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1.
Adv Sci (Weinh) ; 6(20): 1901432, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31637170

RESUMO

Ionic evolution-induced phase transformation can lead to wide ranges of novel material functionalities with promising applications. Here, using the gating voltage during ionic liquid gating as a tuning knob, the brownmillerite SrCoO2.5 is transformed into a series of protonated H x SrCoO2.5 phases with distinct hydrogen contents. The unexpected electron to charge-neutral doping crossover along with the increase of proton concentration from x = 1 to 2 suggests the formation of exotic charge neutral H-H dimers for higher proton concentration, which is directly visualized at the vacant tetrahedron by scanning transmission electron microscopy and then further supported by first principles calculations. Although the H-H dimers cause no change of the valency of Co2+ ions, they result in clear enhancement of electronic bandgap and suppression of magnetization through lattice expansion. These results not only reveal a hydrogen chemical state beyond anion and cation within the complex oxides, but also suggest an effective pathway to design functional materials through tunable ionic evolution.

2.
Biochem Biophys Res Commun ; 520(3): 651-656, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31629472

RESUMO

Melanocortin 4 receptor (MC4R)-deficient mice had been used for several years to study human nonalcoholic steatohepatitis (NASH). However, although liver pathologic and biochemical indicators have been examined, mice models do not always faithfully display the phenotype of the human disease. In this study, we investigated the MC4R knockout phenotype in miniature pigs. We found that pigs lacking MC4R exhibited hyperorexia, insulin resistance, hyperinsulinemia, disordered lipid metabolism and their livers accumulated significant amounts of fat. We have shown that deletion of MC4R results in hyperphagia and increased body fat, ultimately leading to hepatic steatosis without atherogenic diet.

3.
Gut ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383772

RESUMO

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10- 8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10- 9) and 4q28.1 (OR=1.14, p=3.33×10- 11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.

4.
Cancer Med ; 8(5): 2636-2645, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30843663

RESUMO

To investigate the associations between the functional single nucleotide polymorphisms (SNPs) in the miR-125 family and the survival of non-small cell lung cancer (NSCLC) patients, we systematically selected six functional SNPs located in three pre-miRNAs (miR-125a, miR-125b-1, miR-125b-2). Cox proportional hazard regression analyses were conducted to estimate the crude and adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). Reporter gene luciferase assay was performed to examine the relationship between the SNPs and transcriptive activity of the miRNAs. The expression of miRNAs in different cells was detected using quantitative real-time PCR assay. We found that rs2241490 (upstream of miR-125b-1, G > A, adjusted HR = 1.24, 95%CI = 1.05-1.48, P = 0.014, in dominant model; adjusted HR = 1.18, 95%CI = 1.03-1.35, P = 0.014, in additive model), rs512932 (upstream of miR-125b-1, A > G, dominant model: adjusted HR = 1.25, 95%CI = 1.05-1.48, P = 0.013) and rs8111742 (upstream of miR-125a, G > A, dominant model: adjusted HR = 0.84, 95%CI = 0.71-1.00, P = 0.047) were associated with the prognosis of 1001 Chinese NSCLC patients. The combined analysis of the three SNPs related the number of risk alleles (rs2241490-A, rs512932-G and rs8111742-G) to death risk of NSCLC in a locus-dosage mode (P for trend <0.001). Furthermore, luciferase reporter gene assay showed significantly higher levels of luciferase activity with rs512932 variant G than that with A allele in 293T, SPC-A1 and A549 cell lines. Besides, miR-125b was highly expressed in lung cancer cells than the normal lung cell. Our study indicated that genetic variations in miR-125 family were implicated in the survival of NSCLC patients. Larger population-based and functional studies are needed to verify these findings.

5.
Adv Mater ; 31(16): e1900458, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30811706

RESUMO

Ionic-liquid-gating- (ILG-) induced proton evolution has emerged as a novel strategy to realize electron doping and manipulate the electronic and magnetic ground states in complex oxides. While the study of a wide range of systems (e.g., SrCoO2.5 , VO2 , WO3 , etc.) has demonstrated important opportunities to incorporate protons through ILG, protonation remains a big challenge for many others. Furthermore, the mechanism of proton intercalation from the ionic liquid/solid interface to whole film has not yet been revealed. Here, with a model system of inverse spinel NiCo2 O4 , an increase in system temperature during ILG forms a single but effective method to efficiently achieve protonation. Moreover, the ILG induces a novel phase transformation in NiCo2 O4 from ferrimagnetic metallic into antiferromagnetic insulating with protonation at elevated temperatures. This study shows that environmental temperature is an efficient tuning knob to manipulate ILG-induced ionic evolution.

6.
Biomed Res Int ; 2018: 1252849, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30112356

RESUMO

Background: Interleukin 1 receptor associated kinases (IRAKs) play a central role in TLR signaling pathway. Scarce literature has investigated the association of potential functional genetic variants of IRAKs with Hepatitis B Virus- (HBV-) related hepatocellular carcinoma (HCC). Methods: A case-control study with 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers was conducted to evaluate the effects of common missense variants of IRAK family members on HCC. Proliferation assays and real-time polymerase chain reactions were carried out to evaluate the functions. Multivariable adjusted logistic regression was adopted to estimate effect size and identify risk factors. Results: Association analysis indicated that rs4251545 A allele of IRAK4 (p.Ala428Thr) was positively associated with HBV-related HCC risk (OR = 1.30, 95% CI: 1.09-1.54, P = 0.003). Functional annotation indicated that rs4251545 reduced its own expression in liver (P = 0.031). Further molecular functional analysis detected that rs4251545 increased the proliferation rate of L02 cells (P < 0.05). Meanwhile, rs4251545 reduced mRNA expressions of IL-6, IL-8, CXCL-1, and CXCL-2 in L02 cells (P < 0.01). Conclusion: rs4251545 of IRAK4 (p.Ala428Thr) modified the susceptibility to HBV-related HCC via increased proliferation rate and reduced production of inflammatory cytokines and chemokines. Further well-designed experiments are warranted to validate our findings.


Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Hepatite B Crônica/complicações , Quinases Associadas a Receptores de Interleucina-1/genética , Neoplasias Hepáticas/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Genótipo , Vírus da Hepatite B , Hepatite B Crônica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
7.
Onco Targets Ther ; 11: 2815-2830, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29844680

RESUMO

Introduction: Colorectal cancer (CRC) is the fourth most common cause of cancer-related mortality worldwide. The tumor, node, metastasis (TNM) stage remains the standard for CRC prognostication. Identification of meaningful microRNA (miRNA) and gene modules or representative biomarkers related to the pathological stage of colon cancer helps to predict prognosis and reveal the mechanisms behind cancer progression. Materials and methods: We applied a systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA) to detect the pathological stage-related miRNA and gene modules and construct a miRNA-gene network. The Cancer Genome Atlas (TCGA) colon adenocarcinoma (CAC) RNA-sequencing data and miRNA-sequencing data were subjected to WGCNA analysis, and the GSE29623, GSE35602 and GSE39396 were utilized to validate and characterize the results of WGCNA. Results: Two gene modules (Gmagenta and Ggreen) and one miRNA module were associated with the pathological stage. Six hub genes (COL1A2, THBS2, BGN, COL1A1, TAGLN and DACT3) were related to prognosis and validated to be associated with the pathological stage. Five hub miRNAs were identified to be related to prognosis (hsa-miR-125b-5p, hsa-miR-145-5p, hsa-let-7c-5p, hsa-miR-218-5p and hsa-miR-125b-2-3p). A total of 18 hub genes and seven hub miRNAs were predominantly expressed in tumor stroma. Proteoglycans in cancer, focal adhesion, extracellular matrix (ECM)-receptor interaction and so on were common pathways of the three modules. Hsa-let-7c-5p was located at the core of miRNA-gene network. Conclusion: These findings help to advance the understanding of tumor stroma in the progression of CAC and provide prognostic biomarkers as well as therapeutic targets.

8.
Cancer Lett ; 421: 103-111, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29454095

RESUMO

Genome wide association studies (GWAS) have identified a series of genetic variants associated with the risk of esophageal adenocarcinoma (EAC)/Barrett's esophagus (BE), which was different from those loci for esophageal squamous cell carcinoma (ESCC). It is important to evaluate whether these susceptibility loci for EAC/BE are also implicated in ESCC development. In the current study, we analyzed genetic variants at 3p13, 9q22, 16q24 and 19p13 in a case-control study including 2139 ESCC patients and 2463 cancer-free controls in a Chinese population, and further characterized the biological relevance of genetic variants by functional assays. We found that the G allele of rs11789015 at 9q22, as compared with the A allele, was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.77 (95%CI, 0.65-0.90; P = 1.38 × 10-3), whereas the other three loci were not associated with ESCC risk. We further found that rs11789015-G allele correlated with decreased mRNA and protein levels of BARX1. Dual-luciferase reporter gene assay revealed that the A > G change at rs11789015 significantly decreased the promoter activity of BARX1. Both the mRNA and protein levels of BARX1 were significantly higher in ESCC tumor tissues compared with the corresponding normal tissues. Moreover, the deletion of BARX1 substantially reduced ESCC cells growth, migration and invasion. In conclusion, these results suggest that genetic variants at 9q22 are associated with the risk of both EAC/BE and ESCC, possibly by regulating the function of BARX1.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 9 , Neoplasias Esofágicas/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Adenocarcinoma/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
10.
Oncotarget ; 8(62): 105312-105319, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29285253

RESUMO

Recently promoter of NR3C1 has been found to be high methylated in gastric cancer tissues which might be involved in the initiation of gastric carcinoma development. To test whether the variants in NR3C1 could modify the risk of gastric cancer, we evaluated the association between four SNPs (rs6194, rs12521436, rs33388 and rs4912913) in NR3C1 and gastric cancer risk in a case-control study with 1,113 gastric cancer cases and 1,848 cancer-free controls in a Chinese population. We found a significant association between rs4912913 and gastric cancer risk (OR=1.18, 95%CI=1.05-1.33, P=5.49×10-3). We also observed that the A-allele of rs12521436 and rs33388 were significantly associated with a decreased risk of gastric cancer (OR=0.84, 95%CI=0.76-0.94, P=2.78×10-3; OR=0.85, 95%CI=0.75-0.97; P=0.018). Finally, we made a joint effect analysis of rs12521436, rs33388 and rs4912913 on risk of gastric cancer (PTrend =2.83×10-5). These findings indicate that the variants rs4912913, rs33388 and rs12521436 of NR3C1 may contribute to gastric cancer susceptibility.

11.
Sci Rep ; 7(1): 11499, 2017 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-28904398

RESUMO

Protein phosphatase 2A (PP2A), a tumor suppressor protein, has been implicated in cell cycle and apoptosis. Additionally, studies have illustrated its crucial roles in transformation of normal human cells to tumorigenic status. PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, has been recently reported to be associated with several types of cancers. Therefore, we hypothesized that genetic variants in PPP2CA might influence susceptibility of gastric cancer. To test this hypothesis, three tagging single nucleotide polymorphisms (SNPs) in PPP2CA were genotyped in a case-control study including 1,113 cases and 1,848 controls in a Chinese population. Three tagging SNPs in PPP2CA were genotyped using Illumina Human Exome BeadChip. We observed that the A allele of rs13187105 was associated with an increased risk of gastric cancer (adjusted odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.02-1.28, P = 0.017). Further analyses showed that rs13187105 [A] was associated with decreased expression of PPP2CA mRNA (P = 5.1 × 10-6), and PPP2CA mRNA was significantly lower in gastric tumor tissues when comparing that in their adjacent normal tissues (P = 0.037). These findings support our hypothesis that genetic variants in PPP2CA may be implicated in gastric cancer susceptibility in Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Variação Genética , Proteína Fosfatase 2/genética , Alelos , Estudos de Casos e Controles , China/epidemiologia , Bases de Dados Genéticas , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , Locos de Características Quantitativas
12.
Plant Cell ; 29(9): 2197-2213, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28790150

RESUMO

Phosphorylation of histone H3 affects transcription, chromatin condensation, and chromosome segregation. However, the role of phosphorylation of histone H2A remains unclear. Here, we found that Arabidopsis thaliana MUT9P-LIKE-KINASE (MLK4) phosphorylates histone H2A on serine 95, a plant-specific modification in the histone core domain. Mutations in MLK4 caused late flowering under long-day conditions but no notable phenotype under short days. MLK4 interacts with CIRCADIAN CLOCK ASSOCIATED1 (CCA1), which allows MLK4 to bind to the GIGANTEA (GI) promoter. CCA1 interacts with YAF9a, a co-subunit of the Swi2/Snf2-related ATPase (SWR1) and NuA4 complexes, which are responsible for incorporating the histone variant H2A.Z into chromatin and histone H4 acetylase activity, respectively. Importantly, loss of MLK4 function led to delayed flowering by decreasing phosphorylation of H2A serine 95, along with attenuated accumulation of H2A.Z and the acetylation of H4 at GI, thus reducing GI expression. Together, our results provide insight into how phosphorylation of H2A serine 95 promotes flowering time and suggest that phosphorylation of H2A serine 95 modulated by MLK4 is required for the regulation of flowering time and is involved in deposition of the histone variant H2A.Z and H4 acetylation in Arabidopsis.


Assuntos
Arabidopsis/metabolismo , Flores/fisiologia , Histonas/metabolismo , Fosfosserina/metabolismo , Acetilação , Sequência de Aminoácidos , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Teste de Complementação Genética , Histonas/química , Mutação/genética , Fosforilação , Fotoperíodo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Subunidades Proteicas/metabolismo , Frações Subcelulares/metabolismo , Fatores de Tempo
13.
Mol Carcinog ; 56(12): 2593-2600, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28688194

RESUMO

Mitochondrial DNA (mtDNA) copy number (mtCN) may be a potential biomarker in relation to cancer risk. However, the role of mtCN in gastric cancer remains uncertain. We examined the association between peripheral blood leukocytes mtCN level and gastric cancer risk in a case-control study including 984 gastric cancer cases and 984 controls. We measured relative mtCN level by real-time quantitative PCR-based assay, and used logistic regression models to assess the association between mtCN and risk of gastric cancer. The mtCN level in gastric cancer cases was significantly higher than that in controls (median value: 6.53 vs 4.12, P = 1.79 × 10-5 ). Compared with those with low mtCN, the risk for gastric cancer was 1.29 (95% confidence interval [CI] = 1.02-1.63) in the median group and 1.74 (95%CI = 1.39-2.18) in the high mtCN group (P for trend = 1.51 × 10-6 ). Because relative telomere length (RTL) has been associated with gastric cancer risk in our previous study, we also evaluated the combined effects of mtCN and RTL on gastric cancer risk. Multivariable regression model revealed that the effects of mtCN and RTL were independent on gastric cancer risk. Compared with those in the lowest risk group by combining mtCN and RTL, the odds ratio for gastric cancer was 4.30 (95%CI = 2.79-6.63) in the highest risk group. Our results suggest that mtDNA may be implicated in gastric carcinogenesis and mtCN as well as RTL may serve as joint susceptible biomarkers for gastric cancer.


Assuntos
DNA Mitocondrial/genética , Leucócitos/metabolismo , Neoplasias Gástricas/genética , Telômero/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Dosagem de Genes , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Neoplasias Gástricas/etnologia
14.
Hum Genet ; 136(8): 987-997, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28653172

RESUMO

Recent studies have found that cancer-testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls. We found a significant association between rs3747093 located in the CCDC116 promoter and lung cancer risk (OR = 0.91, P meta = 7.81 × 10-6). Although CCDC116 was expressed at lower levels in somatic tissues compared to the testis, the protective allele A of rs3747093 was associated with decreased CCDC116 expression in many normal tissues, including the lung (P = 8.1 × 10-13). We subsequently genotyped this variant in another four commonly diagnosed cancers (gastric, esophageal, colorectal, and breast cancers), as we found expression quantitative trait locus (eQTL) signals for rs3747093 and CCDC116 in their corresponding normal tissues. Interestingly, we observed consistent associations between rs3747093 and multiple cancers (gastric cancer: OR = 0.85, P = 2.21 × 10-4; esophageal cancer: OR = 0.91, P = 2.57 × 10-2; colorectal cancer: OR = 0.80, P = 1.85 × 10-6; and breast cancer: OR = 0.87, P = 1.55 × 10-3). Taken together, the A allele of rs3747093 showed significant protective effects on cancer risk (OR = 0.88, P pool = 6.52 × 10-13) in an Asian population. Moreover, our findings suggest that low abundance expression of CT genes in normal tissues may also contribute to tumorigenesis, providing a new mechanism of CT genes in the development of cancer.


Assuntos
Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Locos de Características Quantitativas , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Variações do Número de Cópias de DNA , Neoplasias Esofágicas/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Modelos Logísticos , Neoplasias Pulmonares/genética , Masculino , Proteínas/metabolismo , Fatores de Risco , Neoplasias Gástricas/genética , Testículo/patologia
15.
Gastroenterology ; 152(8): 2011-2021, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28246015

RESUMO

BACKGROUND & AIMS: Several genetic variants have been associated with gastric cancer risk, although these account for only a fraction of cases of gastric cancer. We aimed to identify low-frequency and other genetic variants that determine gastric cancer susceptibility. METHODS: We performed exome array analysis of DNA in blood samples from 1113 patients with gastric cancer, collected at hospitals from 2006 to 2010 in China, and 1848 individuals without cancer (controls) undergoing physical examinations. Among 71,290 variants analyzed (including 25,784 common variants), 24 variants were selected and replicated in an analysis of DNA in blood samples from 4687 additional cases of gastric cancer and 5780 controls. We compared expression of candidate genes in tumor vs normal gastric tissues using data from TCGA and performed functional annotation analyses. An immortalized human gastric epithelial cell line (GES1) and 7 human gastric cancer lines were used to express transgenes, knock down gene expression (with small interfering RNAs), disrupt genes (using the CRISPR/Cas9 system), or assess expression of reporter constructs. We measured cell proliferation, colony formation, invasion, and migration, and assessed growth of xenograft tumors in nude mice. RESULTS: A low-frequency missense variant rs112754928 in the SPOC domain containing 1 gene (SPOCD1; encoding p.Arg71Trp), at 1p35.2, was reproducibly associated with reduced risk of gastric cancer (odds ratio, 0.56; P = 3.48 × 10-8). SPOCD1 was overexpressed in gastric tumors, and knockout of SPOCD1 reduced gastric cancer cell proliferation, invasive activity, and migration, as well as growth of xenograft tumors in nude mice. We also associated the variant rs1679709 at 6p22.1 with reduced risk for gastric cancer (odds ratio, 0.80; P = 1.17 × 10-13). The protective allele rs1679709-A correlated with the surrounding haplotype rs2799077-T-rs2799079-C, which reduced the enhancer activity of this site to decrease expression of the butyrophilin subfamily 3 member A2 gene (BTN3A2). BTN3A2 is overexpressed in gastric tumors, and deletion of BTN3A2 inhibited proliferation, migration, and invasion of gastric cancer cells. CONCLUSIONS: We have associated variants at 1p35.2 and 6p22.1 with gastric cancer risk, indicating a role for SPOCD1 and BTN3A2 in gastric carcinogenesis.


Assuntos
Biomarcadores Tumorais/genética , Butirofilinas/genética , Exossomos/genética , Variação Genética , Neoplasias Gástricas/genética , Idoso , Animais , Biomarcadores Tumorais/metabolismo , Butirofilinas/metabolismo , Sistemas CRISPR-Cas , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Razão de Chances , Fenótipo , Interferência de RNA , Fatores de Risco , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fatores de Tempo , Transfecção , Carga Tumoral
16.
Plant Cell ; 29(2): 277-291, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28188267

RESUMO

The elongation factor suppressor of Ty 5 homolog (Spt5) is a regulator of transcription and histone methylation. In humans, phosphorylation of SPT5 by P-TEFb, a protein kinase composed of Cyclin-dependent kinase 9 (CDK9) and cyclin T, interacts with the RNA polymerase II-associated factor1 (PAF1) complex. However, the mechanism of SPT5 phosphorylation is not well understood in plants. Here, we examine the function of SPT5 in Arabidopsis thaliana and find that spt5 mutant flowers early under long-day and short-day conditions. SPT5 interacts with the CDK-activating kinase 4 (CAK4; CDKD;2) and is specifically phosphorylated by CDKD;2 at threonines. The phosphorylated SPT5 binds VERNALIZATION INDEPENDENCE5 (VIP5), a subunit of the PAF1 complex. Genetic analysis showed that VIP5 acts downstream of SPT5 and CDKD;2 Loss of SPT5 or CDKD;2 function results in early flowering because of decreased amounts of FLOWERING LOCUS C (FLC) transcript. Importantly, CDKD;2 and SPT5 are required for the deposition of VIP5 and the enhancement of trimethylation of histone 3 lysine 4 in the chromatin of the FLC locus. Together, our results provide insight into the mechanism by which the Arabidopsis elongation factor SPT5 recruits the PAF1 complex via the posttranslational modification of proteins and suggest that the phosphorylation of SPT5 by CDKD;2 enables it to recruit VIP5 to regulate chromatin and transcription in Arabidopsis.


Assuntos
Proteínas de Arabidopsis/fisiologia , Arabidopsis/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Proteínas Imediatamente Precoces/fisiologia , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismo , Quinases Ciclina-Dependentes/fisiologia , Flores/genética , Flores/crescimento & desenvolvimento , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas Imediatamente Precoces/química , Proteínas Imediatamente Precoces/metabolismo , Fosforilação , Fatores de Elongação da Transcrição
17.
Mol Carcinog ; 56(3): 1021-1029, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27597395

RESUMO

Telomeres are essential for maintaining chromosomal stability and are crucial in tumor progression. Previous studies have explored the associations between telomere length and cancer prognosis, but the findings are inconclusive. Genome-wide association studies have identified several genetic variants associated with telomere length in Caucasians. However, the roles of telomere length and related genetic variants on esophageal squamous cell carcinoma (ESCC) prognosis are largely unknown. Therefore, we conducted a case-cohort study with 431 ESCC patients to assess the associations between relative telomere length (RTL), eight known telomere length related variants and the overall survival of ESCC in Chinese population. We found that as compared with the reference group, patients in the fifth (the longest) quintile had a significantly better prognosis [(adjusted hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98, P = 0.041]. Furthermore, A allele of rs2736108 was significantly associated with both the increased RTL (P = 0.048) and the better prognosis of ESCC (adjusted HR = 0.55, 95%CI = 0.38-0.79, P = 1.31 × 10-3 ). Mediation analysis indicated that the effect of rs2736108 on ESCC prognosis was partly explained by RTL (1.99%). Stepwise Cox proportional hazard analysis suggested that rs2736108 played an important protective role in ESCC prognosis (HR = 0.57, 95%CI = 0.40-0.81, P = 1.97 × 10-3 ). Our findings provide evidence that prolonged telomere length is a protective factor for ESCC patients' survival and the known telomere length related genetic variant rs2736108 can contribute to the prognosis of ESCC as well in Chinese population. © 2016 Wiley Periodicals, Inc.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Polimorfismo de Nucleotídeo Único , Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , China , Estudos de Coortes , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Homeostase do Telômero
18.
Cancer Sci ; 108(2): 250-255, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27960044

RESUMO

Genome-wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome-wide association studies with a case-control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.84 (95% confidence interval, 0.77-0.91; P = 2.95 × 10-5 ). The rs7023329-G allele was related to a high expression of MTAP (P = 0.020). The rs1679013-C allele was independently associated with an increased risk of ESCC with a per-allele odds ratio of 1.12 (95% confidence interval, 1.01-1.24; P = 0.039). We also found that the carriers of the risk allele rs1679013-C had lower expression of CDKN2B than non-carriers (P = 0.035). CDKN2B was also significantly downregulated in ESCC tumor tissues compared with adjacent normal tissues (P = 3.50×10-5 ). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of the 9p21.3 locus in cancer development.


Assuntos
Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 9 , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Neoplasias Esofágicas/genética , Variação Genética , Proteínas Associadas aos Microtúbulos/genética , Alelos , Grupo com Ancestrais do Continente Asiático , Carcinoma de Células Escamosas/metabolismo , Estudos de Casos e Controles , China , Intervalos de Confiança , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p18/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago , Estudo de Associação Genômica Ampla , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Razão de Chances , RNA Mensageiro/metabolismo , Fatores de Risco
19.
Sci Rep ; 6: 38729, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27929092

RESUMO

Telomere length varies considerably among individuals. It is highly heritable and decreases with ageing or ageing related diseases. Recently, genome-wide association studies (GWAS) have identified several genetic loci associated with telomere length in adults. However, it is unclear whether these loci represent the genetic basis of telomere length or determine the individual susceptibility to shortening during growth process. Using DNA extracted from peripheral and cord blood of 444 mother-newborn pairs from a Chinese population, we measured relative telomere length (RTL) and genotyped eight known telomere length related variants that were initially identified in populations of European descent. We observed the T allele of rs10936599 and the T allele of rs2736100 were norminally associated with shorter RTL (P = 0.041 and 0.046, respectively) in maternal samples. Furthermore, the Weighted genetic score (WGS) of eight variants was significantly associated with RTL in maternal samples (R2 = 0.012, P = 0.025). However, we didn't detect any significant associations for any individual variant or the combined WGS with RTL in newborns. These findings didn't support the hypothesis that telomere length related loci may affect telomere length at birth, and we suggested that these loci may play a role in telomere length modification during life course.


Assuntos
Telômero , Adulto , Alelos , China , DNA/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Gravidez , Adulto Jovem
20.
Biointerphases ; 11(2): 019009, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26964531

RESUMO

Layer-by-layer (LbL) assembled multicomponent films offer the opportunity to control and to fine-tune cell attachment and behavior on solid surfaces [Layer-by-Layer Films for Biomedical Applications, edited by Picart et al. (Wiley, Weinheim, 2014) and El-Khouri et al., "Multifunctional layer-by-layer architectures for biological applications," in Functional Polymeric Ultrathin Films, edited by Advincula and Knoll (Wiley, Weinheim, 2011), Vol. 1]. At the same time, these films allow for quite detailed physicochemical characterization of static and dynamic surface properties that are typically not available in classic cell culture. In this report, the authors investigate cell adhesion and cytocompatibility of compositionally and morphologically similar thin films composed of oppositely charged synthetic or natural polyelectrolytes in which different physical parameters such as surface charge or water content are varied through chemical composition and deposition conditions. Human adult dermal fibroblasts were chosen as a model because of the need for chemically defined matrix in the field of primary cell amplification. The growth and the stability of the multilayer films in the incubation media were studied dissipation-enhanced quartz crystal micobalance (QCM-D) and ellipsometry. The QCM-D signals observed during the film deposition were analyzed qualitatively to estimate the viscoelastic properties of the films. The authors used contact angle measurements with water to study the contribution of the chemical functionalities to wetting behavior of the films. Most importantly, they also studied the interaction of the films with serum components. Our results underline that cell adhesion is a highly complex process which is not only governed by the functionality of a surface but also by its morphology, its affinity for serum components, and also by changes of surface properties brought about by adsorbing molecules. Of the many LbL-films tested, poly(4-styrenesulfonate)/poly(allyl amine) multilayers were best suited for our fibroblast cultures, which opens a way to avoid gelatin based and similar substrates whose exact chemical composition is unknown.


Assuntos
Materiais Biocompatíveis/química , Adesão Celular , Fenômenos Químicos , Fibroblastos/fisiologia , Propriedades de Superfície , Células Cultivadas , Humanos , Soro/metabolismo
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