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1.
Urol Clin North Am ; 47(4): 487-510, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008499

RESUMO

The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.


Assuntos
Produtos Biológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Idoso , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Previsões , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Resultado do Tratamento , Microambiente Tumoral/genética
2.
Nat Commun ; 11(1): 4301, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879317

RESUMO

Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.


Assuntos
Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Duplicação Gênica , Neoplasias Pancreáticas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/patologia , Conjuntos de Dados como Assunto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Masculino , Taxa de Mutação , Metástase Neoplásica/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Análise de Célula Única , Sequenciamento Completo do Exoma
3.
Nature ; 585(7824): 283-287, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814897

RESUMO

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1-6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9-12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.


Assuntos
Envelhecimento/metabolismo , Progressão da Doença , Ácido Metilmalônico/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/patologia , Adulto , Idoso , Envelhecimento/sangue , Envelhecimento/genética , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Ácido Metilmalônico/sangue , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias/sangue , Neoplasias/genética , Fatores de Transcrição SOXC/metabolismo , Transdução de Sinais , Transcriptoma/genética , Fator de Crescimento Transformador beta/metabolismo
4.
Medicine (Baltimore) ; 99(32): e21505, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769887

RESUMO

The purpose of this study was to investigate novel biomarkers and potential mechanisms in nasopharyngeal carcinoma (NPC) patients with metastasis.Two microarray datasets (GSE103611 and GSE36682) were obtained from GEO database, differentially expressed genes (DEGs) and differentially expressed miRNA (DEMs) were identified, Gene ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted with DEGs and DEMs targeted genes. Protein-protein interactions (PPI) network of the DEGs and DEMs targeted genes were constructed, furthermore, Connectivity Map (CMap) database was applied to select the potential drugs with therapeutic effects.Overall, we identified 396 upregulated and 19 downregulated DEGs. Additionally, we identified 1 upregulated DEM, miR-135b, and a downregulated DEM, miR-574-5p. Functional enrichment analysis indicated that both DEGs and DEMs targeted genes participated in biological process (BP) of regulation of transcription from RNA polymerase II promoter, DNA-templated positive regulation of transcription, and Epstein-Barr virus infection signaling pathway. Besides, upregulated EP300 gene was a hub node both in DEGs and DEMs target genes. CMap database analysis indicated that sanguinarine, verteporfin, and chrysin are potential drugs for prevention and treatment of NPC metastasis.In summary, the common hub gene, biological process and pathway identified in the study provided a novel insight into the potential mechanism of NPC metastasis. Furthermore, we identified several possible small molecule compounds for treatment of NPC metastasis.


Assuntos
MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica/genética , Mapas de Interação de Proteínas , Transdução de Sinais/genética , Regulação para Cima/genética
5.
Nature ; 583(7814): 133-138, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32528174

RESUMO

Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms1-3. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models4-6. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a 'trap' for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-ß-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.


Assuntos
Neoplasias da Mama/patologia , DNA/metabolismo , Armadilhas Extracelulares/genética , Proteínas de Membrana/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neutrófilos/metabolismo , Actinina/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Proteínas de Membrana/genética , Camundongos , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais
7.
PLoS Genet ; 16(6): e1008808, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32497036

RESUMO

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.


Assuntos
Antineoplásicos/farmacologia , Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/genética , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Instabilidade Cromossômica , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/secundário , RNA Helicases DEAD-box/genética , Reparo do DNA , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Estudos de Viabilidade , Feminino , Humanos , Camundongos , Camundongos Knockout , Mutação , Gradação de Tumores , Metástase Neoplásica/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Cultura Primária de Células , Ribonuclease III/genética , Proteína Supressora de Tumor p53/genética
8.
DNA Cell Biol ; 39(7): 1299-1312, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32551879

RESUMO

Although advances have been made in the development of antiangiogenesis targeted therapy and surgery, metastatic clear cell renal cell carcinoma (ccRCC) is still incurable. Activation-induced cytidine deaminase (AID) is mainly expressed in a variety of germ and somatic cells, and induces somatic hypermutation and class-switch recombination, playing a vital role in antibody diversification. We confirmed that AID was expressed at a higher level in ccRCC tissues than in the corresponding nontumor renal tissues. We explored the impact of AID on ccRCC proliferation, invasion, and migration. In 769-p and 786-0 cells, expression of an AID-specific short hairpin RNA significantly reduced AID expression, which markedly inhibited tumor cell invasion, proliferation, and migration. Previous studies showed that AID is associated with Wnt ligand secretion mediator (WLS/GPR177), cyclin-dependent kinase 4 (CDK4), and stromal cell-derived factor-1 (SDF-1/CXCL12) regulation, which was further confirmed in human ccRCC tissues. Therefore, we studied the relationship between AID and these three molecules, and the impact of AID on epithelial-to-mesenchymal transition in ccRCC. WLS/GPR177, SDF-1/CXCL12, and CDK4 were sensitive to 5-azacytidine (a DNA demethylation agent), which reverted the inhibition of carcinogenesis caused by AID repression. In summary, AID is an oncogene that might induce tumorigenesis through DNA demethylation. Targeting AID may represent a novel therapeutic approach to treat metastatic ccRCC.


Assuntos
Carcinoma de Células Renais/patologia , Citidina Desaminase/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Fenótipo , Linhagem Celular Tumoral , Movimento Celular/genética , Humanos , Invasividade Neoplásica/genética , Metástase Neoplásica/genética
9.
Arch Biochem Biophys ; 688: 108407, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32407712

RESUMO

Prostate cancer has the highest incidence among men in advanced countries, as well as a high mortality rate. Despite the efforts of numerous researchers to identify a gene-based therapeutic target as an effective treatment of prostate cancer, there is still a need for further research. The cathepsin gene family is known to have a close correlation with various cancer types and is highly expressed across these cancer types. This study aimed at investigating the correlation between the cathepsin A (CTSA) gene and prostate cancer. Our findings indicated a significantly elevated level of CTSA gene expression in the tissues of patients with prostate cancer when compared with normal prostate tissues. Furthermore, the knockdown of the CTSA gene in the representative prostate cancer cell lines PC3 and DU145 led to reduced proliferation and a marked reduction in anchorage-independent colony formation, which was shown to be caused by cell cycle arrest in the S phase. In addition, CTSA gene-knockdown prostate cancer cell lines showed a substantial decrease in migration and invasion, as well as a decrease in the marker genes that promote epithelial mesenchymal transition (EMT). Such phenotypic changes in prostate cancer cell lines through CTSA gene suppression were found to be mainly caused by reduced p38 MAPK protein phosphorylation; i.e. the inactivation of the p38 MAPK cell signaling pathway. Tumorigenesis was also found to be inhibited in CTSA gene-knockdown prostate cancer cell lines when a xenograft assay was carried out using Balb/c nude mice, and the p38 MAPK phosphorylation was inhibited in tumor tissues. Thus, the CTSA gene is presumed to play a key role in human prostate cancer tissues through high-level expression, and the suppression of the CTSA gene leads to the inhibition of prostate cancer cell proliferation, colony formation, and metastasis. The mechanism, by which these effects occur, was demonstrated to be the inactivation of the p38 MAPK signaling pathway.


Assuntos
Catepsina A/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Neoplasias da Próstata/metabolismo , Transdução de Sinais/fisiologia , Animais , Sequência de Bases , Catepsina A/genética , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos Endogâmicos BALB C , Metástase Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Nat Genet ; 52(7): 692-700, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451459

RESUMO

Genetic diversity among metastases is poorly understood but contains important information about disease evolution at secondary sites. Here we investigate inter- and intra-lesion heterogeneity for two types of metastases that associate with different clinical outcomes: lymph node and distant organ metastases in human colorectal cancer. We develop a rigorous mathematical framework for quantifying metastatic phylogenetic diversity. Distant metastases are typically monophyletic and genetically similar to each other. Lymph node metastases, in contrast, display high levels of inter-lesion diversity. We validate these findings by analyzing 317 multi-region biopsies from an independent cohort of 20 patients. We further demonstrate higher levels of intra-lesion heterogeneity in lymph node than in distant metastases. Our results show that fewer primary tumor lineages seed distant metastases than lymph node metastases, indicating that the two sites are subject to different levels of selection. Thus, lymph node and distant metastases develop through fundamentally different evolutionary mechanisms.


Assuntos
Neoplasias Colorretais/patologia , Metástase Linfática , Estudos de Coortes , Neoplasias Colorretais/genética , Progressão da Doença , Heterogeneidade Genética , Variação Genética , Humanos , Metástase Linfática/genética , Modelos Biológicos , Metástase Neoplásica/genética , Inoculação de Neoplasia , Filogenia
11.
NPJ Syst Biol Appl ; 6(1): 15, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424264

RESUMO

Metastasis is the cause of over 90% of cancer-related deaths. Cancer cells undergoing metastasis can switch dynamically between different phenotypes, enabling them to adapt to harsh challenges, such as overcoming anoikis and evading immune response. This ability, known as phenotypic plasticity, is crucial for the survival of cancer cells during metastasis, as well as acquiring therapy resistance. Various biochemical networks have been identified to contribute to phenotypic plasticity, but how plasticity emerges from the dynamics of these networks remains elusive. Here, we investigated the dynamics of various regulatory networks implicated in Epithelial-mesenchymal plasticity (EMP)-an important arm of phenotypic plasticity-through two different mathematical modelling frameworks: a discrete, parameter-independent framework (Boolean) and a continuous, parameter-agnostic modelling framework (RACIPE). Results from either framework in terms of phenotypic distributions obtained from a given EMP network are qualitatively similar and suggest that these networks are multi-stable and can give rise to phenotypic plasticity. Neither method requires specific kinetic parameters, thus our results emphasize that EMP can emerge through these networks over a wide range of parameter sets, elucidating the importance of network topology in enabling phenotypic plasticity. Furthermore, we show that the ability to exhibit phenotypic plasticity correlates positively with the number of positive feedback loops in a given network. These results pave a way toward an unorthodox network topology-based approach to identify crucial links in a given EMP network that can reduce phenotypic plasticity and possibly inhibit metastasis-by reducing the number of positive feedback loops.


Assuntos
Adaptação Fisiológica/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Redes Reguladoras de Genes/genética , Humanos , Modelos Biológicos , Metástase Neoplásica/genética , Fenótipo
12.
Toxicol Appl Pharmacol ; 399: 115056, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445756

RESUMO

The c-MYC is one of the most commonly discussed oncogenes in almost all cancers. c-MYC, as a proto-oncogene in normal cells, has found to be tightly controlled and regulated, both genetically and epigenetically. Evasion of the controlled checkpoint mechanisms during cancer causes a deregulated expression of c-MYC. Overexpression of c-MYC causes the onset of many hallmarks of cancer. Despite c-MYC being centrally located in several cancers, it is not feasible to target c-MYC in therapeutic resistant cancers. Similarly, long non-coding RNAs (lncRNAs) are deregulated during the genesis and progression of different cancers. LncRNAs contribute to almost 27% human genome and recent findings by tumor genome sequencing revealed many of the lncRNAs loci that are modified, deleted, amplified, and mutated during the different stages of cancer development. Recent studies also reported that multiple lncRNAs regulate c-MYC by different mechanisms and vice versa. Thus, oncogenic lncRNAs and c-MYC interaction are positioned to provide an interesting choice for therapeutic interventions in cancers. In this mini-review, we summarize the recent discoveries and explain how the interaction between oncogenic lncRNAs and c-MYC could be used as a possible target for therapeutic intervention in cancers, especially the therapeutic resistant metastatic cancers.


Assuntos
Metástase Neoplásica/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Animais , Carcinogênese/genética , Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Neoplásica/patologia , Neoplasias/patologia
13.
PLoS One ; 15(5): e0233260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453797

RESUMO

BACKGROUND: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment. METHODS: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported. RESULTS: 27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months). CONCLUSIONS: MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.


Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas , Neoplasias Colorretais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/genética , Síndromes Neoplásicas Hereditárias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Análise de Sobrevida
14.
DNA Cell Biol ; 39(7): 1290-1298, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32364763

RESUMO

Long noncoding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) has been reported to be involved in non-small-cell lung cancer (NSCLC) tumorigenesis. However, the biological role and regulatory mechanism of lncRNA SBF2-AS1 on NSCLC metastasis remain largely unknown. In this study, the expression level and functional role of SBF2-AS1 were investigated in both NSCLC tissues and cell lines. We found that SBF2-AS1 was upregulated in both NSCLC tissues and cell lines. Patients with high levels of SBF2-AS1 have larger tumors, higher malignancy, and poor prognosis. Knockdown of SBF2-AS1 significantly inhibited tumor growth in vivo and cell proliferation, migration, and invasion in vitro. Moreover, bioinformatics analysis, chromatin immunoprecipitation assay, and luciferase reporter assay proved that the upregulation of SBF2-AS1 was mediated by transcription factor E2F1. Further experiments demonstrated that miR-362-3p had complementary binding site with 3'-UTR of SBF2-AS1. Besides, luciferase reporter assay validated that GRB2 was the target protein of miR-362-3p. Rescue experiments showed that SBF2-AS1 silencing inhibited cell invasion and migration, while cotransfection si-SBF2-AS1 and miR-362-3p inhibitor rescued the effect of si-SBF2-AS1. These results demonstrate that E2F1-induced overexpression of SBF2-AS1 promotes the expression of GRB2 by targeting miR-362-3p to facilitate the metastasis of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Fator de Transcrição E2F1/metabolismo , Proteína Adaptadora GRB2/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Regiões 3' não Traduzidas/genética , Células A549 , Sequência de Bases , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/genética , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Regulação para Cima/genética
15.
PLoS One ; 15(5): e0232754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379795

RESUMO

Analyzing cell-free DNA (cfDNA) as a source of circulating tumor DNA is useful for diagnosing or monitoring patients with cancer. However, the concordance between cfDNA within liquid biopsy and genomic DNA (gDNA) within tumor tissue biopsy is still under debate. To evaluate the concordance in a clinical setting, we enrolled 54 patients with metastatic colorectal cancer and analyzed their plasma cfDNA, gDNA from peripheral blood mononuclear cells (PBMC), and gDNA from available matched tumor tissues using ultra-deep sequencing targeting 10 genes (38-kb size) recurrently mutated in colorectal cancer. We first established a highly reliable cut-off value using reference material. The sensitivity of detecting KRAS hotspot mutations in plasma was calculated as 100%, according to digital droplet PCR. We could selectively detect clinically important somatic alterations with a variant allele frequency as low as 0.18%. We next compared somatic mutations of the 10 genes between cfDNA and genomic DNA from tumor tissues and observed an overall 93% concordance rate between the two types of samples. Additionally, the concordance rate of patients with the time interval between liquid biopsy and tumor tissue biopsy within 6 months and no prior exposure to chemotherapy was much higher than those without. The patients with KRAS mutant fragments in plasma had poor prognosis than those without the mutant fragments (33 months vs. 63 months; p<0.05). Consequently, the profiling with our method could achieve highly concordant results and may facilitate the surveillance of the tumor status with liquid biopsy in CRC patients.


Assuntos
Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/genética , Neoplasias Colorretais/genética , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
16.
Life Sci ; 255: 117857, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470446

RESUMO

AIMS: To explore the pro-metastatic role of exosomes derived from highly invasive pancreatic cancer cell and the associated aberrant expression of exosomal microRNAs (miRNAs). MAIN METHODS: Weakly invasive PC-1 cells were treated with exosomes of highly invasive PC-1.0 cells to determine the pro-metastatic effect of PC-1.0 derived exosomes. The exosomal miRNA profile was further investigated using high-throughput sequencing. The level of miR-125b-5p in highly and weakly invasive pancreatic cancer cells was further determined. Pancreatic cancer cells transfected with miR-125b-5p mimic and inhibitor were used to explore the effect of miR-125b-5p on migration, invasion and epithelial-to-mesenchymal transition (EMT). Treatment with PC-1.0 derived exosome and Western blot assay were performed to validate STARD13 as a target of exosomal miR-125b-5p in pancreatic cancer. KEY FINDINGS: PC-1.0 derived exosomes promoted the migration and invasion of weakly invasive PC-1 cells. miRNA sequencing revealed 62 miRNAs upregulated in PC-1.0 derived exosomes. miR-125b-5p most significantly promoted migration and invasion and was associated with metastasis in pancreatic cancer. Further, miR-125b-5p was upregulated in highly invasive pancreatic cancer cells and increased migration, invasion, and EMT. Moreover, its upregulation was associated with activation of MEK2/ERK2 signaling. The tumor suppressor STARD13 was directly targeted by miR-125b-5p in pancreatic cancer, which was associated with good prognosis and was suppressed by exosomes derived from highly invasive cancer cells. SIGNIFICANCE: This study explored the pro-metastatic role of exosomes derived from highly invasive pancreatic cancer cells and the associated aberrant expression of exosomal miRNAs, which may help to elucidate the metastatic mechanism of pancreatic cancer.


Assuntos
Exossomos/genética , Proteínas Ativadoras de GTPase/genética , MicroRNAs/genética , Neoplasias Pancreáticas/patologia , Proteínas Supressoras de Tumor/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Neoplasias Pancreáticas/genética , Fenótipo , Regulação para Cima
17.
Life Sci ; 252: 117656, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289433

RESUMO

AIMS: Diabetes is considered as one of the important risks in the progression of Hepatocellular carcinoma(HCC). Ribosome binding protein 1 (RRBP1), a rough endoplasmic reticulum protein, plays an essential role in diabetes and various cancer. E2F transcription factor 1 (E2F1), an upstream transcription factor of RRBP1, shows promoting tumor progression effect in multifarious cancers. In this research, we tried to identify whether regulating E2F1/RRBP1 pathway could inhibit the proliferation and metastasis of HepG2 cells induced by high glucose. MAIN METHODS: Proteomic, bioinformatics, molecular biology including RT-qPCR and Western blot, cell biology containing Cell Counting Kit-8 (CCK-8), wound healing assay and transwell assay, and biochemistry analyses incorporating Luciferase assay and CHIP assay were used in this study. KEY FINDINGS: High glucose promoted the proliferation and metastasis of HepG2 cells through up-regulating the expression of RRBP1. Bioinformatics analysis predicted that E2F1 might be the transcription factor of RRBP1. Knocking-down of E2F1 down-regulated mRNA and protein expression levels of RRBP1 in HepG2 cells significantly and suppressed the proliferation, migration and invasion of cells remarkably, Reverse effect was observed in cells that E2F1 was overexpressed. Meanwhile, luciferase and CHIP assay determined that E2F1 could bind to the RRBP1 promoter and promote the transcription of RRBP1. Finally, rescue assay verified the important role of RRBP1/E2F1 axis in the process of HepG2 cells proliferation and metastasis. SIGNIFICANCE: All of the above provided possibility to improve the efficiency of HCC complicated with diabetes treatment by regulating the E2F1/RRBP1 pathway.


Assuntos
Carcinoma Hepatocelular/patologia , Proteínas de Transporte/genética , Fator de Transcrição E2F1/genética , Glucose/metabolismo , Neoplasias Hepáticas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Técnicas de Silenciamento de Genes , Células HEK293 , Células Hep G2 , Humanos , Metástase Neoplásica/genética , Regulação para Cima
18.
Adv Exp Med Biol ; 1220: 11-34, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304077

RESUMO

Circulating tumor cells offer an unprecedented window into the metastatic cascade, and to some extent can be considered as intermediates in the process of metastasis. They exhibit dynamic oscillations in epithelial to mesenchymal plasticity and provide important opportunities for prognosis, therapy response monitoring, and targeting of metastatic disease. In this manuscript, we review the involvement of epithelial-mesenchymal plasticity in the early steps of metastasis and what we have learned about its contribution to genomic instability and genetic diversity, tumor progression and therapeutic responses using cell culture, mouse models and circulating tumor cells enriched from patients.


Assuntos
Transição Epitelial-Mesenquimal , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética
19.
Adv Exp Med Biol ; 1220: 117-134, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304083

RESUMO

Liquid biopsy based on the analysis of circulating tumor cells (CTCs) has emerged as an important field of research. Molecular characterization of CTCs can provide insights into cancer biology and biomarkers for the clinic, representing a non-invasive powerful tool for monitoring breast cancer metastasis and predict the therapeutic response. Epigenetic mechanisms play a key role in the control of gene expression and their alteration contributes to cancer development and progression. These epigenetic modifications in CTCs have been described mainly related to modifications of the DNA methylation pattern and changes in the expression profile of noncoding RNAs. Here we summarize the recent findings on the epigenetic characterization of CTCs in breast cancer and their clinical value as tumor biomarkers, and discuss challenges and opportunities in this field.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Epigênese Genética , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Biomarcadores Tumorais , Metilação de DNA , Humanos , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , RNA não Traduzido/genética
20.
PLoS Genet ; 16(4): e1008592, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32343702

RESUMO

Exosomal microRNAs (miRNAs) have been recently shown to play vital regulatory and communication roles in cancers. In this study, we showed that the expression levels of miR-652-5p in tumour tissues and serum samples of oesophageal squamous cell carcinoma (OSCC) patients were lower compared to non-tumorous tissues and serum samples from healthy subjects, respectively. Decreased expression of miR-652-5p was correlated with TNM stages, lymph node metastasis, and short overall survival (OS). More frequent CpG sites hypermethylation in the upstream of miR-652-5p was found in OSCC tissues compared to adjacent normal tissues. Subsequently, miR-652-5p downregulation promoted the proliferation and metastasis of OSCC, and regulated cell cycle both in cells and in vivo. The dual-luciferase reporter assay confirmed that poly (ADP-ribose) glycohydrolase (PARG) and vascular endothelial growth factor A (VEGFA) were the direct targets of miR-652-5p. Moreover, the delivery of miR-652-5p agomir suppressed tumour growth and metastasis, and inhibited the protein expressions of PARG and VEGFA in nude mice. Taken together, our findings provide novel insight into the molecular mechanism underlying OSCC pathogenesis.


Assuntos
Metilação de DNA , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Exossomos/genética , Glicosídeo Hidrolases/metabolismo , MicroRNAs/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular , Proliferação de Células/genética , Progressão da Doença , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Metástase Neoplásica/genética , Soro/citologia , Taxa de Sobrevida
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