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1.
Anticancer Res ; 39(10): 5361-5367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570430

RESUMO

BACKGROUND/AIM: The mechanism responsible for B-cell translocation gene 1 (BTG1) down-regulation in breast carcinoma remains unknown. We examined the BTG1 expression status in breast carcinoma cells and investigated the mechanism underlying the observed alterations. MATERIALS AND METHODS: Four breast carcinoma cell lines (SK-BR-3, MDA-MB-231, T-47D, and MCF-7), and one normal mammary epithelial cell line (MCF-10A) were analyzed. BTG1 expression was examined using quantitative reverse transcription polymerase chain reaction (PCR) and western blot. Methylation status of the BTG1 promoter was analyzed using methylation-specific PCR (MSP). To investigate the effect of methylation on BTG1, the cells were treated with a demethylating agent. RESULTS: The carcinoma cells expressed significantly lower levels of BTG1 mRNA and protein than normal cells. The BTG1 promoter was highly methylated in the carcinoma cells. 5-aza-2-deoxycytidine significantly restored BTG1 expression. CONCLUSION: Down-regulation of BTG1 expression through epigenetic repression is involved in mammary carcinogenesis. BTG1 is a potential diagnostic marker and therapeutic target for breast carcinoma.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , RNA Mensageiro/genética
2.
Bioengineered ; 10(1): 345-352, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411110

RESUMO

This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Antagomirs/genética , Antagomirs/metabolismo , Biomarcadores Tumorais/sangue , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica , Ontologia Genética , Histona Desacetilase 1/sangue , Histona Desacetilase 1/genética , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , Anotação de Sequência Molecular , Análise Multivariada , Proteínas de Neoplasias/sangue , Prognóstico , Curva ROC , Recidiva , Transdução de Sinais , Análise de Sobrevida , Quinases da Família src/sangue , Quinases da Família src/genética
3.
Gene ; 715: 144005, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376410

RESUMO

Members of the highly conserved pleiotropic CK1 family of serine/threonine-specific kinases are tightly regulated in the cell and play crucial regulatory roles in multiple cellular processes from protozoa to human. Since their dysregulation as well as mutations within their coding regions contribute to the development of various different pathologies, including cancer and neurodegenerative diseases, they have become interesting new drug targets within the last decade. However, to develop optimized CK1 isoform-specific therapeutics in personalized therapy concepts, a detailed knowledge of the regulation and functions of the different CK1 isoforms, their various splice variants and orthologs is mandatory. In this review we will focus on the stress-induced CK1 isoform delta (CK1δ), thereby addressing its regulation, physiological functions, the consequences of its deregulation for the development and progression of diseases, and its potential as therapeutic drug target.


Assuntos
Caseína Quinase Idelta/química , Caseína Quinase Idelta/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Transdução de Sinais , Animais , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/genética , Sistemas de Liberação de Medicamentos/métodos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Relação Estrutura-Atividade
4.
Anticancer Res ; 39(8): 4137-4142, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366498

RESUMO

BACKGROUND: P53 is a key regulator of genomic stability and function, acting as a tumor suppressor protein. Our aim was to correlate P53 expression with murine double minute 2 (MDM2), a proto-oncogene that interacts with P53 and forms an auto-regulatory pathway, in laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: A total of 50 LSCC cases were included in the study. Immunohistochemistry was applied by using antibodies to P53 and MDM2 in the corresponding tissue sections. Protein expression levels for both molecules were measured by implementing a digital image analysis assay (immunostaining intensity levels, densitometric evaluation). RESULTS: Overexpression of P53 protein was observed in 16/50 (32%) LSCC cases, while 22/50 (44%) cases strongly expressed MDM2 protein. Interestingly, in 13/50 (26%) cases, combined overexpression of P53/MDM2 was detected. Overall P53 was strongly positively correlated with MDM2 expression (p=0.001). Both P53 and MDM2 overexpression were significantly correlated with advanced stage of LSCC (p=0.032 and p=0.001, respectively). Additionally, MDM2 was found to be associated with poorer survival of patients (p=0.046). CONCLUSION: Aberrant co-expression of P53 and MDM2 is associated with advanced stage in LSCC. Furthermore, MDM2 overexpression is a frequent and critical genetic event in LSCC and seems to negatively affect survival.


Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias Laríngeas/diagnóstico por imagem , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Idoso , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 39(8): 4423-4430, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366540

RESUMO

BACKGROUND/AIM: To evaluate the impact of DEPDC1 expression on patient prognosis after hepatic resection for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We reviewed data from 75 patients who underwent hepatic resection for HCC between 2004 and 2013. Recurrence at 2 years following resection, which mainly included metastatic recurrence, was defined as late recurrence. RESULTS: DEPDC1 was up-regulated in HCC tissue and in non-tumor tissue of patients with HCC compared to normal liver (p<0.01 and p<0.01, respectively). High expression of DEPDC1 was associated with poor overall, disease-specific, and disease-free survival (p=0.02, p<0.01, and p<0.01, respectively). High DEPDC1 expression was an independent predictor of death and recurrence (p=0.03 and p<0.01, respectively). High expression of DEPDC1 in non-tumor liver was an independent risk factor for late recurrence (p=0.04). CONCLUSION: High expression of DEPDC1 in tumor tissue appears to be associated with tumor progression and poor prognosis.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas Ativadoras de GTPase/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Prognóstico , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade
6.
Anticancer Res ; 39(8): 4517-4523, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366554

RESUMO

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have dramatically changed the clinical outcomes of advanced tumours. However, biomarkers for monitoring immunological features during immunotherapy remain unclear, especially those in the peripheral blood, which are easily available. This study evaluated the usefulness of nCounter Analysis System in identifying immunological biomarkers in peripheral blood mononuclear cells (PBMCs) during ICI therapy. PATIENTS AND METHODS: PBMCs from two patients who responded well to ICI therapy were used, and the expression levels of immune-related mRNA and extracellular proteins were analyzed. RESULTS: Changes in the expression levels of 55 genes from pre-treatment to on-treatment were bioinformatically similar between the two cases. The expression levels of PD-1 were consistent with those by flow cytometry analysis, a reliable tool for monitoring various markers. CONCLUSION: The nCounter Analysis System may be a potent tool to simultaneously investigate genes and proteins on PBMCs as biomarkers during immunotherapy using a small amount of sample.


Assuntos
Biomarcadores Tumorais/sangue , Imunoterapia , Neoplasias Pulmonares/sangue , Proteínas de Neoplasias/genética , Idoso , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue
7.
Life Sci ; 234: 116788, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445935

RESUMO

Livin is an important member of the human inhibitor of apoptosis proteins (IAPs) family. IAPs are proteins with antiapoptotic abilities, and their functions are different from the Bcl-2 (B-cell lymphoma-2) family proteins. However, the precise role of Livin in colon cancer progression remains unclear. The purpose of this study is to assess the effect of overexpression Livin in colon cancer cells and to examine its molecular mechanism. We demonstrated that Livin induced a colon cancer phenotype, including proliferation and migration, by regulating H2A.XY39ph (histone family 2A variant (H2AX) phosphorylated on the 39th serine site). We elucidated that Livin degraded Jumonji-C domain-containing 6 protein (JMJD6), which was mediated by the proteasome murine double minute 2 (MDM2), thereby regulating H2A.XY39ph. Above all, the overexpression of JMJD6 recovered H2A.XY39ph in colon cancer cells with a high level of Livin, thus inhibiting colon cancer malignancy progression. These results reveal a previously unrecognized role for Livin in regulating the tumor-initiating capacity in colon cancer and provide a novel treatment strategy in cancer via the interruption of H2A.XY39ph function and the interaction between H2A.XY39ph and JMJD6.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias do Colo/patologia , Histonas/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Humanos , Proteínas Inibidoras de Apoptose/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas de Neoplasias/genética , Proteólise
8.
DNA Cell Biol ; 38(9): 915-921, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31429604

RESUMO

Pharynx-larynx cancer is a complex malignant tumor with the sixth-highest morbidity and mortality rate worldwide. The telomerase reverse transcriptase TERT-CLPTM1L gene, located on chromosome 5p15.33, plays a key role in the occurrence and progression of various cancer. The purpose of this hospital-based case-control study of patients in northern China was to explore the association between two single-nucleotide polymorphisms (SNPs) rs401681 in TERT and rs2736100 in CLPTM1L and the risk of head and neck cancer. We collected samples and relative characteristics and then analyzed the relationship between SNPs and pharynx-larynx cancer susceptibility by logistic regression analysis. The results suggested that the male patients carrying CT and CT+CC genotype model of rs401681 was associated with reduced risk of pharynx-larynx cancer compared with the CC genotype (adjusted odds ratios were 0.701 and 0.704, and 95% confidence intervals were 0.495-0.992 and 0.506-0.980; p-values were 0.045 and 0.038, respectively). In addition, we found that subjects with allele-C showed a relatively low risk of pharyngeal cancer when smoking exposure history was obtained. But the limitation is that in the future we need to further investigate about the exact functional effect of these two variant genes and a larger scale sample. Overall, in this research, our results show that the TERT-CLPTM1L gene could be a meaningful biomarker for pharynx-larynx cancer susceptibility.


Assuntos
Neoplasias Laríngeas/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neoplasias Faríngeas/genética , Polimorfismo de Nucleotídeo Único , Telomerase/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Artigo em Chinês | MEDLINE | ID: mdl-31446696

RESUMO

Objective:To make the molecular diagnosis of a patient complaining hearing loss and with specific facial features, developmental delay, vertebral dysplasia, hypotonia and other suspected phenotypes of Kabuki make-up syndrome(KS); to investigate the characteristics and main phenotypes of KS. Method:①Whole-exome sequencing and bioinformatics analysis were performed for proband and her parents. ②Literatures describing the clinical features of KS patients with clear molecular diagnosis from the period of Aug 2010 to Mar 2019 were collected from databases of PubMed and CNKI. Result:①The proband carries the c. 15777insT variant(p. Pro5260fs*10) in KMT2D gene. The variant causes the termination codon to appear prematurely. KMT2D c. 15777insT was classified as PVS1+PS1+PM2 according to the ACMG variation interpretation standard, which is a disease-causing mutation. The c. 15777insT was first reported as a pathogenic mutation of KS. ②77 peer-reviewed publications on KS were analysed including 462 patients with KS. The main findings were intellectual disability(305 cases), congenital heart defects(227 cases), hypotonia(184 cases), short fingers(147 cases), short stature(144 cases), cleft palate(139 cases), hearing loss(101 cases) and developmental delay(99 cases). Of the 101 patients with hearing loss, 11 were confirmed to have conductive hearing loss(1 with recurrent otitis media), 3 with mixed hearing loss, 12 with sensorineural deafness(1 with recurrence otitis media) and 75 patients with unidentified types of deafness(28 with recurrent otitis media). Conclusion:KS involves defects of a wide range of organs, with each organ showing different severity of symptoms, which is easily misdiagnosed from the phenotypes. We suggest the diagnosis on hearing loss in KS patients should be strengthened. KMT2D and KDM6A are two pathogenic genes that have been identified for KS. With the increase of age, its typical clinical phenotypes become more and more obvious. When there is only atypical suspected KS symptoms in the early neonatal period, relevant genetic test should be performed as soon as possible to achieve early diagnosis and intervention.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Perda Auditiva/etiologia , Doenças Hematológicas/complicações , Doenças Hematológicas/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/complicações , Doenças Vestibulares/genética , Feminino , Humanos , Mutação , Fenótipo
10.
Medicine (Baltimore) ; 98(31): e16715, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374065

RESUMO

Chromosome 8 open reading frame 4 (C8orf4) is an activator of Wnt signaling pathway, and participates in the tumorigenesis and progression of many tumors. The expression levels of C8orf4 and ß-catenin were assessed via immunohistochemical staining in 100 cervical squamous cell carcinoma (CSCC) tissues, 50 high-grade squamous intraepithelial lesions (HSILs), 50 low-grade squamous intraepithelial lesions (LSILs), and 50 normal cervical tissues. Bisulfite sequencing polymerase chain reaction analysis was used to examine the methylation status of the C8orf4 locus in CSCC and normal cervical tissues. The expression rates of C8orf4 and ß-catenin were significantly higher in CSCCs or HSILs than in LSILs or normal cervical tissues (P < .05). C8orf4 expression was positively correlated with the poor differentiation of CSCCs (P = .009), and with aberrant expression of ß-catenin in CSCCs (P = .002) and squamous intraepithelial lesions (P < .001). The methylation rate of C8orf4 in CSCCs was significantly lower than that in normal cervical tissues (P = .001). The Cancer Genome Atlas genomics data also confirmed that the mRNA expression of C8orf4 was positively associated with the copy number alteration of C8orf4 (correlation coefficient = 0.213, P < .001), and negatively correlated with the methylation level of C8orf4 (correlation coefficient = -0.408, P < .001). In conclusion, the expressions of C8orf4 and ß-catenin were synergistically increased in CSCCs and HSILs and higher than those in LSILs and normal cervical tissues. The methylation level of C8orf4 is decreased in CSCCs and is responsible for the increased expression of C8orf4.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasia Intraepitelial Cervical/genética , Proteínas de Neoplasias/biossíntese , Neoplasias do Colo do Útero/genética , beta Catenina/biossíntese , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Neoplasia Intraepitelial Cervical/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt , Adulto Jovem , beta Catenina/genética
11.
Toxicol Lett ; 314: 142-152, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319114

RESUMO

Cadmium (Cd), an established carcinogen, is a risk factor for oral squamous cell carcinoma (OSCC). Macroautophagy/autophagy is proposed to play a pivotal role in Cd-mediated carcinogenic activity. However, the mechanisms underlying Cd-induced autophagy are poorly understood. In the present study, a CAL27 OSCC cell line exposed to 10-6 M Cd for 8 weeks was used as a model system. Repeated Cd exposure induced significant migration and invasion of CAL27 cells. Furthermore, we showed that Cd increased the autophagic flux in CAL27 cells, as evidenced by the upregulation of LC3-II and the downregulation of P62/SQSTM1. The genetic blocking of autophagy inhibited Cd-induced migration and invasion, indicating a carcinogenic role of autophagy in Cd-treated CAL27 cells. Cd-induced NUPR1 expression, which contributes to lysosomal biogenesis and expression of autophagy-related gene, was found to mechanistically initiate autophagy in CAL27 cells. Of note, NUPR1 shRNA abolished Cd-induced autophagy both in vitro and in vivo. We also found that Cd triggered the generation of MDA in a xenograft tumour model and that N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, abrogated the effects of Cd on NUPR1-dependent autophagy in vivo. Taken together, these results demonstrate that ROS-dependent NUPR1-mediated autophagy plays an important role in repeated Cd exposure -induced cell growth, migration and invasion in OSCC cells.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cloreto de Cádmio/toxicidade , Movimento Celular/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Gene ; 715: 144012, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357021

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play an important role in tumor biogenesis and prognosis. The glioma is a grade classified cancer, however, we still lack the knowledge on their function during glioma progression. While previous studies have shown how lncRNAs regulate protein-coding gene epigenetically, it is still unclear how lncRNAs are regulated epigenetically. In this study, we firstly analyzed the RNA-seq data systematically across grades II, IV, and IV of glioma samples. We identified 60 lncRNAs that are significantly differentially expressed over disease progression (DElncRNA), including well-known PVT1, HOTAIR, H19 and rarely studied CARD8-AS, MIR4435-2HG. Secondly, by integrating HM450K methylation microarray data, we demonstrated that some of the lncRNAs are epigenetically regulated by methylation. Thirdly, we developed a DESeq2-GSEA-ceRNA-survival analysis strategy to investigate their functions. Particularly, MIR4435-2HG is highly expressed in high-grade glioma and may have an impact on EMT and TNFα signaling pathway by functioning as a miRNA sponge of miR-125a-5p and miR-125b-5p to increase the expression of CD44. Our results revealed the dynamic expression of lncRNAs in glioma progression and their epigenetic regulation mechanism.


Assuntos
Metilação de DNA , DNA de Neoplasias , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioma , MicroRNAs , RNA Longo não Codificante , RNA Neoplásico , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
13.
Gene ; 715: 144017, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357026

RESUMO

SRY-related high-mobility-group box 9 (SOX9) is a member of the SOX family of transcription factors. Accumulating evidence has shown that SOX9 plays a significant role in various malignancies. However, the role of SOX9 in nasopharyngeal carcinoma (NPC) remains unknown. In the present study, up-regulation of SOX9 was observed in both NPC tissues and different NPC cells. Overexpression of SOX9 promoted NPC cell proliferation, migration and invasion. Conversely, knock down of SOX9 inhibited NPC proliferation, colony formation, migration and invasion. Mechanistically, SOX9 bound directly to the promoter region of BMP2 and increased BMP2 expression. In addition, overexpression of SOX9 activated the mTOR pathway partly through BMP2. Collectively, these results identify a novel role for SOX9 as a potential therapeutic marker for the prevention and treatment of NPC.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Movimento Celular , Proliferação de Células , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição SOX9/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína Morfogenética Óssea 2/genética , Linhagem Celular Tumoral , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Fatores de Transcrição SOX9/genética , Serina-Treonina Quinases TOR/genética
14.
Cytogenet Genome Res ; 158(1): 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31261155

RESUMO

Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1ß stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1ß promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1ß, inhibits IL-1ß-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Butadienos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia
15.
Gene ; 714: 143992, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31330234

RESUMO

Increasing studies have demonstrated the important roles of circular RNAs (circRNAs) in human malignancies. Nevertheless, the molecular mechanisms and functions of circRNAs in hepatocellular carcinoma (HCC) are still not fully understood. In the present study, we evaluated circ_0021093 expression in 82 pairs of HCC tissues and 5 cell lines by qRT-PCR. The clinical implications of circ_0021093 were evaluated. In addition, the viability, apoptosis, migration and invasion capacities of different HCC cells were evaluated by gain-/loss-of-function experiments. Target prediction and dual-luciferase reporter experiments were performed to identify the molecular mechanisms of circ_0021093. Upregulation of circ_0021093 was found in HCC tumor samples and cells. Additionally, upregulated circ_0021093 was related to adverse clinical characteristics and an unfavorable prognosis. Furthermore, downregulated circ_0021093 attenuated cell growth, migration and invasion but increased cell apoptosis. By contrast, ectopically expressed circ_0021093 enhanced the abovementioned malignant biological behaviors. For mechanism exploration, circ_0021093 sponges of miR-766-3p were used in HCC cells. In addition, we found that metastasis-associated protein 3 (MTA3) was a direct target of miR-766-3p and that the oncogenic function of circ_0021093 was partly dependent on the miR-766-3p/MTA3 axis according to rescue assays. In conclusion, the circ_0021093/miR-766-3p/MTA3 regulatory axis may be an effective therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA/genética , Apoptose/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Regulação para Cima/genética
16.
Nat Commun ; 10(1): 2370, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147549

RESUMO

FAM134B/RETREG1 is a selective ER-phagy receptor that regulates the size and shape of the endoplasmic reticulum. The structure of its reticulon-homology domain (RHD), an element shared with other ER-shaping proteins, and the mechanism of membrane shaping remain poorly understood. Using molecular modeling and molecular dynamics (MD) simulations, we assemble a structural model for the RHD of FAM134B. Through MD simulations of FAM134B in flat and curved membranes, we relate the dynamic RHD structure with its two wedge-shaped transmembrane helical hairpins and two amphipathic helices to FAM134B functions in membrane-curvature induction and curvature-mediated protein sorting. FAM134B clustering, as expected to occur in autophagic puncta, amplifies the membrane-shaping effects. Electron microscopy of in vitro liposome remodeling experiments support the membrane remodeling functions of the different RHD structural elements. Disruption of the RHD structure affects selective autophagy flux and leads to disease states.


Assuntos
Retículo Endoplasmático/metabolismo , Proteínas de Neoplasias/genética , Forma das Organelas/genética , Autofagia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Retículo Endoplasmático/ultraestrutura , Humanos , Lipossomos/metabolismo , Lipossomos/ultraestrutura , Proteínas de Membrana/genética , Microscopia Eletrônica , Modelos Moleculares , Simulação de Dinâmica Molecular , Domínios Proteicos , Transporte Proteico/genética
17.
Ann Hematol ; 98(10): 2379-2388, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31227872

RESUMO

A high impact of ARID5B SNPs on acute lymphoblastic leukemia (ALL) susceptibility has been described in Hispanic children; therefore, it is relevant to know if they influence the high incidence of childhood-ALL in Mexicans. Seven SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, rs4948488) of ARID5B were analyzed in 384 controls and 298 ALL children using genomic DNA and TaqMan probes. The SNPs were analyzed for deviation of Hardy-Weinberg equilibrium; Fisher's exact test was used to compare the genotypic and allelic frequencies between controls and patients. The association between SNPs and ALL susceptibility was calculated, and haplotype and ancestry analyses were conducted. All SNPs were associated with ALL, pre-B ALL, and hyperdiploid-ALL susceptibility (p < 0.05). No association with T-ALL and gene fusions was found (p > 0.05). The seven SNPs were associated with risk of pre-B ALL in younger children; however, rs2393732, rs2393782, rs2893881, and rs4948488 were not associated with susceptibility in older children and adolescents. The CAG haplotype (rs10821936, rs10994982, rs7089424) was strongly associated with ALL risk in our population (p < 0.00001). The frequency of all risk alleles in our ALL, pre-B, and hyperdiploid-ALL patients was higher than that in Hispanic children reported. This is the first report showing the association between rs2393732, rs2393782, and rs4948488 with pre-B hyperdiploid-ALL children. The G allele at rs2893881 confers major risk for pre-B hyperdiploid-ALL in Mexican (OR, 2.29) than in Hispanic children (OR, 1.71). The genetic background of our population could influence the susceptibility to ALL and explain its high incidence in Mexico.


Assuntos
Alelos , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Haplótipos , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Fatores de Transcrição/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Lactente , Masculino , México , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Fatores de Transcrição/metabolismo
19.
Cell Mol Biol Lett ; 24: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182966

RESUMO

Background: Exploration of the genes with abnormal expression during the development of breast cancer is essential to provide a deeper understanding of the mechanisms involved. Transcriptome sequencing and bioinformatics analysis of invasive ductal carcinoma and paracancerous tissues from the same patient were performed to identify the key genes and signaling pathways related to breast cancer development. Methods: Samples of breast tumor tissue and paracancerous breast tissue were obtained from 6 patients. Sequencing used the Illumina HiSeq platform. All. Only perfectly matched clean reads were mapped to the reference genome database, further analyzed and annotated based on the reference genome information. Differentially expressed genes (DEGs) were identified using the DESeq R package (1.10.1) and DEGSeq R package (1.12.0). Using KOBAS software to execute the KEGG bioinformatics analyses, enriched signaling pathways of DEGs involved in the occurrence of breast cancer were determined. Subsequently, quantitative real time PCR was used to verify the accuracy of the expression profile of key DEGs from the RNA-seq result and to explore the expression patterns of novel cancer-related genes on 8 different clinical individuals. Results: The transcriptomic sequencing results showed 937 DEGs, including 487 upregulated and 450 downregulated genes in the breast cancer specimens. Further quantitative gene expression analysis was performed and captured 252 DEGs (201 downregulated and 51 upregulated) that showed the same differential expression pattern in all libraries. Finally, 6 upregulated DEGs (CST2, DRP2, CLEC5A, SCD, KIAA1211, DTL) and 6 downregulated DEGs (STAC2, BTNL9, CA4, CD300LG, GPIHBP1 and PIGR), were confirmed in a quantitative real time PCR comparison of breast cancer and paracancerous breast tissues from 8 clinical specimens. KEGG analysis revealed various pathway changes, including 20 upregulated and 21 downregulated gene enrichment pathways. The extracellular matrix-receptor (ECM-receptor) interaction pathway was the most enriched pathway: all genes in this pathway were DEGs, including the THBS family, collagen and fibronectin. These DEGs and the ECM-receptor interaction pathway may perform important roles in breast cancer. Conclusion: Several potential breast cancer-related genes and pathways were captured, including 7 novel upregulated genes and 76 novel downregulated genes that were not found in other studies. These genes are related to cell proliferation, movement and adhesion. They may be important for research into breast cancer mechanisms, particularly CST2 and CA4. A key signaling pathway, the ECM-receptor interaction signal pathway, was also identified as possibly involved in the development of breast cancer.


Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/genética , Regulação para Baixo/genética , Feminino , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Transcriptoma/genética , Regulação para Cima/genética
20.
Dokl Biochem Biophys ; 485(1): 104-106, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201625

RESUMO

Reduced expression of metastatic marker protein S100A4 in triple-negative breast cancer cells MDA-MB-231 leads to a decrease in the migration ability of cells and increases the sensitivity of the modified cells to docetaxel therapy. Cells capable of migration differ from the immotile cells in the content of the S100A4 protein in the cell, and this difference persists after the treatment of cells with the agents that reduce the intracellular level of S100A4. The presence of exogenous S100A4 protein in culture medium reduces the content of this protein in breast cancer cells. The results of the study show that the ability of breast cancer cells to migrate depends on the S100A4 protein concentration in the cell.


Assuntos
Movimento Celular , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Proteína A4 de Ligação a Cálcio da Família S100/biossíntese , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas de Neoplasias/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
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