Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.690
Filtrar
1.
Int J Nanomedicine ; 15: 10171-10181, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363373

RESUMO

Background: In recent years, nanomaterials have justified their dissemination for biosensor application towards the sensitive and selective detections of clinical biomarkers at the lower levels. MXene is a two-dimensional layered transition metal, attractive for biosensing due to its chemical, physical and electrical properties along with the biocompatibility. Materials and Methods: This work was focused on diagnosing osteosarcoma (OS), a common bone cancer, on MXene-modified multiple junction triangles by dielectrode sensing. Survivin protein gene is highly correlated with OS, identified on this sensing surface. Capture DNA was immobilized on MXene by using 3-glycidoxypropyltrimethoxysilane as an amine linker and duplexed by the target DNA sequence. Results: The limitation and sensitivity of detection were found as 1 fM with the acceptable regression co-efficient value (y=1.0037⨰ + 0.525; R2=0.978) and the current enhancement was noted when increasing the target DNA concentrations. Moreover, the control sequences of single- and triple-mismatched and noncomplementary to the target DNA sequences failed to hybridize on the capture DNA, confirming the specificity. In addition, different batches were prepared with capture probe immobilized sensing surfaces and proved the efficient reproducibility. Conclusion: This microgap device with Mxene-modified multiple junction triangles dielectrode surface is beneficial to quantify the survivin gene at its lower level and diagnosing OS complication levels.


Assuntos
Biomarcadores Tumorais/metabolismo , Técnicas Biossensoriais/métodos , Neoplasias Ósseas/diagnóstico , Osteossarcoma/diagnóstico , Elementos de Transição/química , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , DNA de Neoplasias/metabolismo , Eletrodos , Humanos , Microeletrodos , Nanoestruturas/química , Osteossarcoma/patologia , Espectroscopia Fotoeletrônica , Reprodutibilidade dos Testes , Survivina/metabolismo
2.
Nucleic Acids Res ; 48(21): 12380-12393, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33170272

RESUMO

Naphthalene diimides showed significant anticancer activity in animal models, with therapeutic potential related to their ability to strongly interact with G-quadruplexes. Recently, a trifunctionalized naphthalene diimide, named NDI-5, was identified as the best analogue of a mini-library of novel naphthalene diimides for its high G-quadruplex binding affinity along with marked, selective anticancer activity, emerging as promising candidate drug for in vivo studies. Here we used NMR, dynamic light scattering, circular dichroism and fluorescence analyses to investigate the interactions of NDI-5 with G-quadruplexes featuring either parallel or hybrid topology. Interplay of different binding modes of NDI-5 to G-quadruplexes was observed for both parallel and hybrid topologies, with end-stacking always operative as the predominant binding event. While NDI-5 primarily targets the 5'-end quartet of the hybrid G-quadruplex model (m-tel24), the binding to a parallel G-quadruplex model (M2) occurs seemingly simultaneously at the 5'- and 3'-end quartets. With parallel G-quadruplex M2, NDI-5 formed stable complexes with 1:3 DNA:ligand binding stoichiometry. Conversely, when interacting with hybrid G-quadruplex m-tel24, NDI-5 showed multiple binding poses on a single G-quadruplex unit and/or formed different complexes comprising two or more G-quadruplex units. NDI-5 produced stabilizing effects on both G-quadruplexes, forming complexes with dissociation constants in the nM range.


Assuntos
Antineoplásicos/metabolismo , DNA de Neoplasias/metabolismo , Quadruplex G , Guanina/metabolismo , Imidas/metabolismo , Naftalenos/metabolismo , Antineoplásicos/síntese química , Sequência de Bases , Sítios de Ligação , DNA de Neoplasias/química , Guanina/química , Humanos , Imidas/síntese química , Ligantes , Naftalenos/síntese química , Soluções , Termodinâmica
3.
Nucleic Acids Res ; 48(21): 12234-12251, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33211885

RESUMO

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.


Assuntos
Neoplasias do Colo/tratamento farmacológico , DNA Glicosilases/genética , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Poli(ADP-Ribose) Polimerase-1/imunologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Dano ao DNA , DNA Glicosilases/antagonistas & inibidores , DNA Glicosilases/metabolismo , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Guanina/análogos & derivados , Guanina/metabolismo , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Estresse Oxidativo , Poli(ADP-Ribose) Polimerase-1/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
BMC Med Genet ; 21(1): 228, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213418

RESUMO

BACKGROUND: Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL). METHODS: Among 412 bladder cancer cases and 424 controls from the Women's Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking. RESULTS: While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766. CONCLUSIONS: Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.


Assuntos
Antígenos Ly/genética , Carcinogênese/genética , Carcinoma de Células de Transição/genética , DNA de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Receptores Nicotínicos/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Ly/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/patologia , Estudos de Casos e Controles , Fumar Cigarros/fisiopatologia , Ilhas de CpG , Metilação de DNA , DNA de Neoplasias/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Locos de Características Quantitativas , Receptores Nicotínicos/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
5.
Mol Cell ; 80(5): 915-928.e5, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33186547

RESUMO

Transposable elements (TEs) drive genome evolution and are a notable source of pathogenesis, including cancer. While CpG methylation regulates TE activity, the locus-specific methylation landscape of mobile human TEs has to date proven largely inaccessible. Here, we apply new computational tools and long-read nanopore sequencing to directly infer CpG methylation of novel and extant TE insertions in hippocampus, heart, and liver, as well as paired tumor and non-tumor liver. As opposed to an indiscriminate stochastic process, we find pronounced demethylation of young long interspersed element 1 (LINE-1) retrotransposons in cancer, often distinct to the adjacent genome and other TEs. SINE-VNTR-Alu (SVA) retrotransposons, including their internal tandem repeat-associated CpG island, are near-universally methylated. We encounter allele-specific TE methylation and demethylation of aberrantly expressed young LINE-1s in normal tissues. Finally, we recover the complete sequences of tumor-specific LINE-1 insertions and their retrotransposition hallmarks, demonstrating how long-read sequencing can simultaneously survey the epigenome and detect somatic TE mobilization.


Assuntos
Metilação de DNA , Elementos de DNA Transponíveis , DNA de Neoplasias , Epigênese Genética , Epigenoma , Regulação Neoplásica da Expressão Gênica , Elementos Nucleotídeos Longos e Dispersos , Sequenciamento por Nanoporos , Neoplasias , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/metabolismo , Especificidade de Órgãos
6.
Nat Commun ; 11(1): 5079, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033234

RESUMO

Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.


Assuntos
Carcinoma Basocelular/metabolismo , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos , Matriz Extracelular/metabolismo , Ontologia Genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Folículo Piloso/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Proteína Smad3/metabolismo , Transativadores/metabolismo , Regulação para Cima
7.
Exp Hematol ; 90: 1-11, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32961299

RESUMO

Whilst DNA cytosine methylation is the oldest and most well-studied epigenetic modification, basking in its glory days, it may be soon overshadowed by the new kid on the block: RNA adenosine methylation. This juxtaposition is indeed superficial, and a deep exploration toward the fundamental requirements for these essential epigenetic marks provides a clear perspective on their converging and synergistic roles. The recent discovery that both of these modifications are essential for preventing inappropriate activation of the intracellular innate immune responses to endogenous transcripts has provided a lot of interest in targeting them therapeutically as a means to improve cancer immunogenicity. Here we discuss the potential physiological function for DNA and RNA methylation in normal hematopoiesis and how these pervasive epigenetic marks are exploited in cancer, and provide suggestions for future research with a focus on leveraging this knowledge to uncover novel therapeutic targets.


Assuntos
Metilação de DNA , DNA de Neoplasias/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Hematopoese , Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Humanos , Neoplasias/patologia
8.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188392, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32735964

RESUMO

Although the eukaryotic genome is mainly comprised of linear chromosomal DNA, genes can also be found outside of chromosomes. The unconventional presence of extrachromosomal genes is usually found to be circular, and these structures are named extrachromosomal circular DNA (eccDNA), which are often observed in cancer cells. Various types of eccDNA including small polydispersed DNA (spcDNA), telomeric cirlces, microDNA, etc. have been discovered. Among these eccDNA, extrachromosomal DNA (ecDNA), which encompasses the full spectrum of large, gene-containing extrachromosomal particles, has regained great research interest due to recent technological advances such as next-generation sequencing and super-resolution microscopy. In this review, we summarize the different types of eccDNA and discuss the role of eccDNA, especially ecDNA in tumor heterogeneity and progression. Additionally, we discuss some possible future investigative directions related to ecDNA biogenesis and its clinical application.


Assuntos
DNA Circular/classificação , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Heterogeneidade Genética , Neoplasias/genética , DNA Circular/genética , DNA Circular/metabolismo , DNA de Neoplasias/química , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Amplificação de Genes , Humanos , Micronúcleos com Defeito Cromossômico , Neoplasias/patologia , Neoplasias/terapia , Biogênese de Organelas
9.
Biochimie ; 176: 85-102, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32659446

RESUMO

Epigenetic modifications govern gene expression by guiding the human genome on 'what to express and what not to'. DNA methyltransferases (DNMTs) establish methylation patterns on DNA, particularly in CpG islands, and such patterns play a major role in gene silencing. DNMTs are a family of proteins/enzymes (DNMT1, 2, 3A, 3B, and 3L), among which, DNMT1 (maintenance methyltransferase) and DNMT3 (de novo methyltransferases) that direct mammalian development and genome imprinting are highly investigated. In recent decades, many studies revealed a strong association of DNA methylation patterns with gene expression in various clinical conditions. Differential expression of DNMT3 family proteins and their splice variants result in changes in methylation patterns and such alterations have been associated with the initiation and progression of various diseases, especially cancer. This review will discuss the aberrant modifications generated by DNMT3 proteins under various clinical conditions, suggesting a potential signature for de novo methyltransferases in targeted disease therapy. Further, this review discusses the possibility of using 'CpG island methylation signatures' as promising biomarkers and emphasizes 'targeted hypomethylation' by disrupting the interaction of specific DNMT-protein complexes as the future of cancer therapeutics.


Assuntos
DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , DNA de Neoplasias/metabolismo , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Proteínas de Neoplasias , Neoplasias , Animais , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferases/metabolismo , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia
10.
Pediatr Blood Cancer ; 67(9): e28426, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32614133

RESUMO

BACKGROUND: Relapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach. METHODS AND MATERIALS: We analyzed 302 pediatric ependymoma cases. Tumor, demographic, and treatment variables were investigated for association with relapse risk, time to recurrence, and survival after relapse. DNA methylation profiling was performed for 135/302 cases, and predominant subgroups were EPN_PFA (n = 95) and EPN_RELA (n = 24). Chromosome 1q status was ascertained for 185/302 cases by fluorescent in-situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and DNA methylation profiles. RESULTS: Sixty-two percent of cases relapsed, with a median of two recurrences with no difference between posterior fossa and supratentorial locations (66% vs 55% relapse rate). One hundred seventeen (38%) cases relapsed within two years and five (2%) beyond 10 years. The late relapses were clinically heterogeneous. Tumor grade and treatment affected risk and time to relapse variably across subgroups. After relapse, surgery and irradiation delayed disease progression with a minimal impact on survival across the entire cohort. In the EPN_PFA and EPN_RELA groups, 1q gain was independently associated with relapse risk (subhazard ratio [SHR] 4.307, P = 0.027 and SHR 1.982, P = 0.010, respectively) while EPN_PFA had increased relapse risk compared with EPN_RELA (SHR = 0.394, P = 0.018). CONCLUSIONS: Recurrent pediatric ependymoma is an aggressive disease with poor outcomes, for which current treatments are inadequate. We report that chromosome 1q gain increases relapse risk in common molecular subgroups in children but a deeper understanding of the underlying biology at relapse and novel therapeutic approaches are urgently needed.


Assuntos
Neoplasias Encefálicas , Cromossomos Humanos Par 1 , Metilação de DNA , DNA de Neoplasias , Ependimoma , Recidiva Local de Neoplasia , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 1/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/mortalidade , Ependimoma/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estudos Retrospectivos , Fatores de Risco
11.
Nat Genet ; 52(7): 709-718, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32601473

RESUMO

Propagation of clonal regulatory programs contributes to cancer development. It is poorly understood how epigenetic mechanisms interact with genetic drivers to shape this process. Here, we combine single-cell analysis of transcription and DNA methylation with a Luria-Delbrück experimental design to demonstrate the existence of clonally stable epigenetic memory in multiple types of cancer cells. Longitudinal transcriptional and genetic analysis of clonal colon cancer cell populations reveals a slowly drifting spectrum of epithelial-to-mesenchymal transcriptional identities that is seemingly independent of genetic variation. DNA methylation landscapes correlate with these identities but also reflect an independent clock-like methylation loss process. Methylation variation can be explained as an effect of global trans-acting factors in most cases. However, for a specific class of promoters-in particular, cancer-testis antigens-de-repression is correlated with and probably driven by loss of methylation in cis. This study indicates how genetic sub-clonal structure in cancer cells can be diversified by epigenetic memory.


Assuntos
Evolução Clonal , Epigênese Genética , Neoplasias/genética , Neoplasias/patologia , Transcrição Genética , Linhagem Celular , Proliferação de Células/genética , Metilação de DNA , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , RNA Neoplásico/metabolismo , Análise de Célula Única
12.
PLoS One ; 15(7): e0235613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634176

RESUMO

Germline variants inactivating the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome that implies an increased cancer risk, where colon and endometrial cancer are the most frequent. Identification of these pathogenic variants is important to identify endometrial cancer patients with inherited increased risk of new cancers, in order to offer them lifesaving surveillance. However, several other genes are also part of the MMR pathway. It is therefore relevant to search for variants in additional genes that may be associated with cancer risk by including all known genes involved in the MMR pathway. Next-generation sequencing was used to screen 22 genes involved in the MMR pathway in constitutional DNA extracted from full blood from 199 unselected endometrial cancer patients. Bioinformatic pipelines were developed for identification and functional annotation of variants, using several different software tools and custom programs. This facilitated identification of 22 exonic, 4 UTR and 9 intronic variants that could be classified according to pathogenicity. This study has identified several germline variants in genes of the MMR pathway that potentially may be associated with an increased risk for cancer, in particular endometrial cancer, and therefore are relevant for further investigation. We have also developed bioinformatics strategies to analyse targeted sequencing data, including low quality data and genomic regions outside of the protein coding exons of the relevant genes.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/patologia , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Variações do Número de Cópias de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Neoplasias do Endométrio/genética , Éxons , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Fatores de Risco , Regiões não Traduzidas/genética
13.
Oncogene ; 39(24): 4741-4755, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32415241

RESUMO

Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is an independent tumour type with regard to cellular, biological, and clinical features. The use of non-invasive biomarkers such as circulating tumour DNA (ctDNA) may be relevant in early diagnosis and eventually improve the outcomes of patients with head and neck squamous cell carcinoma (HNSCC). Genome-wide discovery using RNA sequencing and reduced representation bisulfite sequencing yielded 21 candidates for methylation-targeted genes. A verification study (252 HNSCC patients) using quantitative methylation-specific PCR (Q-MSP) identified 10 genes (ATP2A1, CALML5, DNAJC5G, GNMT, GPT, LY6D, LYNX1, MAL, MGC16275, and MRGPRF) that showed a significant increase recurrence in methylation groups with OPC. Further study on ctDNA using Q-MSP in HPV-associated OPC showed that three genes (CALML5, DNAJC5G, and LY6D) had a high predictive ability as emerging biomarkers for a validation set, each capable of discriminating between the plasma of the patients from healthy individuals. Among the 42 ctDNA samples, methylated CALML5, DNAJC5G, and LY6D were observed in 31 (73.8%), 19 (45.2%), and 19 (45.2%) samples, respectively. Among pre-treatment ctDNA samples, methylated CALML5, DNAJC5G, and LY6D were observed in 8/8 (100%), 7/8 (87.5%), and 7/8 (87.5%) samples, respectively. Methylated CALML5, DNAJC5G, and LY6D were found in 2/8 (25.0%), 0/8 (0%), and 1/8 (12.5%) of the final samples in the series, respectively. Here, we present the relationship between the methylation status of three specific genes and cancer recurrence for risk classification of HPV-associated OPC cases. In conclusion, ctDNA analysis has the potential to aid in determining patient prognosis and real-time surveillance for disease recurrences and serves as an alternative method of screening for HPV-associated OPC.


Assuntos
Biomarcadores Tumorais , Metilação de DNA , DNA de Neoplasias , Proteínas de Neoplasias , Neoplasias Orofaríngeas , Papillomaviridae , Infecções por Papillomavirus , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/genética , Papillomaviridae/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia
14.
Cancer Res ; 80(15): 3088-3100, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32366475

RESUMO

IL26 is a unique amphipathic member of the IL10 family of cytokines that participates in inflammatory signaling through a canonical receptor pathway. It also directly binds DNA to facilitate cellular transduction and intracellular inflammatory signaling. Although IL26 has almost no described role in cancer, our in vivo screen of inflammatory and cytokine pathway genes revealed IL26 to be one of the most significant inflammatory mediators of mammary engraftment and lung metastatic growth in triple-negative breast cancer (TNBC). Examination of human breast cancers demonstrated elevated IL26 transcripts in TNBC specimens, specifically in tumor cells as well as in Th17 CD4+ T cells within clinical TNBC specimens. IL26 did not have an autocrine effect on human TNBC cells, but rather its effect on engraftment and growth in vivo required neutrophils. IL26 enhanced mouse-derived DNA induction of inflammatory cytokines, which were collectively important for mammary and metastatic lung engraftment. To neutralize this effect, we developed a novel IL26 vaccine to stimulate antibody production and suppress IL26-enhanced engraftment in vivo, suggesting that targeting this inflammatory amplifier could be a unique means to control cancer-promoting inflammation in TNBC and other autoimmune diseases. Thus, we identified IL26 as a novel key modulator of TNBC metastasis and a potential therapeutic target in TNBC as well as other diseases reliant upon IL26-mediated inflammatory stimulation. SIGNIFICANCE: These findings identify IL26 as a unique, clinically relevant, inflammatory amplifier that enhances TNBC engraftment and dissemination in association with neutrophils, which has potential as a therapeutic target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/15/3088/F1.large.jpg.


Assuntos
Adesão Celular , Interleucinas/fisiologia , Transplante de Neoplasias , Neutrófilos/fisiologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Células Cultivadas , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Progressão da Doença , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Mediadores da Inflamação/farmacologia , Mediadores da Inflamação/fisiologia , Interleucinas/genética , Interleucinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Transplante de Neoplasias/imunologia , Transplante de Neoplasias/patologia , Neutrófilos/patologia , Neoplasias de Mama Triplo Negativas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Anticancer Res ; 40(5): 2675-2685, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366412

RESUMO

BACKGROUND/AIM: To evaluate the anti-cancer mechanism of N-Farnesyl-norcantharimide (NC15). MATERIALS AND METHODS: The viability of NC15-treated human leukemic Jurkat T (JKT) cells was assessed using the Kit-8 cell counting method. Flow cytometry analysis, human apoptosis antibody array assay, and whole genome sequencing were adopted to investigate the mechanism underlying the anti-cancer activity of NC15 in JKT cells. RESULTS: The growth inhibition rates of NC15 in JKT cells were about 80% and 95% after treatment with 8 µmol/l NC15 for 24 and 48 h, respectively. The percentages of NC15-treated JKT cells in the sub-G1 phase at 24 and 48 h were 22.0% and 34.3%, respectively, in contrast to the 1.5% in the control. Next-generation sequencing showed that many tumor suppressor genes (TSG) were up-regulated, while many genes associated with steroid biosynthesis, metabolic pathways, and fatty acid metabolism were down-regulated. CONCLUSION: NC15 can reduce the cell viability and increase the percentage of JKT cells in the sub-G1 phase by up-regulating TSG and related genes, and down-regulating the genes for steroid biosynthesis, metabolic pathways and fatty acid metabolism, instead of through apoptosis.


Assuntos
Cantaridina/análogos & derivados , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos/metabolismo , Genes Supressores de Tumor , Redes e Vias Metabólicas/genética , Esteroides/biossíntese , Linfócitos T/citologia , Regulação para Cima/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Cantaridina/química , Cantaridina/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Regulação para Baixo/genética , Humanos , Células Jurkat , Redes e Vias Metabólicas/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Regulação para Cima/genética
16.
J Hematol Oncol ; 13(1): 43, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366279

RESUMO

The novel coronavirus (2019-nCoV) is an emerging causative agent that was first described in late December 2019 and causes a severe respiratory infection in humans. Notably, many of affected patients of COVID-19 were people with malignancies. Moreover, cancer has been identified as an individual risk factor for COVID-19. In addition, the expression of angiotensin converting enzyme 2 (ACE2), the receptor of COVID-19, were aberrantly expressed in many tumors. However, a systematic analysis of ACE2 aberration remained to be elucidated in human cancers. Here, we analyzed genetic alteration, RNA expression, and DNA methylation of ACE2 across over 30 tumors. Notably, overexpression of ACE2 have been observed in including colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). In addition, hypo DNA methylation of ACE2 has also been identified in most of these ACE2 highly expressed tumors. Conclusively, our study for the first time curated both genetic and epigenetic variations of ACE2 in human malignancies. Notably, because our study is a bioinformatics assay, further functional and clinical validation is warranted.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Neoplasias/enzimologia , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral , Receptores Virais , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/virologia , Metilação de DNA , DNA de Neoplasias/metabolismo , Humanos , Neoplasias/complicações , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Pneumonia Viral/enzimologia , Pneumonia Viral/etiologia , Pneumonia Viral/virologia , RNA/biossíntese , Receptores Virais/biossíntese , Receptores Virais/genética
17.
Nat Commun ; 11(1): 2350, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393766

RESUMO

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Azepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Modelos Biológicos , Mutação/genética , Paclitaxel/farmacologia , Piperazinas/farmacologia , Ploidias , Proteínas/metabolismo , Piridinas/farmacologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Resultado do Tratamento , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
18.
Oncogene ; 39(21): 4299-4311, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32300177

RESUMO

Most hereditary tumors show aberrations in DNA repair genes or their regulators. In contrast, only a minority of sporadic tumors show alterations in these genes. As a result, genomic instability is currently considered an enhancer of tumorigenesis rather than an obligatory event in this process. However, tumor heterogeneity presents a significant technical challenge for most cancer genomics studies performed at less than 100× mean resolution depth. To address the importance of genomic instability in prostate carcinogenesis and tumor progression, we performed ultrahigh depth exome sequencing of 124 DNA damage repair/response (repairome) genes in 63 tumors and matched normal tissue samples in African Americans and Caucasians. The average sequence depth was 712-fold for DNA isolated from normal tissue and 368-fold for FFPE tumors. We identified 671 somatic mutations in tumors from African Americans and 762 somatic mutations in tumors in Caucasians. The most frequently mutated DNA repairome genes were EXO1, ATR, POLQ, NEIL3, ERCC6, BRCA2, BRCA1, XPC, JAG1, RPA1, POLE, ATM, and LIG1 in African American men, and POLQ, NEIL3, POLB, BRCA2, EXO1, ERCC6, ATR, RBBP8, BRCA1, ATM, JAG1, XPC, and POLE in Caucasians. We found that 89% of tumors had at least one mutation in nucleotide excision repair pathway genes in African Americans, whereas >40% of tumors had mutations in base excision repair pathway genes in Caucasians. We further identified a marginal increase in mutation rate in tumors in African Americans with increasing age. Tumors in Caucasians did not show a correlation with age, but a progressive increase in the mutation rate was observed at higher Gleason scores. Our data reveal significant differences in the molecular signatures in the DNA repairome in prostate cancer between African Americans and Caucasians. These data also have substantial implications regarding the well-known health disparities in prostate cancer, such as the higher mortality in African Americans than Caucasians.


Assuntos
Afro-Americanos , Reparo do DNA , DNA de Neoplasias/genética , Grupo com Ancestrais do Continente Europeu , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Idoso , DNA de Neoplasias/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/metabolismo
19.
Nutrients ; 12(4)2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32268584

RESUMO

Prostate cancer (PCa) is a multifactorial disease with an unclear etiology. Due to its high prevalence, long latency, and slow progression, PCa is an ideal target for chemoprevention strategies. Many research studies have highlighted the positive effects of natural flavonoids on chronic diseases, including PCa. Different classes of dietary flavonoids exhibit anti-oxidative, anti-inflammatory, anti-mutagenic, anti-aging, cardioprotective, anti-viral/bacterial and anti-carcinogenic properties. We overviewed the most recent evidence of the antitumoral effects exerted by dietary flavonoids, with a special focus on their epigenetic action in PCa. Epigenetic alterations have been identified as key initiating events in several kinds of cancer. Many dietary flavonoids have been found to reverse DNA aberrations that promote neoplastic transformation, particularly for PCa. The epigenetic targets of the actions of flavonoids include oncogenes and tumor suppressor genes, indirectly controlled through the regulation of epigenetic enzymes such as DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC). In addition, flavonoids were found capable of restoring miRNA and lncRNA expression that is altered during diseases. The optimization of the use of flavonoids as natural epigenetic modulators for chemoprevention and as a possible treatment of PCa and other kinds of cancers could represent a promising and valid strategy to inhibit carcinogenesis and fight cancer.


Assuntos
Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Epigênese Genética/efeitos dos fármacos , Flavonoides/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata , Humanos , Masculino , Proteínas de Neoplasias/biossíntese , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , RNA Neoplásico/biossíntese
20.
Chem Biol Interact ; 323: 109075, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32229109

RESUMO

The use of orchids in herbal medicine has a very long history. Dendrobium species are known to produce a variety of secondary metabolites such as phenanthrens, bibenzyls, fluorenones and sesquiterpenes, and alkaloids and are responsible for their wide variety of medicinal properties. For decades, bibenzyls, which are the main bioactive components derived from Dendrobium species, have been subjected to extensive investigation as likely candidates for cancer treatment. The present study was undertaken to investigate the effect of moscatilin, a bibenzyl derivative from the orchid Dendrobium loddigesii on human melanoma cells. In A375 cells compound moscatilin showed a clear dose-response relationship in the range of 6.25-50 µM concentrations. In addition, we demonstrated an apoptotic response after treatment of cancer cells with this bibenzyl compound at 6.25 and 12.5 µM concentrations that probably involves PTEN activity, inhibition of Hsp70 expression and reactive oxygen species production. Alternatively, the inhibition of the caspase cascade at higher concentrations, 25 and 50 µM, correlated with additional reactive oxygen species increase, probably switched the mode of moscatilin-induced cell death from apoptosis to necrosis.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Benzil/uso terapêutico , Dendrobium/química , Melanoma/tratamento farmacológico , Melanoma/patologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Glutationa/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA