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1.
Medicine (Baltimore) ; 98(50): e18194, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852075

RESUMO

OBJECTIVE: To date, there are several published studies on the value of IDH-1 (isocitrate dehydrogenase-1) mutation and MGMT (O6-Methylguanine-DNA methyltransferas) promoter methylated status on the diagnosis of pseudoprogression (PSP) and true tumor progression after or within chemo-radiotherapy of high grade glioma (HGG). We performed a meta-analysis about the significant value of these 2 molecular markers on the diagnosis of PsP in high- grade glioma. METHODS: We searched the eligible studies from PubMed, Medline, Embase, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wan Fang Database. The relevant studies published before October 2018 were identified. ORs (odds ratios) with 95%CIs (confidence intervals) were used to evaluate the value using fixed- or random-effect model. RESULTS: Thirteen studies about MGMT promoter methylated status and 4 studies about IDH-1 mutations were found eligible for this present meta-analysis. Significant value of MGMT promoter methylation status (OR = 4.02, 95%CI = 2.76-5.87, P < .001) and IDH-1 mutations (OR = 12.78, 95%CI = 3.86-42.35, P < .001) were observed. CONCLUSIONS: This meta-analysis provided evidences that MGMT promoter methylation status and IDH-1 mutations could distinguish PSP from true tumor progression.


Assuntos
Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Estadiamento de Neoplasias , Proteínas Supressoras de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/metabolismo , Progressão da Doença , Glioma/diagnóstico , Glioma/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/metabolismo
3.
Ann Hematol ; 98(12): 2703-2709, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748924

RESUMO

Philadelphia negative (Ph-neg) myeloproliferative neoplasms (MPN) are a heterogenous group of clonal stem cell disorders. Approved treatment options include hydroxyurea, anagrelide, and ruxolitinib, which are not curative. The concept of synthetic lethality may become an additional therapeutic strategy in these diseases. In our study, we show that DNA repair is altered in classical Ph-neg MPN, as analyzed by gene expression analysis of 11 genes involved in the homologous recombination repair pathway (HRR), the non-homologous end-joining pathway (NHEJ), and the single-strand break repair pathway (SSB). Altogether, peripheral blood-derived cells from 57 patients with classical Ph-neg MPN and 13 healthy controls were analyzed. LIG3 as an essential part of the SSB was significantly lower expressed compared to controls in all three entities (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)). In addition, while genes of other DNA-repair pathways showed-possibly compensatory-increased expression in ET (HRR, NHEJ) and PV (NHEJ), MF samples displayed downregulation of all genes involved in NHEJ. With regard to the JAK2 mutational status (analyzed in ET and MF only), no upregulation of the HRR was detected. Though further studies are needed, based on these findings, we conclude that synthetic lethality may become a promising strategy in treating patients with Ph-neg MPN.


Assuntos
Reparo do DNA , DNA de Neoplasias , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Proteínas de Neoplasias , Transcrição Genética , Adulto , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Cromossomo Filadélfia
4.
Molecules ; 24(16)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31404982

RESUMO

Epigenetic modifications are important mechanisms responsible for cancer progression. Accumulating data suggest that (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, may hamper carcinogenesis by targeting epigenetic alterations. We found that signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 2 (SCUBE2), a tumor suppressor gene, was hypermethylated in breast tumors. However, it is unknown whether EGCG regulates SCUBE2 methylation, and the mechanisms remain undefined. This study was designed to investigate the effect of EGCG on SCUBE2 methylation in breast cancer cells. We reveal that EGCG possesses a significantly inhibitory effect on cell viability in a dose- and time-dependent manner and presents more effects than other catechins. EGCG treatment resulted in enhancement of the SCUBE2 gene, along with elevated E-cadherin and decreased vimentin expression, leading to significant suppression of cell migration and invasion. The inhibitory effect of EGCG on SCUBE2 knock-down cells was remarkably alleviated. Further study demonstrated that EGCG significantly decreased the SCUBE2 methylation status by reducing DNA methyltransferase (DNMT) expression and activity. In summary, this study reported for the first time that SCUBE2 methylation can be reversed by EGCG treatment, finally resulting in the inhibition of breast cancer progression. These results suggest the epigenetic role of EGCG and its potential implication in breast cancer therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Neoplasias da Mama/tratamento farmacológico , Proteínas de Ligação ao Cálcio/biossíntese , Catequina/análogos & derivados , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Catequina/farmacologia , Feminino , Humanos , Células MCF-7
5.
BMC Res Notes ; 12(1): 476, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370865

RESUMO

OBJECTIVE: A previous study undertaken at our centre to identify common genetic variants associated with sporadic breast cancer in Sri Lankan women showed that the T allele of rs3218550, located in the 3'untranslated region of X-ray repair cross-complementing gene-2 (XRCC2), increased breast cancer risk by 1.5-fold. Dual luciferase reporter assays performed in MCF-7 breast cancer cells showed a putative transcriptional repressor effect exerted mainly by the T allele. Electrophoretic mobility shift assays were conducted to further investigate the interaction of this variant with DNA-binding protein, using nuclear protein extracts derived from MCF-7 cells. RESULTS: An allele-specific differential binding was observed. The T allele resulted in differential DNA-protein complex binding as evidenced by the presence of multiple bands of increased intensity compared to the wild-type C allele. This implies possible alteration in binding of regulatory proteins by the variant allele. These results implicate XRCC2:rs3218550C>T as a potential low-penetrant susceptibility allele for sporadic breast cancer. XRCC2 is known to play an essential role in homologous recombination repair of DNA double-strand breaks. It is plausible that this variant may be exerting regulatory effects on XRCC2 gene expression leading to altered DNA repair capacity. Further functional studies are warranted to validate this finding.


Assuntos
Neoplasias da Mama/genética , Reparo do DNA , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Alelos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Quebras de DNA de Cadeia Dupla , DNA de Neoplasias/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Expressão Gênica , Frequência do Gene , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Células MCF-7 , Penetrância , Ligação Proteica
6.
Genome Res ; 29(8): 1363-1375, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31340985

RESUMO

The prediction of transcription factor (TF) activities from the gene expression of their targets (i.e., TF regulon) is becoming a widely used approach to characterize the functional status of transcriptional regulatory circuits. Several strategies and data sets have been proposed to link the target genes likely regulated by a TF, each one providing a different level of evidence. The most established ones are (1) manually curated repositories, (2) interactions derived from ChIP-seq binding data, (3) in silico prediction of TF binding on gene promoters, and (4) reverse-engineered regulons from large gene expression data sets. However, it is not known how these different sources of regulons affect the TF activity estimations and, thereby, downstream analysis and interpretation. Here we compared the accuracy and biases of these strategies to define human TF regulons by means of their ability to predict changes in TF activities in three reference benchmark data sets. We assembled a collection of TF-target interactions for 1541 human TFs and evaluated how different molecular and regulatory properties of the TFs, such as the DNA-binding domain, specificities, or mode of interaction with the chromatin, affect the predictions of TF activity. We assessed their coverage and found little overlap on the regulons derived from each strategy and better performance by literature-curated information followed by ChIP-seq data. We provide an integrated resource of all TF-target interactions derived through these strategies, with confidence scores, as a resource for enhanced prediction of TF activities.


Assuntos
Benchmarking , DNA de Neoplasias/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Fatores de Transcrição/genética , Transcrição Genética , Sítios de Ligação , Cromatina/química , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Biologia Computacional/métodos , DNA de Neoplasias/metabolismo , Conjuntos de Dados como Assunto , Redes Reguladoras de Genes , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/classificação , Neoplasias/metabolismo , Neoplasias/patologia , Regiões Promotoras Genéticas , Ligação Proteica , Regulon , Fatores de Transcrição/metabolismo
7.
World Neurosurg ; 130: 405-409, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330336

RESUMO

BACKGROUND: Spinal myxopapillary ependymoma (SP-MPE) is a subgroup of ependymomas in which after initial gross tumor resection, recurrences occur in more than half of the patients. Anaplastic transformation may also occur and contributes to intraneural and extraneural metastatic dissemination. Extraneural metastases from SP-MPE are rare and worsen the prognosis. In this situation, the noninvasive detection of recurrent somatic mutations in the circulating tumor DNA (ctDNA) from plasma is challenging. Telomerase-reverse transcriptase gene promoter (TERTp) mutation has been identified in a subset of ependymomas with aggressive behavior. CASE DESCRIPTION: We report on a patient with TERTp mutated SP-MPE presenting with an extraneural anaplastic metastatic dissemination after iterative local recurrences. From the initial SP-MPE to pleural anaplastic lesion, TERTp C228T mutation was present with allele frequency varying from 33% to 39%. Interestingly, TERTp mutation was also detected by droplet digital polymerase chain reaction in the plasma with a frequency of 2.1% at the time of pleural metastases, highlighting that ctDNA is released in plasma of patients suffering from SP-MPE with extraneural metastatic dissemination. CONCLUSIONS: Despite the rarity of this evolution, plasmatic liquid biopsy appears to be a useful diagnostic and follow-up tool in a subset of primary brain tumors.


Assuntos
Ependimoma/genética , Neoplasias Pulmonares/secundário , Mutação/genética , Neoplasias da Medula Espinal/genética , Telomerase/genética , Adulto , Biomarcadores Tumorais/metabolismo , Ácidos Nucleicos Livres/metabolismo , DNA de Neoplasias/metabolismo , Ependimoma/sangue , Ependimoma/secundário , Feminino , Humanos , Neoplasias Pulmonares/sangue , Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas/genética , Neoplasias da Medula Espinal/sangue
8.
ACS Appl Mater Interfaces ; 11(27): 23870-23879, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31257851

RESUMO

A multiple-functionalized targeting delivery system was prepared by self-assembly for efficient delivery of Cas9/sgRNA plasmids to targeted tumor cell nuclei. The Cas9/sgRNA plasmids were compacted by protamine in the presence of calcium ions to form nanosized cores, which were further decorated by peptide and aptamer conjugated alginate derivatives. With the help of the nuclear location signal peptide and AS1411 aptamer with specific affinity for nucleolin in the tumor cell membrane and nuclei, the delivery vector can specifically deliver the plasmid to the nuclei of tumorous cells for knocking out the protein tyrosine kinase 2 (PTK2) gene to down-regulate focal adhesion kinase (FAK). The tumor cell apoptosis induced by genome editing is mitochondrial-dependent. In addition, FAK knockout results in negative regulation on the PI3K/AKT signaling pathway. Meanwhile, favorable modulation on various proteins involved in tumor progression can be realized by genome editing. The enhanced E-cadherin and decreased MMPs, vimentin, and VEGF imply the desirable effects of genome editing on suppression of tumor development. Wound healing and transwell assays confirm that the genome editing system can suppress tumor invasion and metastasis in edited cells efficiently. The investigation provides a facile and effective strategy to fabricate multiple-functionalized delivery vectors for genome editing.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Técnicas de Transferência de Genes , Neoplasias , Peptídeos , Plasmídeos , Apoptose/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Células HEK293 , Células HeLa , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Peptídeos/química , Peptídeos/farmacologia , Plasmídeos/química , Plasmídeos/genética , Plasmídeos/farmacologia , Transdução de Sinais/genética
9.
Oncol Rep ; 42(3): 953-962, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322278

RESUMO

Breast cancer is the most common type of malignancies in women worldwide, and genotoxic chemotherapeutic drugs are effective by causing DNA damage in cancer cells. However, >90% of patients with metastatic cancer are resistant to chemotherapy. The Forkhead box M1 (FOXM1) transcription factor plays a pivotal role in the resistance of breast cancer cells to chemotherapy by promoting DNA damage repair following genotoxic drug treatment. The aim of the present study was to investigate the inhibition of the FOXM1 protein by thiostrepton, a natural antibiotic produced by the Streptomyces species. Experimental studies were designed to examine the effectiveness of thiostrepton in downregulating FOXM1 mRNA expression and activity, leading to senescence and apoptosis of breast cancer cells. The cytotoxicity of thiostrepton in breast cancer was determined using cell viability assay. Additionally, thiostrepton treatment decreased the mRNA expression of cyclin B1 (CCNB1), a downstream target of FOXM1. The present results indicated that thiostrepton inhibited FOXM1 mRNA expression and its effect on CCNB1. Molecular dynamic simulations were performed to study the interactions between FOXM1­DNA and thiostrepton after molecular docking. The results revealed that the possible mechanism underlying the inhibitory effect of thiostrepton on FOXM1 function was by forming a tight complex with the DNA and FOXM1 via its binding domain. Collectively, these results indicated that thiostrepton is a specific and direct inhibitor of the FOXM1 protein in breast cancer. The findings of the present study may lead to the development of novel therapeutic strategies for breast cancer and help overcome resistance to conventional chemotherapeutic drugs.


Assuntos
Antibacterianos/farmacologia , Neoplasias da Mama/patologia , Ciclina B1/antagonistas & inibidores , Proteína Forkhead Box M1/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tioestreptona/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células , Ciclina B1/genética , Ciclina B1/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Feminino , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Células Tumorais Cultivadas
10.
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
11.
Biomarkers ; 24(6): 524-529, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31220949

RESUMO

Background: Anti-EGFR mAb are recommended treatment for metastatic colorectal cancer (mCRC). Accurate mutation profiling and disease monitoring are challenging. The current study investigates the potential use of transrenal DNA as a biomarker for disease management. Methods: Agreement between archival tissue specimens and transrenal DNA extracted from 200 post-treated mCRC patients was determined. Total DNA concentrations were measured and mutations within the KRAS and EGFR genes were profiled for each specimen. To ascertain therapy resistance; patients were serially monitored monthly. Results: Concordance measurement with matched tissues at baseline was remarkably high (92%) for EGFR and KRAS mutations. Sensitivity and specificity were 98.4% and 89.1% respectively. Newly detectable mutations for a subgroup of patients with initial wildtype characteristics were evident after 4 months of anti-EGFR mAb therapy. Survival analysis using adjusted estimates showed that patients detected by transrenal DNA for key mutations or had higher mutant DNA content had poorer outcome. Conclusion: Transrenal DNA offers new options to follow clinical treatment in mCRC. It demonstrates the ability to capture newly acquired mutations that has strong associative links to therapy resistance. Patients with these mutations fared poorly for survival outcomes and indicated possible prognostic value for transrenal DNA detection.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Biomarcadores Tumorais/imunologia , Cetuximab/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/imunologia , Feminino , Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Mutação , Panitumumabe/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Análise de Sobrevida
12.
PLoS One ; 14(5): e0216374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31059558

RESUMO

Reactivation of interspersed repetitive sequences due to loss of methylation is associated with genomic instability, one of the hallmarks of cancer cells. LINE-1 hypomethylation is a surrogate marker for global methylation loss and is potentially a new diagnostic and prognostic biomarker in tumors. However, the correlation of LINE-1 hypomethylation with clinicopathological parameters and the CpG island methylator phenotype (CIMP) in patients with liver tumors is not yet well defined, particularly in Caucasians who show quite low rates of HCV/HBV infection and a higher incidence of liver steatosis. Therefore, quantitative DNA methylation analysis of LINE-1, RASSF1A, and CCND2 using pyrosequencing was performed in human hepatocellular carcinomas (HCC, n = 40), hepatocellular adenoma (HCA, n = 10), focal nodular hyperplasia (FNH, n = 5), and corresponding peritumoral liver tissues as well as healthy liver tissues (n = 5) from Caucasian patients. Methylation results were correlated with histopathological findings and clinical data. We found loss of LINE-1 DNA methylation only in HCC. It correlated significantly with poor survival (log rank test, p = 0.007). An inverse correlation was found for LINE-1 and RASSF1A DNA methylation levels (r2 = -0.47, p = 0.002). LINE-1 hypomethylation correlated with concurrent RASSF1/CCND2 hypermethylation (Fisher's exact test, p = 0.02). Both LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation were not found in benign hepatocellular tumors (HCA and FNH). Our results show that LINE-1 hypomethylation and RASSF1A/CCND2 hypermethylation are epigenetic aberrations specific for the process of malignant liver transformation. In addition, LINE-1 hypomethylation might serve as a future predictive biomarker to identify HCC patients with unfavorable overall survival.


Assuntos
Carcinoma Hepatocelular , Metilação de DNA , DNA de Neoplasias/metabolismo , Neoplasias Hepáticas , Elementos Nucleotídeos Longos e Dispersos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Ciclina D2/metabolismo , Intervalo Livre de Doença , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Taxa de Sobrevida , Proteínas Supressoras de Tumor/metabolismo
13.
Surg Clin North Am ; 99(3): 403-418, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31047032

RESUMO

Esophageal cancer and gastric cancer are leading causes of cancer-related mortality worldwide. In this article, the authors discuss the molecular biology of esophageal and gastric cancer with a focus on esophageal adenocarcinoma. They review data from The Cancer Genome Atlas project and advances in the molecular stratification and classification of esophageal carcinoma and gastric cancer. They also summarize advances in microRNA, molecular staging, gene expression profiling, tumor microenvironment, and detection of circulating tumor DNA. Finally, the authors summarize some of the implications of understanding the molecular basis of esophageal cancer and future directions in the management of esophageal cancer.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Neoplasias Gástricas/genética , Adenocarcinoma/epidemiologia , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/genética , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Neoplasias Esofágicas/epidemiologia , Previsões , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Metástase Linfática , MicroRNAs , Mutação/genética , Estadiamento de Neoplasias , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Microambiente Tumoral
14.
Mol Cell ; 74(6): 1215-1226.e4, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31053471

RESUMO

Programmed death ligand 1 (PD-L1, also called B7-H1) is an immune checkpoint protein that inhibits immune function through its binding of the programmed cell death protein 1 (PD-1) receptor. Clinically approved antibodies block extracellular PD-1 and PD-L1 binding, yet the role of intracellular PD-L1 in cancer remains poorly understood. Here, we discovered that intracellular PD-L1 acts as an RNA binding protein that regulates the mRNA stability of NBS1, BRCA1, and other DNA damage-related genes. Through competition with the RNA exosome, intracellular PD-L1 protects targeted RNAs from degradation, thereby increasing cellular resistance to DNA damage. RNA immunoprecipitation and RNA-seq experiments demonstrated that PD-L1 regulates RNA stability genome-wide. Furthermore, we developed a PD-L1 antibody, H1A, which abrogates the interaction of PD-L1 with CMTM6, thereby promoting PD-L1 degradation. Intracellular PD-L1 may be a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy in cancer through the inhibition of DNA damage response and repair.


Assuntos
Antígeno B7-H1/genética , Reparo do DNA , DNA de Neoplasias/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Regulação Neoplásica da Expressão Gênica , Receptor de Morte Celular Programada 1/genética , Animais , Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Dano ao DNA , DNA de Neoplasias/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Raios gama/uso terapêutico , Células HCT116 , Células HeLa , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Proteólise/efeitos dos fármacos , Proteólise/efeitos da radiação , Estabilidade de RNA/efeitos dos fármacos , Estabilidade de RNA/efeitos da radiação , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
BMB Rep ; 52(5): 342-347, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31068247

RESUMO

Methylation is a primary epigenetic mechanism regulating gene expression. 5-aza-2'-deoxycytidine is an FDA-approved drug prescribed for treatment of cancer by inhibiting DNA-Methyl-Transferase 1 (DNMT1). Results of this study suggest that prolonged treatment with 5-aza-2'-deoxycytidine could induce centrosome abnormalities in cancer cells and that CEP131, a centrosome protein, is regulated by DNMT1. Interestingly, cancer cell growth was attenuated in vitro and in vivo by inhibiting the expression of Cep131. Finally, Cep131-deficient cells were more sensitive to treatment with DNMT1 inhibitors. These findings suggest that Cep131 is a potential novel anti-cancer target. Agents that can inhibit this protein may be useful alone or in combination with DNMT1 inhibitors to treat cancer. [BMB Reports 2019; 52(5): 342-347].


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Decitabina/farmacologia , Proteínas dos Microtúbulos/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Epigênese Genética , Feminino , Células HEK293 , Células HeLa , Humanos , Proteínas dos Microtúbulos/genética , Proteínas dos Microtúbulos/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
16.
Biomarkers ; 24(6): 574-583, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31002268

RESUMO

Purpose: To develop peripheral blood mRNA expression profiles of drug metabolizing enzymes (DMEs) as a surrogate to monitor tobacco induced head and neck squamous cell carcinoma (HNSCC), attempts were made to investigate (i) similarities in alterations with the cancer marker genes in biopsy samples and (ii) if alterations similar to that seen in biopsy samples are reflected in peripheral blood. Methods: Total RNA from eight soft gingival tissues and eight biopsy samples of HNSCC patients and total DNA and RNA from blood of healthy controls (n = 150) and HNSCC patients (n = 150) was processed for expression and genotyping studies. Blood from patients receiving chemo-radiotherapy was processed for follow-up study. Results: qRT-PCR revealed significant increase in mRNA expression of DMEs in biopsy and blood samples of HNSCC patients when compared to controls. Similar alterations were observed in cancer marker genes in these samples. Patients with variant genotypes of DMEs showed greater magnitude of alterations in mRNA expression when compared to wild type controls. Responders of chemo-radiotherapy showed significant decline in induction of mRNA expression of DMEs and cancer marker genes Conclusions: The data suggest that peripheral blood expression profiles could be used to monitor tobacco-induced HNSCC as well as the treatment response.


Assuntos
Biomarcadores Tumorais/genética , Sistema Enzimático do Citocromo P-450/genética , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Neoplasias/genética , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Biópsia , Estudos de Casos e Controles , Sistema Enzimático do Citocromo P-450/sangue , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Raios gama/uso terapêutico , Expressão Gênica , Perfilação da Expressão Gênica , Gengiva/metabolismo , Gengiva/patologia , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Uso de Tabaco/efeitos adversos
17.
J Cancer Res Clin Oncol ; 145(6): 1437-1448, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30941572

RESUMO

PURPOSE: Despite considerable evidence that supports the NF-kB role in the immune system and lymphomagenesis, it is unclear whether specific NF-kB dimers control a particular set of genes that account for their biological functions. Our previous work showed that Hodgkin Lymphoma (HL) is unique, among germinal center (GC)-derived lymphomas, with respect to its dependency on Rel-B to survive. In contrast, diffuse large B-Cell lymphoma (DLBCL) including both Activated B-Cell-Like and Germinal Center B-Cell-Like, requires cREL and Rel-A to survive and it is not affected by Rel-B depletion. These findings highlighted the activity of specific NF-kB subunits in different GC-derived lymphomas. METHODS: Sequenced chromatin immunoprecipitated DNA fragments (ChIP-Seq) analysis revealed an extensive NF-kB DNA-binding network in DLBCL and HL. The ChIP-Seq data was merged with microarray analysis following the Rel-A, Rel-B or cRel knockdown to determine effectively regulated genes. RESULTS: Downstream target analysis showed enrichment for cell cycle control, among other signatures. Rel-B and cRel controlled different genes within the same signature in HL and DLBCL, respectively. BCL2 was exclusively controlled by Rel-B in HL. Both mRNA and protein levels decreased following Rel-B depletion meanwhile there was no change upon cRel knock-down. BCL2 exogenous expression partially rescued the death induced by decreased Rel-B in HL cells. CONCLUSION: The Rel-B hierarchical network defined HL and the cRel hierarchical network characterized DLBCL. Each Rel member performs specific functions in distinct GC-derived lymphomas. This result should be considered for the development of targeted therapies that are aimed to selectively inhibit individual NF-kB dimers.


Assuntos
DNA de Neoplasias/metabolismo , Doença de Hodgkin/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , NF-kappa B/metabolismo , Apoptose/genética , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Perfilação da Expressão Gênica , Células HEK293 , Doença de Hodgkin/genética , Humanos , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-rel/genética , Proteínas Proto-Oncogênicas c-rel/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/metabolismo , Transcrição Genética
18.
PLoS One ; 14(3): e0214073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883611

RESUMO

Growth differentiation factor 11 (GDF11), is a member of the transforming growth factor-beta (TGF-ß) superfamily and bone morphogenetic protein (BMP) subfamily. In this study, we aimed to assess the expression profile of GDF11, its prognostic value in terms of OS, as well as the potential mechanisms leading to its dysregulation in uveal melanoma. A retrospective study was conducted using our primary data and genetic, clinicopathological and overall survival (OS) data from the Cancer Genome Atlas-Uveal Melanoma (TCGA-UVM). Results showed that GDF11 expression was significantly higher in tumor tissues compared with that in adjacent normal tissues. High GDF11 expression was associated with uveal melanoma in advanced stages (IV), epithelioid cell dominant subtype, as well as extrascleral extension. Univariate analysis showed that older age, epithelioid cell dominant, with extrascleral extension and increased GDF11 expression were associated with unfavorable OS. Multivariate analysis confirmed that GDF11 expression was an independent prognostic indicator of unfavorable OS (HR: 1.704, 95%CI: 1.143-2.540, p = 0.009), after adjustment of age, histological subtypes and extrascleral extension. Among the 80 cases of uveal melanoma, only 3 cases had low-level copy gain (+1) and 2 cases had heterozygous loss (-1). No somatic mutations, including SNPs and small INDELs were observed in GDF11 DNA. The methylation of these four CpG sites had weakly (cg22950598 and cg23689080), moderately (cg09890930), or strongly (cg05511733) negative correlation with GDF11 expression. In addition, the patients with high methylation of these four sites had significantly better OS compared to the group with low methylation. Based on these findings, we infer that methylation modulated GDF11 expression might be a valuable prognostic biomarker regarding OS in uveal melanoma.


Assuntos
Biomarcadores Tumorais , Proteínas Morfogenéticas Ósseas , Metilação de DNA , DNA de Neoplasias , Regulação Neoplásica da Expressão Gênica , Fatores de Diferenciação de Crescimento , Melanoma , Regulação para Cima , Neoplasias Uveais , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Proteínas Morfogenéticas Ósseas/biossíntese , Proteínas Morfogenéticas Ósseas/genética , Ilhas de CpG , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Intervalo Livre de Doença , Feminino , Fatores de Diferenciação de Crescimento/biossíntese , Fatores de Diferenciação de Crescimento/genética , Humanos , Mutação INDEL , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/mortalidade , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Taxa de Sobrevida , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismo , Neoplasias Uveais/mortalidade
19.
J Biol Chem ; 294(14): 5700-5719, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30733337

RESUMO

The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia-mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 + 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 + 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active (i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fator de Transcrição E2F1/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/deficiência , Transcrição Genética , Proteínas Supressoras de Tumor/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Reparo do DNA/efeitos dos fármacos , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição E2F1/genética , Histonas/genética , Histonas/metabolismo , Humanos , Proteína Homóloga a MRE11/genética , Proteína Homóloga a MRE11/metabolismo , Neoplasias/genética , Neoplasias/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Cancer Cell ; 35(2): 297-314.e8, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30753827

RESUMO

Promoter CpG islands are typically unmethylated in normal cells, but in cancer a proportion are subject to hypermethylation. Using methylome sequencing we identified CpG islands that display partial methylation encroachment across the 5' or 3' CpG island borders. CpG island methylation encroachment is widespread in prostate and breast cancer and commonly associates with gene suppression. We show that the pattern of H3K4me1 at CpG island borders in normal cells predicts the different modes of cancer CpG island hypermethylation. Notably, genetic manipulation of Kmt2d results in concordant alterations in H3K4me1 levels and CpG island border DNA methylation encroachment. Our findings suggest a role for H3K4me1 in the demarcation of CpG island methylation borders in normal cells, which become eroded in cancer.


Assuntos
Ilhas de CpG , Metilação de DNA , DNA de Neoplasias/metabolismo , Histonas/metabolismo , Neoplasias/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Humanos , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Regiões Promotoras Genéticas
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