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1.
Cancers (Basel) ; 13(19)2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34638280

RESUMEN

Peritoneal metastases are frequently found in high-grade serous carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of ovarian cancer cells cocultured in omental conditioned medium (OCM), which mimics the ascites microenvironment, and in vivo tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and fatty acid ß-oxidation in ovarian cancer cells, indicating that miR-33b may play a novel tumor suppressor role in the lipid-mediated oncogenic properties of metastatic ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of fatty acid synthase (FASN) and carnitine palmitoyltransferase 1A (CPT1A) in modulating lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of ovarian cancer cells. Thus, our data suggest that a lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates ovarian cancer peritoneal metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling.

3.
Clin Epigenetics ; 13(1): 142, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34294135

RESUMEN

BACKGROUND: In contrast to stable genetic events, epigenetic changes are highly plastic and play crucial roles in tumor evolution and development. Epithelial ovarian cancer (EOC) is a highly heterogeneous disease that is generally associated with poor prognosis and treatment failure. Profiling epigenome-wide DNA methylation status is therefore essential to better characterize the impact of epigenetic alterations on the heterogeneity of EOC. METHODS: An epigenome-wide association study was conducted to evaluate global DNA methylation in a retrospective cohort of 80 mixed subtypes of primary ovarian cancers and 30 patients with high-grade serous ovarian carcinoma (HGSOC). Three demethylating agents, azacytidine, decitabine, and thioguanine, were tested their anti-cancer and anti-chemoresistant effects on HGSOC cells. RESULTS: Global DNA hypermethylation was significantly associated with high-grade tumors, platinum resistance, and poor prognosis. We determined that 9313 differentially methylated probes (DMPs) were enriched in their relative gene regions of 4938 genes involved in small GTPases and were significantly correlated with the PI3K-AKT, MAPK, RAS, and WNT oncogenic pathways. On the other hand, global DNA hypermethylation was preferentially associated with recurrent HGSOC. A total of 2969 DMPs corresponding to 1471 genes were involved in olfactory transduction, and calcium and cAMP signaling. Co-treatment with demethylating agents showed significant growth retardation in ovarian cancer cells through differential inductions, such as cell apoptosis by azacytidine or G2/M cell cycle arrest by decitabine and thioguanine. Notably, azacytidine and decitabine, though not thioguanine, synergistically enhanced cisplatin-mediated cytotoxicity in HGSOC cells. CONCLUSIONS: This study demonstrates the significant association of global hypermethylation with poor prognosis and drug resistance in high-grade EOC and highlights the potential of demethylating agents in cancer treatment.


Asunto(s)
Resistencia a Medicamentos/genética , Epigenoma/genética , Neoplasias Ováricas/genética , Metilación de ADN/efectos de los fármacos , Resistencia a Medicamentos/fisiología , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/mortalidad , Estudios Retrospectivos
4.
Cancers (Basel) ; 12(10)2020 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-33053752

RESUMEN

Immunocompetent metastatic head and neck cancer (HNC) models, although scarce, can help understanding cancer progression and therapy responses in vivo. Their comprehensive genome characterizations are essential for translational research. We first exome-sequenced the two most widely used spontaneous metastatic immunocompetent models, namely AT-84 and SCC VII, followed by comprehensive genomic analyses with three prior-sequenced models (MOC2, MOC2-10, and 4MOSC2), together with patient tumors for utility assessment. AT-84 and SCC VII bear high HNC tumor resemblance regarding mutational signatures-Trp53, Fanconi anemia, and MAPK and PI3K pathway defects. Collectively, the five models harbor genetic aberrations across 10 cancer hallmarks and 14 signaling pathways and machineries (metabolic, epigenetic, immune evasion), to extents similar in patients. Immune defects in HLA-A (H2-Q10, H2-Q4, H2-Q7, and H2-K1), Pdcd1, Tgfb1, Il2ra, Il12a, Cd40, and Tnfrsf14 are identified. Invasion/metastatic genome analyses first highlight potential druggable ERBB4 and KRAS mutations, for advanced/metastatic oral cavity cancer, as well as known metastasis players (Muc5ac, Trem3, Trp53, and Ttn) frequently captured by all models. Notable immunotherapy and precision druggable targets (Pdcd1, Erbb4, Fgfr1, H/Kras, Jak1, and Map2k2) and three druggable hubs (RTK family, MAPK, and DNA repair pathways) are frequently represented by these models. Immunocompetent metastatic HNC models are worth developing to address therapy- and invasion/metastasis-related questions in host immunity contexts.

5.
Curr Cancer Drug Targets ; 15(4): 327-36, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25714698

RESUMEN

The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK, etc.). Clinical use of ALK inhibitors for "ALK-rearranged" lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK-gene rearrangement, can be oncogenic. Thus, ALK mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK-mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK mutation studies in various cancer types.


Asunto(s)
Antineoplásicos/farmacología , Terapia Molecular Dirigida/métodos , Mutación , Neoplasias , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico , Carcinogénesis/genética , Amplificación de Genes , Reordenamiento Génico , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias/clasificación , Neoplasias/genética , Neoplasias/terapia
6.
BMC Microbiol ; 13: 104, 2013 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-23663545

RESUMEN

BACKGROUND: Avian influenza remains a serious threat to human health. The consequence of human infection varies markedly among different subtypes of avian influenza viruses. In addition to viral factors, the difference in host cellular response is likely to play a critical role. This study aims at elucidating how avian influenza infection perturbs the host's miRNA regulatory pathways that may lead to adverse pathological events, such as cytokine storm, using the miRNA microarray approach. RESULTS: The results showed that dysregulation of miRNA expression was mainly observed in highly pathogenic avian influenza A H5N1 infection. We found that miR-21*, miR-100*, miR-141, miR-574-3p, miR-1274a and miR1274b were differentially expressed in response to influenza A virus infection. Interestingly, we demonstrated that miR-141, which was more highly induced by H5N1 than by H1N1 (p < 0.05), had an ability to suppress the expression of a cytokine - transforming growth factor (TGF)-ß2. This was supported by the observation that the inhibitory effect could be reversed by antagomiR-141. CONCLUSIONS: Since TGF-ß2 is an important cytokine that can act as both an immunosuppressive agent and a potent proinflammatory molecule through its ability to attract and regulate inflammatory molecules, and previous report showed that only seasonal influenza H1N1 (but not the other avian influenza subtypes) could induce a persistent expression of TGF-ß2, we speculate that the modulation of TGF-ß2 expression by different influenza subtypes via miR-141 might be a critical step for determining the outcome of either normal or excessive inflammation progression.


Asunto(s)
Células Epiteliales/virología , Interacciones Huésped-Patógeno , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , MicroARNs/biosíntesis , Línea Celular , Perfilación de la Expresión Génica , Humanos
7.
Antivir Ther ; 16(2): 237-47, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21447873

RESUMEN

BACKGROUND: Little is known about the virological and inflammatory responses of severe pandemic 2009 influenza A(H1N1) virus pneumonia during antiviral treatment. METHODS: In a prospective observational study, we recruited consecutive adults hospitalized with confirmed pandemic 2009 H1N1 infection during a 16-week period. Nasopharyngeal aspirate and non-respiratory samples (blood, stool and urine) were collected at presentation, and serial nasopharyngeal flocked swabs (NPFS) and tracheal aspirates (TA) were collected after initiating oseltamivir treatment for quantitative viral RNA assay, using real-time reverse transcriptase-PCR. Serial plasma samples were collected for cytokine/chemokine assay using cytometric bead array. Patients with severe pneumonia (lung infiltrates and hypoxaemia) were compared to those with milder illnesses. RESULTS: A total of 66 patients were studied (mean age 43 ±20 years); 28 (42%) developed severe pneumonia, of whom 10 (15%) required intubation. Severe pneumonia was associated with older age, dyspnoea, delayed presentation >2 days from onset, extrapulmonary virus detection (13-28%) and higher viral concentration despite late-presentation (multiple linear regression, ß=0.94, 95% confidence interval 0.15-1.74; P=0.02). Patients with severe pneumonia exhibited slow viral clearance with oseltamivir treatment, particularly in the lower respiratory tract (median [interquartile range] durations of RNA positivity after antiviral initiation were NPFS 6.0 days [3.0-8.0], TA 11.0 days [7.8-14.3] versus milder illness group NPFS of 2.0 days [1.0-3.0] days; P<0.01). High viral load in lower respiratory tract despite upper-tract RNA negativity and viral rebound after stopping treatment were noted in some patients. H275Y mutation was absent. High plasma levels of interleukin (IL)-6, CXCL-8 (IL-8), CCL2 (monocyte chemoattractant protein-1) and soluble tumour necrosis factor receptor-1 were observed, which correlated with the extent and progression of pneumonia in hospital. CONCLUSIONS: In severe 2009 H1N1 pneumonia, viral clearance is slow with treatment, particularly in the lower respiratory tract. A more sustained antiviral regime appears warranted.


Asunto(s)
Antivirales/uso terapéutico , Hospitalización/estadística & datos numéricos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/epidemiología , Pandemias , Adolescente , Adulto , Citocinas/metabolismo , Femenino , Humanos , Inflamación/inmunología , Subtipo H1N1 del Virus de la Influenza A/fisiología , Gripe Humana/tratamiento farmacológico , Gripe Humana/inmunología , Gripe Humana/fisiopatología , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Nasofaringe/virología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/fisiopatología , Neumonía Viral/virología , ARN Viral/análisis , Índice de Severidad de la Enfermedad , Tráquea/virología , Adulto Joven
8.
J Med Virol ; 82(8): 1295-8, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20572070

RESUMEN

In early 2008, a sudden increase in oseltamivir (Tamiflu)-resistant influenza A H1N1 viruses was reported from several European countries. This resistant virus has spread globally and accounted for more than 95% of H1N1 viruses isolated in the following influenza season. A continuous close monitoring on the prevalence of this resistant virus is necessary to rationalize the choice of antiviral agents. The resistance of this novel strain to oseltamivir is conferred by an amino acid substitution from histidine to tyrosine at position 275 (H275Y) of the neuraminidase protein. This study developed and evaluated allele-specific conventional reverse-transcription polymerase chain reaction (cRT-PCR) assays to provide a simple, rapid, and low-cost option for discriminating oseltamivir-resistant influenza A H1N1 (H275Y) mutant from wild-type viruses. The evaluation was based on 90 nasopharyngeal aspirate specimens collected before, during the initial phase and at the peak of emergence of resistance. Thirty-six (40%) of these specimens were H275Y mutant, whereas the other 54 (60%) were wild-type viruses as confirmed by sequencing of the neuraminidase gene. When applied directly on the 90 nasopharyngeal aspirate specimens, the allele-specific cRT-PCR assays achieved an unequivocal discrimination for 82 (91%) specimens. Further improvement in performance is expected when applied to cell culture isolates with a higher viral titer. These allele-specific cRT-PCR assays can be a simple, low-cost option for large-scale screening of influenza isolates.


Asunto(s)
Sustitución de Aminoácidos/genética , Farmacorresistencia Viral , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Neuraminidasa/genética , Oseltamivir/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Proteínas Virales/genética , Virología/métodos , Antivirales/farmacología , Humanos , Subtipo H1N1 del Virus de la Influenza A/clasificación , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/virología , Tamizaje Masivo/métodos , Datos de Secuencia Molecular , Nasofaringe/virología , ARN Viral/genética , Sensibilidad y Especificidad , Análisis de Secuencia de ADN
9.
Hepatology ; 45(6): 1382-9, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17539025

RESUMEN

UNLABELLED: HCC is a common cause of morbidity and mortality. For patients who are not candidates for curative surgery, systemic chemotherapy is one of the standard treatments. In parts of China and the Far East, over 80% of HCC patients have chronic HBV infection. In this study, we aimed to assess the relationship between pre-chemotherapy HBV viral load and the survival of HCC patients. HBV infection status was determined prior to chemotherapy in 188 patients, 170 of whom had evidence of HBV chronic infection/exposure (160 hepatitis B surface antigen [HBsAg]-positive, 10 HBsAg-negative/hepatitis B core antibody-positive). Of these, 125 had pretreatment HBV DNA levels determined via real-time PCR. Virological data were analyzed using conventional clinical variables to identify factors that influenced survival. Multivariate analysis revealed that high total bilirubin (P = 0.0016; hazard ratio = 1.040 per 1 muM increase; 95% CI 1.015-1.065), HCV infection (P = 0.0095; hazard ratio = 6.955; 95% CI 1.606-30.129), and high HBV DNA level (P = 0.0217; hazard ratio = 1.650; 95% CI 1.076-2.531) affected survival significantly. Exploratory analysis revealed that high levels of pretreatment HBV DNA had a significantly higher incidence of severe hepatitis during chemotherapy. CONCLUSION: For HCC patients with HBV chronic infection/exposure, a high viral load prior to treatment is an adverse factor for survival and may be associated with a higher incidence of severe hepatitis during chemotherapy. Future strategies to improve the prognosis of HCC patients undergoing chemotherapy should consider supportive therapy that incorporates antiviral therapies to reduce HBV viral load.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Hepatitis B Crónica/mortalidad , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Carga Viral , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Antivirales/farmacología , Carcinoma Hepatocelular/virología , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/farmacología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Proteínas Recombinantes , Análisis de Supervivencia
10.
J Cell Biochem ; 97(4): 795-812, 2006 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-16237706

RESUMEN

Ethanolic extract of Phyllanthus nanus (P. nanus) treatment exhibited potent antiviral activity against Hepatitis B virus (HBV). The effects of these extracts on HBV in the HBV genome integrated cell lines--Alexander cells and HepG2 2.2.15 cells were examined. Experimental results showed that the ethanolic extract of P. nanus produced suppressive effect on HBsAg secretion and HBsAg mRNA expression. The extract also inhibited HBV replication as measured by HBV DNA level in vitro. In addition, using a duck HBV (DHBV) primary culture model, the P. nanus ethanolic extract suppressed viral replication of DHBV in DHBV infected primary duck hepatocytes. The gene expression pattern in Alexander cells that had been treated with the ethanolic extract of P. nanus was also revealed by microarray techniques. The microarray results indicated that there was up-regulation of expression of several genes, including annexin A7 (Axn7). The subcellular localization of Axn7 and anti-HBV effect of Axn7 over-expression in Alexander cells were also investigated. Results showed that expression of Axn7-GFP fusion protein are localized around the secretory vesicles and could cause a decrease in HBsAg secretion in Alexander cells. Axn7 protein might play an important role in the medicinal effect of the active principle(s) of P. nanus.


Asunto(s)
Virus de la Hepatitis B del Pato/efectos de los fármacos , Virus de la Hepatitis B del Pato/genética , Virus de la Hepatitis B/efectos de los fármacos , Hepatocitos/virología , Phyllanthus/química , Replicación Viral/efectos de los fármacos , Animales , Anexina A7/metabolismo , Anexina A7/fisiología , Antivirales/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , ADN Viral/metabolismo , Relación Dosis-Respuesta a Droga , Patos , Etanol/farmacología , Regulación de la Expresión Génica , Antígenos de Superficie de la Hepatitis B/metabolismo , Virus de la Hepatitis B del Pato/inmunología , Análisis por Micromatrices , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Transfección , Proteínas del Envoltorio Viral/metabolismo
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