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1.
Anticancer Res ; 39(9): 4865-4876, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519589

RESUMO

BACKGROUND/AIM: Hypoxia promotes tumor proliferation and metastasis in colorectal cancer (CRC). Since the tumor microenvironment is generally characterized by hypoxia, its understanding is important for cancer therapy. We hypothesized that hypoxia promotes the mitochondrial function, mobility, and proliferation of CRC by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). MATERIALS AND METHODS: To assess the effects of PGC-1α under hypoxia, we investigated the mitochondrial function, cell motility, and sphere formation as well as proliferation and apoptosis of CRC. RESULTS: Under hypoxia, we confirmed the increased expression of PGC-1α and reduced production of reactive oxygen species (ROS) by activating anti-oxidant enzymes. Also, up-regulation of PGC-1α enhanced the motility, sphere formation, and proliferation of CRC. Under the presence of the anti-cancer drug 5-fluorouracil (5FU), up-regulation of PGC-1α under hypoxia promoted resistance of CRC against 5FU-induced apoptosis. CONCLUSION: Targeting PGC-1α could to be a powerful strategy for CRC therapy.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Hipóxia/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Apoptose , Catalase/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
2.
J Cancer Res Clin Oncol ; 145(10): 2413-2422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31492983

RESUMO

PURPOSE: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that regulates centriole duplication. PLK4 deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability and, consequently, tumorigenesis. Therefore, PLK4 has emerged as a therapeutic target for the treatment of multiple cancers. In this review, we summarize the critical role of centrosome amplification and PLK4 in cancer. We also highlight recent advances in the development of PLK4 inhibitors and discuss potential combination therapies for cancer. METHODS: The relevant literature from PubMed is reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: PLK4 is aberrantly expressed in multiple cancers and has prognostic value. Targeting PLK4 with inhibitors suppresses tumor growth in vitro and in vivo. CONCLUSIONS: PLK4 plays an important role in centrosome amplification and tumor progression. PLK4 inhibitors used alone or in combination with other drugs have shown significant anticancer efficacy, suggesting a potential therapeutic strategy for cancer. The results of relevant clinical trials await evaluation.


Assuntos
Biomarcadores Tumorais , Neoplasias/etiologia , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centrossomo/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Especificidade de Órgãos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Toxicol Lett ; 313: 150-158, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276768

RESUMO

Ochratoxin A (OTA), one of the most abundant food-contaminating mycotoxins, is a possible carcinogen to humans. We previously demonstrated that long-term (40 weeks) OTA exposure induces the malignant transformation of human gastric epithelium cells (GES-1) in vitro. However, the specific mechanism underlying OTA-induced gastric carcinogenesis is complex. In the present study, we used 2-DE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF MS) combined with bioinformatics and immunoblotting to investigate the differentially expressed proteins between GES-1 and OTA-malignant transformed GES-1 cells (OTA-GES-1T cells) in vitro. We found that four differentially expressed proteins were identified after malignant transformation, including actin, cytoplasmic 1 (ACTB), F-actin-capping protein subunit alpha-1 (CAPZA1), Annexin A3 (ANXA3), thioredoxin peroxidase B from red blood cells (TPx-B) and Fibrinogen beta B (Fibrinogen ß). Among the differentially expressed proteins, the effect of Annexin A3 was analyzed by MTT assay, western blot, cell cycle analysis, wound healing assay, Transwell assay, and colony formation assay in OTA-GES-1T cells. The results showed that inhibition of Annexin A3 by siRNA effectively prevented the proliferation, migration, and invasion abilities of OTA-GES-1T cells. Collectively, the results of this study will guide future research on OTA carcinogenicity.


Assuntos
Anexina A3/metabolismo , Carcinógenos/toxicidade , Transformação Celular Neoplásica/induzido quimicamente , Células Epiteliais/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Ocratoxinas/toxicidade , Neoplasias Gástricas/induzido quimicamente , Anexina A3/genética , Western Blotting , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Biologia Computacional , Eletroforese em Gel Bidimensional , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Invasividade Neoplásica , Proteômica/métodos , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
4.
Gastroenterology ; 157(3): 744-759.e4, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31154022

RESUMO

BACKGROUND & AIMS: Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis. METHODS: Colon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS: Levels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS: Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.


Assuntos
Adenocarcinoma/prevenção & controle , Colo/enzimologia , Neoplasias do Colo/prevenção & controle , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Proteínas Nucleares/metabolismo , PPAR alfa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Anticarcinógenos/farmacologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Colo/patologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/efeitos dos fármacos , Bases de Dados Genéticas , Modelos Animais de Doenças , Fenofibrato/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , PPAR alfa/agonistas , PPAR alfa/deficiência , PPAR alfa/genética , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais
5.
Nat Immunol ; 20(7): 835-851, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160797

RESUMO

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.


Assuntos
Apresentação do Antígeno/imunologia , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/imunologia , Oncogenes , RNA Longo não Codificante/genética , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Adenoma/genética , Adenoma/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Clin Pathol ; 72(8): 513-519, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154423

RESUMO

The importance of circular RNAs (circRNAs) in pathological processes like cancer is evident. Among the circRNAs, recent studies have brought circPVT1 under focus as the most potent oncogenic non-coding RNA. Recent studies on various aspects of circPVT1, including its biogenesis, molecular alteration and its probable role in oncogenesis, have been conducted for research and clinical interest. In this review, a first attempt has been made to summarise the available data on circPVT1 from PubMed and other relevant databases with special emphasis on its role in development, progression and prognosis of various malignant conditions. CircPVT1 is derived from the same genetic locus encoding for long non-coding RNA lncPVT1; however, existing literature suggested circPVT1 and lncPVT1 are transcripted independently by different promoters. The interaction between circRNA and microRNA has been highlighted in majority of the few malignancies in which circPVT1 was studied. Besides its importance in diagnostic and prognostic procedures, circPVT1 seemed to have huge therapeutic potential as evident from differential drug response of cancer cell line as well as primary tumors depending on expression level of the candidate. circPVT1 in cancer therapeutics might be promising as a biomarker to make the existing treatment protocol more effective and also as potential target for designing novel therapeutic intervention.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias/genética , RNA/genética , Animais , Biomarcadores Tumorais/biossíntese , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas de Diagnóstico Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Valor Preditivo dos Testes , Prognóstico , RNA/biossíntese , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/metabolismo
7.
Environ Pollut ; 252(Pt A): 607-615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185349

RESUMO

Coke oven emissions (COEs) are common particle pollutants in occupational environment and the major constituents of COEs are polycyclic aromatic hydrocarbons (PAHs). Previously, we identified aberrant methylation of the fms related tyrosine kinase 1 (FLT1) gene over the course of benzo(a)pyrene (BaP)-induced cell transformation via genome-wide methylation array. To quantify FLT1 methylation, we established a bisulfite pyrosequencing assay and examined the FLT1 hypermethylation in several human cancers. The results revealed that 70.0% (21/30 pairs) of lung cancers harbored hypermethylated FLT1 and concomitant suppression of gene expression compared to the adjacent tissues. This implies that FLT1 hypermethylation might play a role in malignant cell transformation. In addition, FLT1 hypermethylation and gene suppression appeared in primary human lymphocytes in a dose-response manner following COEs treatment. To explore whether FLT1 methylation is correlated with COEs exposure and DNA damage, we recruited 144 male subjects who had been exposed to high levels of COEs and 84 male control subjects. Notably, the FLT1 methylation in peripheral blood lymphocytes (PBLCs) of the COEs-exposed group (19.8 ±â€¯3.2%) was enhanced by 17.9% compared to that of the control group (16.8 ±â€¯2.8%) (P < 0.001). The FLT1 methylation status was positively correlated with urinary 1-hydroxypyrene (1-OHP) levels, an internal exposure marker of PAHs (ß = 0.029, 95% CI = 0.010-0.048, P = 0.003) and positively correlated with DNA damage (ßOTM = 0.024, 95% CI = 0.007-0.040, P = 0.005; ßTail DNA = 0.035, 95% CI = 0.0017-0.054, P < 0.001) indicated by comet assay. Taken together, these findings indicate that FLT1 might be a tumor suppressor, and its hypermethylation might contribute to PAHs-induced carcinogenicity.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Adulto , Poluentes Ocupacionais do Ar/análise , Benzo(a)pireno/metabolismo , Biomarcadores/metabolismo , Transformação Celular Neoplásica/metabolismo , Coque , Ensaio Cometa , Dano ao DNA , Metilação de DNA , Humanos , Linfócitos/metabolismo , Masculino , Exposição Ocupacional , Hidrocarbonetos Policíclicos Aromáticos/análise , Pirenos/metabolismo , Sulfitos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular
8.
J Mass Spectrom ; 54(8): 693-703, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31116903

RESUMO

Cervicovaginal fluid (CVF) is a valuable source of clinical information about the female reproductive tract in both nonpregnant and pregnant women. The aim of this study is to specify the CVF proteome at different stages of cervix neoplastic transformation by label-free quantitation approach based on liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The proteome composition of CVF from 40 women of reproductive age with human papillomavirus (HPV)-associated cervix neoplastic transformation (low-grade squamous intraepithelial lesion [LSIL], high-grade squamous intraepithelial lesion [HSIL], and CANCER) was investigated. Hierarchical clustering and principal component analysis (PCA) of the proteomic data obtained by a label-free quantitation approach show the distribution of the sample set between four major clusters (no intraepithelial lesion or malignancy [NILM], LSIL, HSIL and CANCER) depending on the form of cervical lesion. Multisample ANOVA with subsequent Welch's t test resulted in 117 that changed significantly across the four clinical stages, including 27 proteins significantly changed in cervical cancer. Some of them were indicated as promising biomarkers previously (ACTN4, VTN, ANXA1, CAP1, ANXA2, and MUC5B). CVF proteomic data from the discovery stage were analyzed by the partial least squares-discriminant analysis (PLS-DA) method to build a statistical model, allowing to differentiate severe dysplasia (HSIL and CANCER) from the mild/normal stage (NILM and LSIL), and receiver operating characteristic (ROC) area under the curve (AUC) were obtained on an independent set of 33 samples. The sensitivity of the model was 77%, and the specificity was 94%; AUC was equal to 0.87. CVF proteome proved to be reflect the stage of cervical epithelium neoplastic process.


Assuntos
Líquidos Corporais/metabolismo , Transformação Celular Neoplásica/metabolismo , Colo do Útero/metabolismo , Proteoma/análise , Neoplasias do Colo do Útero/diagnóstico , Vagina/metabolismo , Adulto , Biomarcadores/análise , Transformação Celular Neoplásica/patologia , Colo do Útero/patologia , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Papillomaviridae/fisiologia , Infecções por Papillomavirus/metabolismo , Gravidez , Proteoma/metabolismo , Espectrometria de Massas em Tandem , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Vagina/patologia , Esfregaço Vaginal
9.
Int J Mol Sci ; 20(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035338

RESUMO

Ubiquitination and deubiquitination of cellular proteins are reciprocal reactions catalyzed by ubiquitination-related enzymes and deubiquitinase (DUB) which regulate almost all cellular processes. Marek's disease virus (MDV) encodes a viral DUB that plays an important role in the MDV pathogenicity. Chicken CD4+ T-cell lymphoma induced by MDV is a key contributor to multiple visceral tumors and immunosuppression of chickens with Marek's disease (MD). However, alterations in the ubiquitylome of MDV-induced T lymphoma cells are still unclear. In this study, a specific antibody against K-ε-GG was used to isolate ubiquitinated peptides from CD4+ T cells and MD T lymphoma cells. Mass spectrometry was used to compare and analyze alterations in the ubiquitylome. Our results showed that the ubiquitination of 717 and 778 proteins was significantly up- and downregulated, respectively, in T lymphoma cells. MDV up- and downregulated ubiquitination of a similar percentage of proteins. The ubiquitination of transferases, especially serine/threonine kinases, was the main regulatory target of MDV. Compared with CD4+ T cells of the control group, MDV mainly altered the ubiquitylome associated with the signal transduction, immune system, cancer, and infectious disease pathways in T lymphoma cells. In these pathways, the ubiquitination of CDK1, IL-18, PRKCB, ETV6, and EST1 proteins was significantly up- or downregulated as shown by immunoblotting. The current study revealed that the MDV infection could exert a significant influence on the ubiquitylome of CD4+ T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença de Marek/imunologia , Doença de Marek/metabolismo , Animais , Carcinogênese/imunologia , Carcinogênese/metabolismo , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Galinhas , Interleucina-18/metabolismo , Espectrometria de Massas
10.
Molecules ; 24(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974882

RESUMO

Hepatocellular carcinoma (HCC) is one of the most deadly genetic diseases, but surprisingly chemotherapeutic approaches against HCC are only limited to a few targets. In particular, considering the difficulty of a chemotherapeutic drug development in terms of cost and time enforces searching for surrogates to minimize effort and maximize efficiency in anti-cancer therapy. In spite of the report that approximately one thousand lichen-derived metabolites have been isolated, the knowledge about their functions and consequences in cancer development is relatively limited. Moreover, one of the major second metabolites from lichens, Atranorin has never been studied in HCC. Regarding this, we comprehensively analyze the effect of Atranorin by employing representative HCC cell lines and experimental approaches. Cell proliferation and cell cycle analysis using the compound consistently show the inhibitory effects of Atranorin. Moreover, cell death determination using Annexin-V and (Propidium Iodide) PI staining suggests that it induces cell death through necrosis. Lastly, the metastatic potential of HCC cell lines is significantly inhibited by the drug. Taken these together, we claim a novel functional finding that Atranorin comprehensively suppresses HCC tumorigenesis and metastatic potential, which could provide an important basis for anti-cancer therapeutics.


Assuntos
Carcinoma Hepatocelular , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica , Hidroxibenzoatos , Líquens/química , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/isolamento & purificação , Hidroxibenzoatos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia
11.
J Biochem Mol Toxicol ; 33(7): e22334, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30958909

RESUMO

Chronic arsenic exposure through water intake is a worldwide issue, which has caused many diseases. Lungs are the first target organ of arsenic and lung inflammation, autophagy, and even the onset of tumors can be induced by arsenic exposure. Here, we tested the outcome of low-concentration arsenic exposure in rat lungs. Tissue changes, inflammation, autophagy, and other physiological responses were observed in this study. Results showed that low-concentration exposure of arsenite through water intake could initiate autophagy and inflammation in lungs but high concentration exposure produced a weak autophagy response and accentuated inflammation with the possibility of a chronic inflammation environment emerging followed by tumorigenesis.


Assuntos
Arsênico/toxicidade , Autofagia/efeitos dos fármacos , Transformação Celular Neoplásica , Neoplasias Pulmonares , Pulmão , Pneumonia , Animais , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia , Ratos , Ratos Sprague-Dawley
12.
Int J Mol Sci ; 20(8)2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-31013941

RESUMO

Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10-20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6-7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients.


Assuntos
Transformação Celular Neoplásica , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/metabolismo , Animais , Biomarcadores , Crise Blástica/genética , Crise Blástica/metabolismo , Crise Blástica/patologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Aberrações Cromossômicas , Terapia Combinada , Progressão da Doença , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Mutação , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/patologia , Fatores de Risco
13.
J Exp Clin Cancer Res ; 38(1): 165, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987652

RESUMO

BACKGROUND: miRNAs play crucial role in the progression of K-Ras-mutated nonsmall cell lung cancer (NSCLC). However, most studies have focused on miRNAs that target K-Ras. Here, we investigated miRNAs regulated by mutant K-Ras and their functions. METHODS: miRNAs regulated by mutant K-Ras were screened using miRNA arrays. miR-199b expression levels were measured by qRT-PCR. The protein expression levels were measured using Western blot and immunohistochemistry. The effects of miR-199b on NSCLC were examined both in vitro and in vivo by overexpressing or inhibiting miR-199b. DNA methylation was measured by bisulfite sequencing. RESULTS: An inverse correlation was observed between K-Ras mutation status and miR-199b levels in NSCLC specimens and cell lines. The inhibition of miR-199b stimulated NSCLC growth and metastasis, while restoration of miR-199b suppressed K-Ras mutation-driven lung tumorigenesis as well as K-Ras-mutated NSCLC growth and metastasis. miR-199b inactivated ERK and Akt pathways by targeting K-Ras, KSR2, PIK3R1, Akt1, and Rheb1. Furthermore, we determined that mutant K-Ras inhibits miR-199b expression by increasing miR-199b promoter methylation. CONCLUSION: Our findings suggest that mutant K-Ras plays an oncogenic role through downregulating miR-199b in NSCLC and that overexpression of miR-199b is a novel strategy for the treatment of K-Ras-mutated NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Metilação de DNA , Progressão da Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Neoplasias Pulmonares/patologia , Modelos Moleculares , Mutação , Proteínas Proto-Oncogênicas c-akt/metabolismo
14.
Best Pract Res Clin Haematol ; 32(1): 65-73, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927977

RESUMO

Myeloproliferative Neoplasms (MPNs) are a group of progressive diseases that share a common pathogenesis, clinical and laboratory features, as well as a spontaneous risk of secondary AML. Certain MPN therapies have been associated with an increased risk of leukemic conversion, with robust data highlighting the highest rates with 32P, chlorambucil, and pipobroman. Herein, we review risk factors for leukemic transformation, including therapy-related MPN-BP, with a focus on the debate surrounding the potential leukemogenicity of hydroxyurea. Lastly, we discuss emerging studies on the association between ruxolitinib and high grade B-cell lymphomas. We conclude that statistical associations have not implicated hydroxyurea monotherapy as leukemogenic. However, it is difficult to definitely disprove an association, as large prospective, controlled studies with decades of follow-up would be needed to draw conclusions. Overall, the concept of therapy-related neoplasms remains important to the field, and mandates judicious selection and sequencing of therapies for MPN patients.


Assuntos
Transformação Celular Neoplásica , Neoplasias Hematológicas , Hidroxiureia/efeitos adversos , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Pirazóis/efeitos adversos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Hematológicas/induzido quimicamente , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Hidroxiureia/uso terapêutico , Transtornos Mieloproliferativos/induzido quimicamente , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/terapia , Pirazóis/uso terapêutico
15.
Int J Oncol ; 54(4): 1143-1154, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968149

RESUMO

Iron is an essential element for biological processes. Iron homeostasis is regulated through several mechanisms, from absorption by enterocytes to recycling by macrophages and storage in hepatocytes. Iron has dual properties, which may facilitate tumor growth or cell death. Cancer cells exhibit an increased dependence on iron compared with normal cells. Macrophages potentially deliver iron to cancer cells, resulting in tumor promotion. Mitochondria utilize cellular iron to synthesize cofactors, including heme and iron sulfur clusters. The latter is composed of essential enzymes involved in DNA synthesis and repair, oxidation­reduction reactions, and other cellular processes. However, highly increased iron concentrations result in cell death through membrane lipid peroxidation, termed ferroptosis. Ferroptosis, an emerging pathway for cancer treatment, is similar to pyroptosis, apoptosis and necroptosis. In the present review, previous studies on the physiology of iron metabolism and its role in cancer are summarized. Additionally, the significance of iron regulation, and the association between iron homeostasis and carcinogenic mechanisms are discussed.


Assuntos
Transformação Celular Neoplásica/metabolismo , Ferro/metabolismo , Neoplasias/metabolismo , Animais , Apoptose , Homeostase , Humanos , Peroxidação de Lipídeos , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/patologia
16.
Oncol Rep ; 41(6): 3555-3564, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002368

RESUMO

Neoplastic transformation is characterized by metabolic rewiring to sustain the elevated biosynthetic demands of highly proliferative cancer cells. To obtain the precursors for macromolecule biosynthesis, cancer cells avidly uptake and metabolize glucose and glutamine. Thus, targeting the availability or metabolism of these nutrients is an attractive anticancer therapeutic strategy. To improve our knowledge concerning how cancer cells respond to nutrient withdrawal, the response to glutamine and/or glucose starvation was studied in human in vitro transformed fibroblasts, deeply characterized at the cellular and molecular level. Concomitant starvation of both nutrients led to rapid loss of cellular adhesion (~16 h after starvation), followed by cell death. Deprivation of glucose alone had the same effect, although at a later time (~48 h after starvation), suggesting that glucose plays a key role in enabling cell attachment to the extracellular matrix. Glutamine deprivation did not induce rapid cell death, but caused a prolonged arrest of cellular proliferation; the cells started dying only 96 h after starvation. Before massive cell death occurred, the effects of all the starvation conditions were reversible. Autophagy activation was observed in cells incubated in the absence of glucose for more than 48 h, while autophagy was not detected under the other starvation conditions. Markers of apoptotic cell death, such as caspase 3, caspase 9 and poly(ADP­ribose) polymerase 1 (PARP­1) proteolytic fragments, were not observed under any growth condition. Glucose and/or glutamine deprivation caused very rapid PARP­1 activation, with marked PARP­1 (poly­ADP) ribosylation and protein (poly­ADP) ribosylation. This activation was not due to starvation­induced DNA double­strand breaks, which appeared at the late stages of deprivation, when most cells died. Collectively, these results highlight a broad range of consequences of glucose and glutamine starvation, which may be taken into account when nutrient availability is used as a target for anticancer therapies.


Assuntos
Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Glucose/metabolismo , Glutamina/metabolismo , Apoptose/genética , Autofagia/genética , Caspases/genética , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Morte Celular/genética , Transformação Celular Neoplásica/metabolismo , Quebras de DNA de Cadeia Dupla , Fibroblastos/metabolismo , Fibroblastos/patologia , Glucose/genética , Glutamina/genética , Humanos , Terapia de Alvo Molecular , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inanição/genética , Inanição/metabolismo
17.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018488

RESUMO

Histopathological findings of oral neoplasm cell differentiation and metaplasia suggest that tumor cells induce their own dedifferentiation and re-differentiation and may lead to the formation of tumor-specific histological features. Notch signaling is involved in the maintenance of tissue stem cell nature and regulation of differentiation and is responsible for the cytological regulation of cell fate, morphogenesis, and/or development. In our previous study, immunohistochemistry was used to examine Notch expression using cases of odontogenic tumors and pleomorphic adenoma as oral neoplasms. According to our results, Notch signaling was specifically associated with tumor cell differentiation and metaplastic cells of developmental tissues. Notch signaling was involved in the differentiation of the ductal epithelial cells of salivary gland tumors and ameloblast-like cells of odontogenic tumors. However, Notch signaling was also involved in squamous metaplasia, irrespective of the type of developmental tissue. In odontogenic tumors, Notch signaling was involved in epithelial-mesenchymal interactions and may be related to tumor development and tumorigenesis. This signaling may also be associated with the malignant transformation of ameloblastomas. Overall, Notch signaling appears to play a major role in the formation of the characteristic cellular composition and histological features of oral neoplasms, and this involvement has been reviewed here.


Assuntos
Adenoma Pleomorfo/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Bucais/patologia , Mixoma/patologia , Tumores Odontogênicos/patologia , Receptores Notch/metabolismo , Transdução de Sinais , Adenoma Pleomorfo/metabolismo , Ameloblastoma/metabolismo , Ameloblastoma/patologia , Animais , Diferenciação Celular , Transformação Celular Neoplásica/metabolismo , Humanos , Neoplasias Bucais/metabolismo , Mixoma/metabolismo , Tumores Odontogênicos/metabolismo
18.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013830

RESUMO

Breast cancer is the most common malignancy in women worldwide and can be categorized into several subtypes according to histopathological parameters or genomic signatures. Such heterogeneity of breast cancer can arise from the reactivation of mammary stem cells in situ during tumorigenesis. Moreover, different breast cancer subtypes exhibit varieties of cancer incidence, therapeutic response, and patient prognosis, suggesting that a specific therapeutic protocol is required for each breast cancer subtype. Recent studies using molecular and cellular assays identified a link between specific genetic/epigenetic alterations and distinct cells of origin of breast cancer subtypes. These alterations include oncogenes, tumor suppressor genes, and cell-lineage determinants, which can induce cell reprogramming (dedifferentiation and transdifferentiation) among two lineage-committed mammary epithelial cells, namely basal and luminal cells. The interconversion of cell states through cell reprogramming into the intermediates of mammary stem cells can give rise to heterogeneous breast cancers that complicate effective therapies of breast cancer. A better understanding of mechanisms underlying cell reprogramming in breast cancer can help in not only elucidating tumorigenesis but also developing therapeutics for breast cancer. This review introduces recent findings on cancer gene-mediated cell reprogramming in breast cancer and discusses the therapeutic potential of targeting cell reprogramming.


Assuntos
Neoplasias da Mama/etiologia , Transformação Celular Neoplásica , Reprogramação Celular , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem da Célula/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Epigênese Genética/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Terapia de Alvo Molecular , Células-Tronco/metabolismo , Células-Tronco/patologia
19.
Nat Commun ; 10(1): 1841, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015463

RESUMO

Transcriptional reprogramming of cellular metabolism is a hallmark of cancer. However, systematic approaches to study the role of transcriptional regulators (TRs) in mediating cancer metabolic rewiring are missing. Here, we chart a genome-scale map of TR-metabolite associations in human cells using a combined computational-experimental framework for large-scale metabolic profiling of adherent cell lines. By integrating intracellular metabolic profiles of 54 cancer cell lines with transcriptomic and proteomic data, we unraveled a large space of associations between TRs and metabolic pathways. We found a global regulatory signature coordinating glucose- and one-carbon metabolism, suggesting that regulation of carbon metabolism in cancer may be more diverse and flexible than previously appreciated. Here, we demonstrate how this TR-metabolite map can serve as a resource to predict TRs potentially responsible for metabolic transformation in patient-derived tumor samples, opening new opportunities in understanding disease etiology, selecting therapeutic treatments and in designing modulators of cancer-related TRs.


Assuntos
Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Mapas de Interação de Proteínas/genética , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Perfilação da Expressão Gênica/métodos , Genoma Humano , Humanos , Redes e Vias Metabólicas , Metaboloma , Metabolômica/métodos , Neoplasias/metabolismo , Neoplasias/patologia , Mapeamento de Interação de Proteínas , Proteômica/métodos , Transcriptoma
20.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018569

RESUMO

Ribosomal S6 kinase 2 (RSK2), regulated by Ras/Raf/MEKs/ERKs, transmits upstream activation signals to downstream substrates including kinases and transcription and epigenetic factors. We observed that ELK members, including ELK1, 3, and 4, highly interacted with RSK2. We further observed that the RSK2-ELK3 interaction was mediated by N-terminal kinase and linker domains of RSK2, and the D and C domains of ELK3, resulting in the phosphorylation of ELK3. Importantly, RSK2-mediated ELK3 enhanced c-fos promoter activity. Notably, chemical inhibition of RSK2 signaling using kaempferol (a RSK2 inhibitor) or U0126 (a selective MEK inhibitor) suppressed EGF-induced c-fos promoter activity. Moreover, functional deletion of RSK2 by knockdown or knockout showed that RSK2 deficiency suppressed EGF-induced c-fos promoter activity, resulting in inhibition of AP-1 transactivation activity and Ras-mediated foci formation in NIH3T3 cells. Immunocytofluorescence assay demonstrated that RSK2 deficiency reduced ELK3 localization in the nucleus. In MDA-MB-231 breast cancer cells, knockdown of RSK2 or ELK3 suppressed cell proliferation with accumulation at the G1 cell cycle phase, resulting in inhibition of foci formation and anchorage-independent cancer colony growth in soft agar. Taken together, these results indicate that a novel RSK2/ELK3 signaling axis, by enhancing c-Fos-mediated AP-1 transactivation activity, has an essential role in cancer cell proliferation and colony growth.


Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Fatores de Transcrição/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Fatores de Transcrição/genética
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