMan methylation-specific PCR and functional traits were explored for CDO1. RESULTS: TaqMethVs were associated between CDO1 and HOPX (r2=0.072, p=0.002). Multivariate Cox proportional hazards model could identify CDO1 hypermethylation as well as Ki-67 as independent prognostic factors related to disease-specific survival (p=0.016, p<0.001). Overexpression of CDO1 decreased the anchorage-independent growth capacity in BC cell lines. CONCLUSION: CDO1 is a definite tumor suppressor gene, while its prognostic relevance was more than expected in the context of its functional relevance.


Assuntos
Neoplasias da Mama/genética , Cisteína Dioxigenase/genética , Metilação de DNA/genética , Proteínas de Homeodomínio/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais
14.
BMC Neurol ; 19(1): 89, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053103

RESUMO

BACKGROUND: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. CASE PRESENTATION: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686 T > G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. CONCLUSIONS: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes.


Assuntos
Doenças Desmielinizantes/genética , Leucoencefalopatias/genética , Doenças do Sistema Nervoso Periférico/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Criança , Pré-Escolar , Cistos/genética , Feminino , Humanos , Lactente , Recém-Nascido , Mutação , Mutação de Sentido Incorreto , Fenótipo
15.
Nat Commun ; 10(1): 2130, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086178

RESUMO

Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.


Assuntos
Hipóxia Celular , Hipertensão Pulmonar/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Supressoras de Tumor/metabolismo , Animais , Modelos Animais de Doenças , Glicólise , Células HEK293 , Células HeLa , Humanos , Hipertensão Pulmonar/cirurgia , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/cirurgia , Masculino , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso , NADPH Oxidase 1/metabolismo , Cultura Primária de Células , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteína Quinase C/metabolismo , Proteólise , Artéria Pulmonar/citologia , Transdução de Sinais , Proteínas Supressoras de Tumor/genética
16.
Mol Med Rep ; 19(6): 5263-5274, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059041

RESUMO

Genetic biomarkers for the diagnosis of ankylosing spondylitis (AS) remain unreported except for human leukocyte antigen B27 (HLA­B27). Therefore, the aim of the present study was to screen the differentially expressed genes (DEGs), and those that also possess differential single nucleotide polymorphism (SNP) loci in the whole blood of AS patients compared with healthy controls by integrating two mRNA expression profiles (GSE73754 and GSE25101) and SNP microarray data (GSE39428) collected from the Gene Expression Omnibus (GEO). Using the t­test, 1,056 and 1,073 DEGs were identified in the GSE73754 and GSE25101 datasets, respectively. Among them, 234 DEGs were found to be shared in both datasets, which were subsequently overlapped with 122 differential SNPs of genes in the GSE39428 dataset, resulting in identification of two common genes [eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) and serpin family A member 1 (SERPINA1)]. Their expression levels were significantly upregulated and the average expression log R ratios of SNP sites in these genes were significantly higher in AS patients than those in controls. Function enrichment analysis revealed that EEF1E1 was involved in AS by influencing the aminoacyl­tRNA biosynthesis, while SERPINA1 may be associated with AS by participating in platelet degranulation. However, only the genotype and allele frequencies of SNPs (rs7763907 and rs7751386) in EEF1E1 between AS and controls were significantly different between AS and the controls, but not SERPINA1. These findings suggest that EEF1E1 may be an underlying genetic biomarker for the diagnosis of AS.


Assuntos
Biomarcadores/metabolismo , Fatores de Alongamento de Peptídeos/genética , Espondilite Anquilosante/diagnóstico , Proteínas Supressoras de Tumor/genética , Alelos , Estudos de Casos e Controles , Bases de Dados Genéticas , Frequência do Gene , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas/genética , RNA de Transferência/metabolismo , Espondilite Anquilosante/genética , Transcriptoma , alfa 1-Antitripsina/genética
17.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075975

RESUMO

PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFßTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.


Assuntos
Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Animais , Apoptose/genética , Carcinogênese/genética , Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Fosforilação , Transcrição Genética , Proteínas Supressoras de Tumor/química
18.
Wei Sheng Yan Jiu ; 48(2): 273-278, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-31133107

RESUMO

OBJECTIVE: To study the effect of Bcl-2 family members on experimental autoimmune thyroiditis(EAT) and explore the pathogenesis of autoimmune thyroiditis. METHODS: Twenty-four female 4-5 week old NOD-SCID mice were randomly divided into four groups(six mice in each group): control group, high iodine group, poly(I:C) group and high iodine combined with poly(I:C) group. Control group and poly(I:C) group were fed with distilled water, while the high iodine group and high iodine combined with poly(I:C) group were supplied with 0. 05% NaI in their drinking water for 16 weeks. Poly(I:C) group and high iodine combined with poly(I:C) group received intraperitoneal injection of 100 µL poly(I:C)(1 µg/µL) at monday, wednesday and friday of the 11 th and 15 th week. Serum and thyroid were obtained at the last day of the 16 th week. The EAT model was confirmed by ELISA method and pathological HE staining, the apoptosis of thyroid cell were detected by TUNEL method and Cyt-C immunocytochemistry assay, and the mRNA levels of Bcl-2 family members in thyroid were determined by real-time qPCR method. RESULTS: EAT model was established using NOD-SCID mice through high-iodine feeding combined with poly(I:C) intraperitoneal injection. The degree of cell apoptosis and the Cyt-C expression levels were positively correlated with inflammation in thyroid follicular epithelial cells. The mRNA levels of Noxa, PUMA and Bid of high iodine group and high iodine combined with poly(I:C) group were higher than those in control and poly(I:C) groups(P<0. 05). CONCLUSION: Mitochondrial apoptosis pathway is involved in the thyroid cell apoptosis of EAT induced by high iodine, and the apoptosis may be regulated by the up-regulation of Noxa, PUMA and Bid, which belong to the pro-apoptotic members of Bcl-2 family.


Assuntos
Apoptose , Iodo/efeitos adversos , Glândula Tireoide/metabolismo , Tireoidite Autoimune/patologia , Animais , Proteínas Reguladoras de Apoptose/genética , Feminino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas/genética , RNA Mensageiro , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Tireoidite Autoimune/induzido quimicamente , Tireoidite Autoimune/metabolismo , Proteínas Supressoras de Tumor/genética
19.
Nat Mater ; 18(6): 638-649, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31114072

RESUMO

The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.


Assuntos
Adesões Focais/metabolismo , Integrinas/metabolismo , Microtúbulos/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Humanos , Mecanotransdução Celular , Podossomos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo
20.
Int J Mol Sci ; 20(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060342

RESUMO

The prospero homeobox 1 (PROX1) transcription factor is a product of one of the lymphangiogenesis master genes. It has also been suggested to play a role in carcinogenesis, although its precise role in tumour development and metastasis remains unclear. The aim of this study was to gain more knowledge on the PROX1 function in thyroid tumorigenesis. Follicular thyroid cancer-derived cells-CGTH-W-1-were transfected with PROX1-siRNA (small interfering RNA) and their proliferation, cell cycle, apoptosis and motility were then analysed. The transcriptional signature of PROX1 depletion was determined using RNA-Sequencing (RNA-Seq) and the expression of relevant genes was further validated using reverse transcriptase quantitative PCR (RT-qPCR), Western blot and immunocytochemistry. PROX1 depletion resulted in a decreased cell motility, with both migratory and invasive potential being significantly reduced. The cell morphology was also affected, while the other studied cancer-related cell characteristics were not significantly altered. RNA-seq analysis revealed significant changes in the expression of transcripts encoding genes involved in both motility and cytoskeleton organization. Our transcriptional analysis of PROX1-depleted follicular thyroid carcinoma cells followed by functional and phenotypical analyses provide, for the first time, evidence that PROX1 plays an important role in the metastasis of thyroid cancer cells by regulating genes involved in focal adhesion and cytoskeleton organization in tumour cells.


Assuntos
Adenocarcinoma Folicular/genética , Proteínas de Homeodomínio/genética , Proteínas Supressoras de Tumor/genética , Adenocarcinoma Folicular/patologia , Apoptose/genética , Biomarcadores Tumorais , Biópsia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , RNA Interferente Pequeno/genética , Transcriptoma
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