Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.325
Filtrar
1.
Anticancer Res ; 39(10): 5311-5327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570425

RESUMO

BACKGROUND/AIM: MiR-221, often described both as an oncogenic microRNA and as a tumour suppressor, targets mRNAs involved in carcinogenesis. While other oncogenic microRNAs showed correlations with prostate cancer cell lines' aggressiveness, miR-221 showed an unusual overexpression in PC3. MATERIALS AND METHODS: CRISPR was used to delete miR-221 from PC3 cells. Analysing the characteristics of PC3miR-221del cells, a reduced growth rate and expression of cell-cycle genes was observed. In global gene expression/ontology analysis of PC3miR-221del cells, cell-cell and cell-substrate adhesion pathways were found to be greatly affected. In addition, reduced levels of adhesion, invasion and motility for PC3miR-221del cells, a change in F-actin localisation and a reduction of EMT markers were observed. RESULTS: The tumour suppressor gene, DIRAS3, was a predicted target of miR-221. In PC3miR-221del cells DIRAS3 was up-regulated at the gene and protein level. Ectopic expression of DIRAS3 in PC3wt cells recapitulated the cellular morphology changes seen in PC3miR-221del cells. DIRAS3 3'UTR was more stable in PC3miR-221del cells, as measured by semi-quantitative PCR and luciferase fusion reporter assays. CONCLUSION: MiR-221 promotes aggressiveness of PC3 cells by down-regulating DIRAS3, and promoting epithelial-to-mesenchymal transition.


Assuntos
Adesão Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , Deleção de Sequência/genética , Regiões 3' não Traduzidas/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Oncogenes/genética , Células PC-3 , Neoplasias da Próstata/genética , Regulação para Cima/genética , Proteínas rho de Ligação ao GTP/genética
2.
Anticancer Res ; 39(10): 5345-5352, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570428

RESUMO

BACKGROUND/AIM: Accurate and timely assessment of the human epidermal growth factor receptor 2 (HER2/neu) overexpression is pivotal for the identification of breast cancer (BC) patients that could benefit from HER2-targeted therapy. Currently approved tissue-based HER2 assays (tHER2) are limited to testing HER2 status on tumor samples obtained at a few points in time during the course of the disease. Herein, we assessed serum HER2 (sHER2) status longitudinally in 81 serial samples prospectively collected from 43 consenting patients pre- and post-therapy to revisit the idea of serum testing in the follow-up of BC patients. PATIENTS AND METHODS: The cohort included 11 patients with early BC (EBC), 17 with locally advanced BC (LABC), and 15 with metastatic BC (MBC). sHER2 concentrations were measured using a quantitative ELISA-based technique, using 15 ng/ml as the cut-off for positivity. RESULTS: At baseline, sHER2 was negative in all EBC patients while positive in 1 LABC and 5 MBC patients. Sixteen BC patients (10 LABC, 1 EBC, and 5 MBC) were tHER2 positive. sHER2 and tHER2 results were discordant in 14 patients. Among the 16 tHER2 positive patients, 9 LABC, 1 EBC and 2 MBC patients were sHER2 negative. Conversely, 2 MBC patients were sHER2 positive, despite being tHER2 negative. A rise or drop of sHER2 by >20% correlated with disease progression or pathological response to therapy, respectively. CONCLUSION: The study demonstrated the technical validity and feasibility of the sHER2 assay. Findings suggest that post initial tissue diagnosis (tHER2), sHER2 assay may supplement subsequent tissue tests to monitor disease status and response to therapy. Further studies to assess the role of HER2 targeted therapies in sHER-positive/tHER2-negative cases upon disease progression are warranted.


Assuntos
Neoplasias da Mama/sangue , Receptor ErbB-2/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Oncogenes/genética , Projetos Piloto
3.
Anticancer Res ; 39(10): 5789-5795, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570483

RESUMO

BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. PATIENTS AND METHODS: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. RESULTS: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). CONCLUSION: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.


Assuntos
Antígeno B7-H1/genética , Carcinoma/genética , Carcinoma/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Oncogenes/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
4.
Zhonghua Wai Ke Za Zhi ; 57(9): 691-697, 2019 Sep 01.
Artigo em Chinês | MEDLINE | ID: mdl-31474062

RESUMO

Objectives: To examine the expression of the long coding RNA GSTM3TV2 in pancreatic cancer tissues and to examine its role and mechanism in chemoresistance of pancreatic cancer cells. Methods: The expression of lncRNA GSTM3TV2 in 15 pancreatic cancer specimens and corresponding adjacent to cancer tissue samples diagnosed by Department of Pathology, Peking Union Medical College Hospital was detected by real-time PCR.And the expressions of GSTM3TV2 in pancreatic cancer cell AsPC-1, BxPC-3, MIAPaCa-2, PanC-1, SU86.86, T3M4, and chemoresistant cells AsPC-1/GR and MIAPaCa-2/GR, and human pancreatic nestin-expressing cells hTERT-HPNE were detected. Pancreatic cancer cell lines were transfected with GSTM3TV2-pcDNA3.1(+)in order to get cells with GSTM3TV2 overexpression.GSTM3TV2-siRNA was transfected into pancreatic cancer cells to knock down GSTM3TV2. The cell chemoresistance was measured by CCK-8 and flow cytometry assay when incubated with nab-paclitaxel. At the same time, subcutaneous xenograft tumor models were established in nude mice to observe the effect of GSTM3TV2 on chemoresistance of tumor growth in nude mice.Western blot assay was also performed to detect the molecular mechanism of chemoresistance of GSTM3TV2. Results: Comparing toadjacent tissues(0.084±0.019), GSTM3TV2 expression was significantly upregulated in the pancreatic cancer tissues(0.493±0.084) (t=5.146, P<0.05). GSTM3TV2 expression were higher in the chemotherapy resistance pancreatic cancer cells AsPC-1/GR(210.799±19.788) and MIAPaCa-2/GR(122.408±23.419) than that in the AsPC-1(3.793±0.615) and the MIAPaCa-2(5.179±1.095)(t=21.800,P<0.05;t=-18.490,P<0.05). The results of in vivo experiments showed that the volume of subcutaneously transplanted tumors in the overexpressing GSTM3TV2 group ((1 059.609±102.498)mm(3)) was significantly larger than that in the control group((566.414±81.087) mm(3)) by treated with nab-paclitaxel(t=4.230,P<0.05).Meanwhile, GSTM3TV2 could promote the expression of Cyclin D1, CDK6, Cyclin E1, Vimentin, N-cadherin, ZEB1, Snail and Slug; but decrease cleaved caspase-3, cleaved PARP in pancreatic cancer cells. Conclusions: The expression level of GSTM3TV2 in pancreatic canceris higher than that in paired adjacent tissues. GSTM3TV2 may act as an oncogene to promote chemoresistance in pancreatic cancer through regulation of cell proliferation, apoptosis, and epithelial-mesenchymal transition.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Glutationa Transferase/genética , Oncogenes/genética , Neoplasias Pancreáticas/genética , RNA não Traduzido/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Sci ; 110(8): 2643-2651, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222839

RESUMO

Scirrhous-type gastric cancer (SGC) is one of the most intractable cancer subtypes in humans, and its therapeutic targets have been rarely identified to date. Exploration of somatic mutations in the SGC genome with the next-generation sequencers has been hampered by markedly increased fibrous tissues. Thus, SGC cell lines may be useful resources for searching for novel oncogenes. Here we have conducted whole exome sequencing and RNA sequencing on 2 SGC cell lines, OCUM-8 and OCUM-9. Interestingly, most of the mutations thus identified have not been reported. In OCUM-8 cells, a novel CD44-IGF1R fusion gene is discovered, the protein product of which ligates the amino-terminus of CD44 to the transmembrane and tyrosine-kinase domains of IGF1R. Furthermore, both CD44 and IGF1R are markedly amplified in the OCUM-8 genome and abundantly expressed. CD44-IGF1R has a transforming ability, and the suppression of its kinase activity leads to rapid cell death of OCUM-8. To the best of our knowledge, this is the first report describing the transforming activity of IGF1R fusion genes. However, OCUM-9 seems to possess multiple oncogenic events in its genome. In particular, a novel BORCS5-ETV6 fusion gene is identified in the OCUM-9 genome. BORCS5-ETV6 possesses oncogenic activity, and suppression of its message partially inhibits cell growth. Prevalence of these novel fusion genes among SGC awaits further investigation, but we validate the significance of cell lines as appropriate reagents for detailed genomic analyses of SGC.


Assuntos
Adenocarcinoma Esquirroso/genética , Oncogenes/genética , Neoplasias Gástricas/genética , Células 3T3 , Adenocarcinoma Esquirroso/patologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Células HEK293 , Humanos , Receptores de Hialuronatos/genética , Proteínas de Membrana/genética , Camundongos , Mutação/genética , Receptor IGF Tipo 1/genética , Estômago/patologia , Neoplasias Gástricas/patologia
6.
Nat Commun ; 10(1): 2037, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048690

RESUMO

Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.


Assuntos
Oncogenes/genética , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Caderinas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Éxons/genética , Feminino , Duplicação Gênica/genética , Variação Estrutural do Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Sequenciamento Completo do Genoma
7.
Biomed Pharmacother ; 114: 108862, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981105

RESUMO

Small Nucleolar RNA Host Gene (SNHG16) is a novel cancer-related long noncoding RNA (lncRNA) and functions as an oncogene in a variety of cancers. Nonetheless, the expression patterns, biological function, and potential mechanisms in SNHG16 in pancreatic cancer (PC) remain rarely known. An increase in expression of SNHG16 in PC samples against adjacent normal tissues was shown here. Increased SNHG16 was linked intimately to the tumor-node-metastasis (TNM) stage, distant metastasis, tumor differentiation, and poor overall survival. Loss-of-function experiments revealed that SNHG16 knockdown suppressed the proliferation, formation of colonies, ability to migrate and invade in vitro, along with a lowered growth of the tumor in a mouse model. Mechanistically, SNHG16 might serve as a sponge competitive endogenous RNA (ceRNA) for miR-218-5p, thereby playing a role in regulating the expression of high mobility group box 1 (HMGB1) expression, a known direct miR-218-5p target in PC cells. These results provide novel insight into PC tumorigenesis and suggest that SNHG16 could serve as a likely therapeutic intervention in PC.


Assuntos
Proliferação de Células/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , Animais , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGB1/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes/genética
8.
BMC Cancer ; 19(1): 311, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947707

RESUMO

BACKGROUND: Feline injection-site sarcoma (FISS), an aggressive iatrogenic subcutaneous malignancy, is challenging to manage clinically and little is known about the molecular basis of its pathogenesis. Tumor transcriptome profiling has proved valuable for gaining insights into the molecular basis of cancers and for identifying new therapeutic targets. Here, we report the first study of the FISS transcriptome and the first cross-species comparison of the FISS transcriptome with those of anatomically similar soft-tissue sarcomas in dogs and humans. METHODS: Using high-throughput short-read paired-end sequencing, we comparatively profiled FISS tumors vs. normal tissue samples as well as cultured FISS-derived cell lines vs. skin-derived fibroblasts. We analyzed the mRNA-seq data to compare cancer/normal gene expression level, identify biological processes and molecular pathways that are associated with the pathogenesis of FISS, and identify multimegabase genomic regions of potential somatic copy number alteration (SCNA) in FISS. We additionally conducted cross-species analyses to compare the transcriptome of FISS to those of soft-tissue sarcomas in dogs and humans, at the level of cancer/normal gene expression ratios. RESULTS: We found: (1) substantial differential expression biases in feline orthologs of human oncogenes and tumor suppressor genes suggesting conserved functions in FISS; (2) a genomic region with recurrent SCNA in human sarcomas that is syntenic to a feline genomic region of probable SCNA in FISS; and (3) significant overlap of the pattern of transcriptional alterations in FISS with the patterns of transcriptional alterations in soft-tissue sarcomas in humans and in dogs. We demonstrated that a protein, BarH-like homeobox 1 (BARX1), has increased expression in FISS cells at the protein level. We identified 11 drugs and four target proteins as potential new therapies for FISS, and validated that one of them (GSK-1059615) inhibits growth of FISS-derived cells in vitro. CONCLUSIONS: (1) Window-based analysis of mRNA-seq data can uncover SCNAs. (2) The transcriptome of FISS-derived cells is highly consistent with that of FISS tumors. (3) FISS is highly similar to soft-tissue sarcomas in dogs and humans, at the level of gene expression. This work underscores the potential utility of comparative oncology in improving understanding and treatment of FISS.


Assuntos
Doenças do Gato/genética , Perfilação da Expressão Gênica , Reação no Local da Injeção/veterinária , Sarcoma/veterinária , Animais , Antineoplásicos/uso terapêutico , Gatos , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Cães , Genes Supressores de Tumor , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Reação no Local da Injeção/etiologia , Reação no Local da Injeção/genética , Masculino , Oncogenes/genética , Cultura Primária de Células , RNA Mensageiro/genética , Sarcoma/tratamento farmacológico , Sarcoma/etiologia , Sarcoma/genética , Análise de Sequência de RNA/métodos , Especificidade da Espécie , Células Tumorais Cultivadas
9.
Nat Genet ; 51(4): 611-617, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926969

RESUMO

Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences1-3. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence oncogenesis in a process termed onco-exaptation4. However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Here, we analyzed 7,769 tumors and 625 normal datasets from 15 cancer types, identifying 129 TE cryptic promoter-activation events involving 106 oncogenes across 3,864 tumors. Furthermore, we interrogated the AluJb-LIN28B candidate: the genetic deletion of the TE eliminated oncogene expression, while dynamic DNA methylation modulated promoter activity, illustrating the necessity and sufficiency of a TE for oncogene activation. Collectively, our results characterize the global profile of TE onco-exaptation and highlight this prevalent phenomenon as an important mechanism for promiscuous oncogene activation and ultimately tumorigenesis.


Assuntos
Elementos de DNA Transponíveis/genética , Neoplasias/genética , Oncogenes/genética , Linhagem Celular , Linhagem Celular Tumoral , Metilação de DNA/genética , Evolução Molecular , Células HEK293 , Humanos , Células K562 , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico/genética
10.
Biomed Pharmacother ; 111: 1297-1301, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841443

RESUMO

MIR210HG is a novel long noncoding RNA (lncRNA) and has been found to be overexpresed in osteosarcoma and glioma. However, the level of MIR210HG and its clinical significance in hepatocellular carcinoma (HCC) are not well known. In results of our research, MIR210HG expression was increased in HCC tissue samples and cells compared with paired adjacent normal liver tissue samples and normal liver cell line respectively, and a good marker to discriminate HCC tissues from non-tumorous tissues. MIR210HG high-expression was correlated advanced clinical stage, big tumor size, present vascular invasion and unfavorable histological differentiation. The survival analysis from our cohort and TCGA cohort consistently suggested that HCC patients with MIR210HG high-expression had poorer prognosis than HCC patients with MIR210HG low-expression. Furthermore, univariate and multivariate Cox regression analyses showed that MIR210HG high-expression was an independent unfavorable prognostic factor for overall survival in HCC patients. The in vitro study showed that silencing of MIR210HG depressed HCC cell proliferation, migration and invasion. In conclusion, MIR210HG functions as an oncogenic lncRNA in HCC, and may be a potential biomarker for predicting clinical progression and prognosis.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Oncogenes/genética , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Osteossarcoma/genética , Prognóstico
11.
Oncol Rep ; 41(4): 2471-2481, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816466

RESUMO

Gastric cancer (GC) is an aggressive and highly lethal gastrointestinal cancer, with an exceedingly poor prognosis. In the present study, the carcinogenic mechanism of human GC and the role of cell division cycle­associated 3 (CDCA3) were investigated. The expression levels of CDCA3 were investigated in GC samples and matched, peritumoral tissues by reverse transcription­quantitative polymerase chain reaction and immunohistochemical analysis. The effects of CDCA3 on cell proliferation were explored by Cell Counting Kit­8, colony formation, flow cytometric analysis and western blotting in vitro, and in vivo tumorigenesis in nude mice. The results demonstrated that CDCA3 expression was increased in human GC tissues compared with those in adjacent non­tumor tissues. Evaluation of the clinicopathological significance indicated that CDCA3 was closely associated with features of GC and patients with unfavorable overall survival times. CDCA3 overexpression resulted in the stimulation of cell growth and colony formation in vitro and xenograft tumors in vivo. Conversely, knockdown of CDCA3 inhibited these effects. Furthermore, the ectopic expression of CDCA3 in SGC7901 cells consistently promoted the cell cycle transition from the G0/G1 phase to the S phase; whereas knockdown of CDCA3 in BGC823 cells blocked the transition from the G0/G1 phase. Additionally, the present study revealed that the Ras signaling pathway was involved in CDCA3­mediated regulation of GC cell proliferation. CDCA3 activated the Ras signaling pathway to promote cell proliferation in vitro and in vivo in GC cells. Levels of CDCA3 greatly accelerated the progression of human GC. CDCA3 served as an oncogene, and may be a significant prognostic predictor and a novel therapeutic target for patients with GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Gástricas/patologia , Animais , Biomarcadores Tumorais/genética , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Seguimentos , Gastrectomia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Oncogenes/genética , Prognóstico , RNA Interferente Pequeno/metabolismo , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nat Rev Cancer ; 19(5): 283-288, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872802

RESUMO

Recent reports have demonstrated that oncogene amplification on extrachromosomal DNA (ecDNA) is a frequent event in cancer, providing new momentum to explore a phenomenon first discovered several decades ago. The direct consequence of ecDNA gains in these cases is an increase in DNA copy number of the oncogenes residing on the extrachromosomal element. A secondary effect, perhaps even more important, is that the unequal segregation of ecDNA from a parental tumour cell to offspring cells rapidly increases tumour heterogeneity, thus providing the tumour with an additional array of responses to microenvironment-induced and therapy-induced stress factors and perhaps providing an evolutionary advantage. This Perspectives article discusses the current knowledge and potential implications of oncogene amplification on ecDNA in cancer.


Assuntos
Cromossomos/genética , Amplificação de Genes/genética , Neoplasias/genética , Neoplasias/patologia , Oncogenes/genética , Animais , Variações do Número de Cópias de DNA/genética , Humanos , Microambiente Tumoral/genética
13.
Oncol Rep ; 41(4): 2137-2147, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816499

RESUMO

Basic helix­loop­helix family member e41 (BHLHE41) serves an important role in regulating cell differentiation, circadian rhythms and the response to hypoxia. However, the roles of BHLHE41 in clear cell renal cell carcinoma (ccRCC) remain unclear. The aim of the present study was to analyze the expression of BHLHE41 in ccRCC and investigate the effect of downregulated BHLHE41 on the growth and migration of ccRCC cells. The expression of BHLHE41 in ccRCC was demonstrated to be significantly increased in gene expression microarray datasets and RNA sequencing data. Reverse transcription­quantitative polymerase chain reaction and western blot analysis demonstrated that BHLHE41 expression in fresh ccRCC tissues was increased, compared with than their adjacent non­tumorous controls. BHLHE41 knockdown significantly reduced cell proliferation and migration of A498 and CAKI­1 cells. For the investigation of the molecules mediated by BHLHE41, immunoblotting analyses revealed that phosphorylation of p70S6K and protein levels of E­cadherin were reduced. Additionally, a lower frequency methylation was determined in the BHLHE41 3'­untranslated region through The Cancer Genome Atlas dataset analysis for the first time. These observations demonstrated that BHLHE41 could be a biomarker and an oncogene for ccRCC.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Metilação de DNA/genética , Conjuntos de Dados como Assunto , Feminino , Humanos , Rim/patologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Oncogenes/genética , Regulação para Cima/genética
14.
BMC Cancer ; 19(1): 253, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898113

RESUMO

BACKGROUND: Despite its relatively low incidence, pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths because of the aggressive growth/metastasis of the tumor, the lack of early symptoms, and the poor treatment options. Basic research to identify potential therapeutic targets for PDAC is greatly needed. METHODS: We used a negative-selection genome-wide CRISPR screen to identify essential genes in the PANC-1 human pancreatic carcinoma cell line. We validated the top hits with follow-up siRNA screens, using the HPNE, HPAF-II, AsPC-1, and Mia PaCa-2 cell lines. RESULTS: The PSMA6 gene was an identified candidate hit after the CRISPR screen, siRNA validation screen, and siRNA deconvolution screen. Spheroid formation assays and flow cytometry analysis showed that PSMA6 is critical for survival in many pancreatic ductal carcinoma cell models. Lastly, as PSMA6 protein is a proteosomal subunit of the 20S core complex, we showed that bortezomib, a proteasome inhibitor, was especially toxic in PANC-1 cells. CONCLUSIONS: Further study of PSMA6 and the proteasome subunit that it encodes, along with other hits identified in our CRISPR screens, may provide valuable insights into potential therapeutic targets for PDAC.


Assuntos
Carcinoma Ductal Pancreático/genética , Oncogenes/genética , Neoplasias Pancreáticas/genética , Complexo de Endopeptidases do Proteassoma/genética , Bortezomib/farmacologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Genoma Humano/genética , Genômica/métodos , Humanos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/farmacologia , Inibidores de Proteassoma/farmacologia , RNA Interferente Pequeno/genética , Esferoides Celulares
15.
In Vivo ; 33(2): 303-311, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30804107

RESUMO

AIM: To demonstrate that Fanconi anemia complementation group D2-deficient (Fancd2-/-) hematopoietic progenitor cell lines can be transformed by transfection with a plasmid containing either the E6 or E7 oncogene of human papillomavirus (HPV) to generate malignant plasmacytoma-inducing cell lines. MATERIALS AND METHODS: In order to determine whether a single HPV type 16 (HPV16) oncogene induced malignant transformation, Fancd2-/- and Fancd2+/+ interleukin 3 (IL3)-dependent hematopoietic progenitor cell lines were transfected with plasmids containing E6 or E7 oncogene, or control empty plasmid. RESULTS: Fancd2-/- but not Fancd2+/+ cells were transformed into malignant IL3-independent cells by both E6, and E7 oncogenes, but not by empty plasmid. Hematopoietic cell lines and tumors induced by Fancd2-/- E6 and Fancd2-/- E7 cell lines were positive for each respective HPV RNA and protein. CONCLUSION: A single HPV16 oncogene is adequate to produce malignant transformation of Fancd2-/- hematopoietic cells.


Assuntos
Transformação Celular Neoplásica/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Células-Tronco Hematopoéticas/virologia , Interleucina-3/genética , Linhagem Celular Tumoral , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/patogenicidade , Humanos , Proteínas Oncogênicas Virais/genética , Oncogenes/genética , Proteínas E7 de Papillomavirus/genética , Plasmídeos/genética , Proteínas Repressoras/genética , Transfecção/métodos
16.
Int J Mol Sci ; 20(3)2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759825

RESUMO

The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome. These neoplasms may or may not transform to overt acute leukemia over time. Thus, depending on the type and number of somatic mutations, clonal hematopoiesis (CH) can be divided into CH with indeterminate potential (CHIP) and CH with oncogenic potential (CHOP). Whereas CHIP mutations per se usually create the molecular background of a neoplastic process, CHOP mutations are disease-related or even disease-specific lesions that trigger differentiation and/or proliferation of neoplastic cells. Over time, the acquisition of additional oncogenic events converts preleukemic neoplasms into secondary acute myeloid leukemia (sAML). In the present article, recent developments in the field are discussed with a focus on CHOP mutations that lead to distinct myeloid neoplasms, their role in disease evolution, and the impact of additional lesions that can drive a preleukemic neoplasm into sAML.


Assuntos
Carcinogênese/genética , Hematopoese/genética , Leucemia Mieloide Aguda/genética , Oncogenes/genética , Carcinogênese/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Mutação/genética , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia
17.
Pathol Res Pract ; 215(3): 600-606, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30712887

RESUMO

Gliomas are the most common primary brain malignant tumors in humans. Glioblastoma multiforme(GBM) is the most malignant intracranial tumor with a relatively poor prognosis. There promote us to find effective anti-cancer therapies to reduce cancer mortality. By using bioinformatic analysis, we found SSFA2 as a gene with elevated expression in the glioma tissues. We detected the expression of SSFA2 in glioma tissues and in the glioma cell lines, as well as in normal brain tissues. SSFA2 expression was higher in glioma tissues, especially in glioblastoma multiforme than normal brain tissues. Subsequently, we found that down-regulate SSFA2 in glioma cell lines can regulate the cell cycle to reduce the proliferation ability and induce the early apoptosis rate in shSSFA2 cells relative to control cells. Moreover, we found that down-regulate SSFA2 in glioma cell line U87(shSSFA2-U87) inhibited the growth effectiveness compared to the control cell line U87. These result reveals us that SSFA2 may act as oncogene to promote the progression of glioma. For further research specific mechanisms of SSFA2 in gliomas, we used the gene chip to detect the downstream gene in U87. We found that 30 genes also may be as target gene of SSFA2, and we testify the protein expression by western-blot. The result reveal that IL1A, IL1B and CDK6 as target gene of SSFA2 to regulate the progression of glioma. These finding suggest that SSFA2 could be a new therapeutic target for gliomas.


Assuntos
Antígenos de Superfície/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/patologia , Adulto , Idoso , Animais , Apoptose/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Oncogenes/genética
18.
Gene ; 697: 57-66, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30796966

RESUMO

Oncogenes can potentially cause uncontrolled cell growth, leading to cancer development, and these genes are normally mutated and over-expressed in tumor cells. Genomic alteration of oncogenes might result in oncogenesis and promotion of cancer progression. To date, researchers have focused mainly on the roles of oncogenes in particular cancers, but investigation of oncogenes with gain-of-function mutations in multiple cancer types are less represented in the literature. Furthermore, the effect of those gain-of-function are not validated in gene expression level. To meet this demand, we performed a systematic analysis of gene expression in oncogenes to identify the occurrence of gain-of-function mutations in pan-cancer. We identified 33,551 oncogenic mutations in 5000 samples. From our analysis, we identified three tissues with the highest frequency of gain-of-functional oncogenic mutations in hundreds of samples: breast (739 samples), central nervous system (646 samples) and large intestine (498 samples). By further counting the number of occurrences of oncogenes across cancer types, we identified a list cross-cancer mutational signatures of 99 oncogenes highly mutated in >400 samples in breast, central nervous system and large intestine samples. By further overlapping with gene expression data in the matched tumor samples, we further identified 1875 gain-of-functional mutations/events with consistent gene up-regulation in 1031 samples from multiple cancers. This result may offer additional insight into the relationship between gene dosage and oncogenesis and maybe useful in targeted cancer therapy. In summary, this study provides the first globally examining on the genetic alteration of oncogenes across cancer types. Clinical association analysis has shown that these 99 genes have a significant effect on survival.


Assuntos
Mutação com Ganho de Função/genética , Neoplasias/genética , Oncogenes/genética , Carcinogênese , Bases de Dados Genéticas , Dosagem de Genes/genética , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Genômica , Humanos , Mutação , Transcriptoma/genética
19.
Gastroenterology ; 156(6): 1731-1741, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30738047

RESUMO

BACKGROUND & AIMS: In a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib. METHODS: We obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model. RESULTS: Decreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders. CONCLUSION: We identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. ClinicalTrials.gov number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/sangue , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Idoso , Angiopoietina-1/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Quimiocina CCL3/sangue , Cistatina B/sangue , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Mutação , Oncogenes/genética , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Receptores Depuradores Classe E/sangue , Taxa de Sobrevida , Transcriptoma , Fator de Crescimento Transformador beta1/sangue , Proteínas Supressoras de Tumor/genética , Fator A de Crescimento do Endotélio Vascular/genética , alfa-Fetoproteínas/metabolismo , beta Catenina/genética
20.
Oncogene ; 38(18): 3504-3520, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30651601

RESUMO

The underlying forces that shape mutational patterns within any type of cancer have been poorly characterized. One of the best preserved exclusionary relationships is that between BRAF(V600E) and NRAS(Q61) in melanomas. To explore possible mechanisms which could explain this phenomenon, we overexpressed NRAS(Q61) in a set of BRAF(V600E) melanoma lines and vice versa. Controlled expression of a second activating oncogene led to growth arrest ("synthetic suppression") in a subset of cells, which was accompanied by cell cycle arrest and senescence in several melanoma cell lines along with apoptosis. Through differential gene expression analysis, we identified SPRY4 as the potential mediator of this synthetic response to dual oncogene suppression. Ectopic introduction of SPRY4 recapitulated the growth arrest phenotype of dual BRAF(V600E)/NRAS(Q61) expression while SPRY4 depletion led to a partial rescue from oncogenic antagonism. This study thus defined SPRY4 as a potential mediator of synthetic suppression, which is likely to contribute to the observed exclusivity between BRAF(V600E) and NRAS(Q61R) mutations in melanoma. Further leverage of the SPRY4 pathway may also hold therapeutic promise for NRAS(Q61) melanomas.


Assuntos
Proliferação de Células/genética , GTP Fosfo-Hidrolases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melanoma/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Oncogenes/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Animais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Expressão Gênica/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação/genética , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA