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1.
Biochemistry (Mosc) ; 84(10): 1117-1128, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694508

RESUMO

According to modern concepts, tumor formation is associated with impairments in the structure of protooncogenes and/or deactivation of suppressor genes, regardless of the nature of carcinogenic factor. As a consequence, unregulated oncoproteins activate extracellular proteases, resulting in the destruction of the extracellular matrix, which facilitates cell invasion, deterioration of the cell-cell contacts, and metastasis. Tumor development requires activation of certain transcription factors; however, many oncoproteins are not transcription factors. It can be assumed that these oncoproteins are not the ultimate effectors of tumor development, but rather transmitters of the carcinogenic signal to the transcription factors promoting tumorigenesis. Here, we describe the mechanisms of carcinogenesis caused by various oncogenes/oncoproteins. We conclude that the common feature of these mechanisms is stimulation of aerobic glycolysis (Warburg effect) regulated, as a rule, through the activation of the HIFα transcription factor. The role of aerobic glycolysis at the early stages of carcinogenesis is discussed.


Assuntos
Carcinogênese/metabolismo , Glicólise , Neoplasias/metabolismo , Proteínas Oncogênicas/metabolismo , Animais , Carcinogênese/genética , Humanos , Neoplasias/genética , Proteínas Oncogênicas/genética
2.
Life Sci ; 235: 116822, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476310

RESUMO

AIMS: To investigate the effects of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) on cognitive dysfunction, the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and amyloid ß peptide (Aß) in the hippocampus, as well as dendritic pathology in the hippocampal CA1 region in sepsis-associated encephalopathy (SAE) rats. MAIN METHODS: The rats were randomly divided into four groups: 1) control group (subjected to sham surgery), 2) control plus Mfhas1 siRNA group (rats received intracerebroventricular injection of Mfhas1 siRNA after sham surgery), 3) CLP plus control siRNA group (rats received intracerebroventricular injection of control siRNA after cecal ligation and puncture (CLP)), 4) CLP plus Mfhas1 siRNA group (rats received intracerebroventricular injection of Mfhas1 siRNA after CLP). The learning and memory capabilities of the rats were examined by means of fear conditioning and Barnes maze test. The concentration of TNF-α and IL-1ß was determined by enzyme-linked immunosorbent assay. The efficiency of siRNA transfection, MFHAS1 and Aß expression were detected by Western blotting. Total branch lengths of pyramidal dendrites of the CA1 basilar trees and spine density were determined by Golgi staining. KEY FINDINGS: We observed that MFHAS1 knock-down by Mfhas1 siRNA intracerebroventricular injection could improve cognitive impairment, reduce the expression of TNF-α, IL-1ß and Aß in the hippocampus induced by CLP, and alleviate the dendritic spinal loss of the pyramidal neurons, as well as increase the dendritic branching of the CA1 basilar trees of septic rats. SIGNIFICANCE: MFHAS1 knock-down can alleviate cognitive impairment, neuroinflammation and dendritic spinal loss in SAE rats.


Assuntos
Disfunção Cognitiva/prevenção & controle , Dendritos/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Proteínas Oncogênicas/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Encefalopatia Associada a Sepse/complicações , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Dendritos/metabolismo , Dendritos/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar
3.
BMC Mol Cell Biol ; 20(1): 35, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426742

RESUMO

BACKGROUND: HPV16 infection is one of the main risk factors involved in the development of cervical cancer, mainly due to the high oncogenic potential of the viral proteins E6 and E7, which are involved in the different processes of malignant transformation. There is a broad spectrum of intratypical variation of E6, which is reflected in its high diversity, biological behavior, global distribution and risk of causing cervical cancer. Experimental studies have shown that the intratypical variants of the protein E6 from the European variants (E-G350, E-A176/G350, E-C188/G350) and Asian-American variants (AAa and AAc), are capable of inducing the differential expression of genes involved in the development of cervical cancer. RESULTS: An in silico analysis was performed to characterize the molecular effects of these variations using the structure of the HPV16 E6 oncoprotein (PDB: 4XR8; chain H) as a template. In particular, we evaluated the 3D structures of the intratypical variants by structural alignment, ERRAT, Ramachandran plots and prediction of protein disorder, which was further validated by molecular dynamics simulations. Our results, in general, showed no significant changes in the protein 3D structure. However, we observed subtle changes in protein physicochemical features and structural disorder in the N- and C-termini. CONCLUSIONS: Our results showed that mutations in the viral oncogene E6 of six high-risk HPV16 variants are effectively neutral and do not cause significant structural changes except slight variations of structural disorder. As structural disorder is involved in rewiring protein-protein interactions, these results suggest a differential pattern of interaction of E6 with the target protein P53 and possibly different patterns of tumor aggressiveness associated with certain types of variants of the E6 oncoprotein.


Assuntos
Simulação por Computador , Variação Genética , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Proteínas Repressoras/química , Proteínas Repressoras/genética , Sequência de Aminoácidos , Humanos , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína
4.
Nat Commun ; 10(1): 3858, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451685

RESUMO

The Polycomb group of proteins is required for the proper orchestration of gene expression due to its role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip in mice leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This does not affect the initial number of follicles but is associated with a reduction of follicles in aging. Our results suggest that mature oocytes Ezhip-/- might not be fully functional and indicate that fertility is strongly impaired in Ezhip-/- females. Altogether, our study uncovers EZHIP as a regulator of chromatin landscape in gametes.


Assuntos
Proteínas Oncogênicas/metabolismo , Óvulo/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Espermatozoides/metabolismo , Adulto , Animais , Linhagem Celular Tumoral , Cromatina/metabolismo , Feminino , Células HEK293 , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/isolamento & purificação , Oogênese , Ovário/citologia , Ovário/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Células Sf9 , Espermatogênese , Testículo/citologia , Testículo/patologia
5.
Cancer Sci ; 110(10): 3098-3109, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31389121

RESUMO

Lysosomal-associated protein transmembrane 4 beta (LAPTM4B), a proto-oncogene, has been shown to be a positive modulator in cancer progression. However, the mechanism of LAPTM4B regulation is not fully elucidated. Aberrant microRNAs (miRNAs) can regulate gene expression by interfering with target transcripts and/or translation to exert tumor-suppressive or oncogenic effects in breast cancer. In the present study, miR-132-3p, which was predicted by relevant software, was confirmed to directly bind to the 3' untranslated region (3'UTR) of LAPTM4B and negatively regulate its expression in luciferase reporter and western blot assays. Subsequently, we validated that miR-132-3p was downregulated in breast cancer tissues. Receiver-operating characteristic curve analysis indicated that miR-132-3p had accurate diagnostic value, and a Kaplan-Meier and Cox regression model showed that miR-132-3p was a potential prognostic marker for recurrence, showing low levels in breast cancer patients. In addition, we showed that miR-132-3p was inversely correlated with LAPTM4B expression in the above samples. Functionally, miR-132-3p suppressed the migration and invasion of breast carcinoma cells through LAPTM4B by mediating epithelial-mesenchymal transition signals, and partially reversed the carcinogenic effects of LAPTM4B by inhibiting the PI3K-AKT-mTOR signaling pathway. Taken together, these findings provide the first comprehensive analysis of miR-132-3p as a direct LAPTM4B-targeted miRNA, and shed light on miR-132-3p/LAPTM4B as a significant functional axis involved in the oncogenesis and metastasis of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Regiões 3' não Traduzidas , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Invasividade Neoplásica , Estadiamento de Neoplasias , Curva ROC , Transdução de Sinais , Análise de Sobrevida
6.
Nat Commun ; 10(1): 2913, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266935

RESUMO

Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.


Assuntos
Proteínas de Homeodomínio/metabolismo , Leucemia/metabolismo , Família Multigênica , Animais , Proliferação de Células , Epigênese Genética , Feminino , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Leucemia/genética , Leucemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Modelos Genéticos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo
7.
Nat Commun ; 10(1): 2935, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270335

RESUMO

Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Histonas/química , Histonas/imunologia , Imunidade Humoral , Lisina/imunologia , Animais , Linfócitos B/química , Linfócitos B/citologia , Ciclo Celular , Células Cultivadas , Ciclina E/genética , Ciclina E/imunologia , Desmetilação , Proteínas F-Box/genética , Proteínas F-Box/imunologia , Histonas/genética , Ferro/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/imunologia , Ativação Linfocitária , Lisina/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Regiões Promotoras Genéticas , Linfócitos T/citologia , Linfócitos T/imunologia
8.
Exp Oncol ; 41(2): 138-143, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31262163

RESUMO

AIM: To analyze copy number variations of HER-2/neu, c-MYC and CCNE1 oncogenes and their protein expression in endometrioid endometrial carcinomas in relation to the degree of tumor progression and presence of a family history of cancer in cancer patients. MATERIALS AND METHODS: The study was conducted on endometrial cancer (EC) samples from 68 patients with I-II FIGO stages of disease. Copy number analysis of HER-2/neu, c-MYC and CCNE1 genes was performed by quantitative PCR. Protein expression was analyzed using immunohistochemistry. RESULTS: Assessment of copy number variations of HER-2/neu, c-MYC and CCNE1 genes revealed their amplification in the tumors of 18.8, 25.0 and 14.3% of EC patients, respectively. High expression of corresponding proteins was detected in 14.6, 23.5 and 65.6% of patients, respectively. It was established that HER-2/neu gene amplification is more common in the group of tumors of low differentiation grade than in moderate grade EC (35.7 and 5.5% of cases, respectively, p < 0.05). Also, high expression of c-Myc protein was more frequently observed in low differentiated tumors compared to the moderately differentiated EC (36.6 and 13.2% of cases, respectively, p < 0.05). Expression of HER-2/neu and cyclin E proteins was found to be dependent on the depth of tumor invasion into the myometrium. High expression of HER-2/neu protein was observed in 25.0 and 4.1% of EC patients with tumor invasion > ½ and < ½ of the myometrium, respectively, and cyclin E - in 86.7 and 46.6% of cases, respectively, p < 0.05. It was shown that among patients with a family history of cancer, a larger proportion of cases with high expression of c-Myc protein was observed compared to the group of patients with sporadic tumors (43.8 and 17.3%, respectively; p < 0.05). CONCLUSIONS: Amplification of HER-2/neu gene, along with high expression of c-Myc, HER-2/neu and cyclin E proteins, are associated with such indices of tumor progression as a low differentiation grade and deep myometrial invasion, suggesting the potential possibility of including these markers in the panel for determining the molecular EC subtype associated with an aggressive course of the disease. In a certain category of EC patients, there is a relationship between a family history of cancer and high expression of c-Myc protein.


Assuntos
Carcinoma Endometrioide/genética , Ciclina E/genética , Neoplasias do Endométrio/genética , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptor ErbB-2/genética , Sequência de Bases , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/patologia , Variações do Número de Cópias de DNA/genética , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Amplificação de Genes/genética , Humanos , Pessoa de Meia-Idade , Miométrio/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia
9.
Pathol Res Pract ; 215(8): 152434, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178228

RESUMO

With targeted therapies becoming the new standard of care in oncology, next generation sequencing (NGS) is emerging as a valuable method for analyzing the molecular underpinnings of individual tumors. Cyclin E1, encoded by CCNE1 causes activation of E2F mediated transcription and drives cells from G1 into S phase with cyclin-dependent kinase 2 (CDK2). CCNE1 amplification has been found in 11-12% of gastric cancers, but the clinical significance of this amplification remains controversial, and its association with liver metastasis has not been studied. This study included 226 patients diagnosed with advanced gastric adenocarcinoma. We performed multi-gene panel tests containing 143 genes using DNA and RNA obtained from primary (n = 197; 120 endoscopic biopsies and 77 resections) or metastatic cancer tissues (n = 29; 26 biopsies, 2 excisions, and 1 fin. needle aspiration). Among the 226 cases, 28 cases (12.4%) had CCNE1 amplification, almost half of which (n = 13, 46.4%) showed liver metastasis. In patients with CCNE1 amplification (n = 28), TP53 mutations (n = 23, 82.1%) and ERBB2 amplification (n = 8, 28.6%) were the most frequent concurrent genetic alterations. In contrast, 42 (21.2%) of 198 patients without CCNE1 amplification showed liver metastasis. CCNE1 amplification was significantly associated with liver metastasis (p = 0.004; odds ratio, 3.219). Our results show that CCNE1 amplification is significantly associated with liver metastasis in a TP53-mutated gastric cancer subtype. Given the frequent association of CCNE1 amplification with liver metastasis, close follow up for liver metastasis and further clinical trials targeting CDK2 inhibitors are warranted.


Assuntos
Ciclina E/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , Proteínas Oncogênicas/genética , Neoplasias Gástricas/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Amplificação de Genes/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Gástricas/genética
10.
Gastroenterology ; 157(4): 1123-1137.e22, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31175866

RESUMO

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Mutação , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/genética , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/patologia , Cromograninas/genética , Evolução Clonal , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Evolução Molecular , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Estadiamento de Neoplasias , Proteínas Oncogênicas/genética , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos
11.
Folia Histochem Cytobiol ; 57(2): 64-73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31246264

RESUMO

INTRODUCTION: This study endeavors to analyze the effects of miR-1204 on the expression of DEK oncogene in non-small cell lung cancer (NSCLC) cell lines and to study the molecular mechanisms of these effects. MATERIAL AND METHODS: The miR-1204 mimics and inhibitors were transfected into the (A549 and SPC) NSCLC cells. Then the mRNA levels, cell viability, apoptosis rate, morphology and caspase activity were determined. The expression of apoptosis-related proteins Bcl-2 and Bax was also analyzed. RESULTS: In NSCLC cell lines (A549 and SPC), DEK mRNA levels were down-regulated in miR-1204 overex-pression group. In miR-1204 inhibition group, the expression of DEK mRNA showed an opposite trend. The overexpression of miR-1204 increases the apoptosis rate in NSCLC cells. The Bcl-2 levels in the miR-1204 over-expression group were decreased, while the Bax level was increased. In the miR-1204 inhibition group, expression of Bcl-2 and Bax showed opposite trends. Cell staining revealed cell's morphological changes; the apoptosis in the miR-1204 overexpression group revealed significant morphological features, such as brighter nuclei and nu-clear condensation. Results indicated a typical characteristic of apoptosis in the miR-1204 overexpression group. Caspase-9 and Caspase-3 were involved in the apoptosis pathway, which was mediated by miR-1204 and DEK. CONCLUSIONS: The miR-1204 induces apoptosis of NSCLC cells by inhibiting the expression of DEK. The mech-anism of apoptosis involves down-regulation of Bcl-2 and up-regulation of Bax expression. Moreover, the apoptosis was mediated by mitochondria-related caspase 9/3 pathway.


Assuntos
Apoptose/fisiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Cromossômicas não Histona/genética , Neoplasias Pulmonares/genética , MicroRNAs/fisiologia , Proteínas Oncogênicas/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Mensageiro/fisiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
12.
Biomed Res Int ; 2019: 9085435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205947

RESUMO

Interferon-induced transmembrane protein 1 (IFITM1), a 17-kDa membrane protein, is generally known as a modulator in many cellular functions. Recent studies showed overexpression of IFITM1 in cancers and relationship between IFITM1 overexpression and tumor progression. However, the role of IFITM1 in lung cancer remains unclear. Here, we presented the overexpression of IFITM1 in lung cancer tissues and cell lines A549 and H460 using quantitative Real-Time RT-PCR. In vitro assay indicated IFITM1 silencing inhibited lung cancer cell proliferation, migration, and invasion. Further, in vivo assay showed that IFITM1 silencing markedly suppressed cell growth and metastasis of lung cancer in tumor-bearing BALB/c nude mice. Mechanistically, we found that IFITM1 silencing significantly alleviated the protein levels of ß-catenin, cyclin D1, and c-Mycin lung cancer cells and tumor samples. Taken together, our study revealed the role of IFITM1 as a tumor promoter during lung cancer development and the possible molecular mechanism.


Assuntos
Antígenos de Diferenciação/biossíntese , Movimento Celular , Proliferação de Células , Neoplasias Pulmonares/metabolismo , Proteínas Oncogênicas/biossíntese , Células A549 , Animais , Antígenos de Diferenciação/genética , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Proteínas Oncogênicas/genética
13.
Oncol Res ; 27(8): 935-944, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31046876

RESUMO

Acute lymphoblastic leukemia (ALL) is the most prevalent of pediatric cancers. Neuroepithelial cell-transforming 1 (NET1) has been associated with malignancy in a number of cancers, but the role of NET1 in ALL development is unclear. In the present study, we investigated the effect of NET1 gene in ALL cell proliferation and chemoresistance. We analyzed GEO microarray data comparing bone marrow expression profiles of pediatric B-cell ALL samples and those of age-matched controls. MTT and colony formation assays were performed to analyze cell proliferation. ELISA assays, Western blot analyses, and TUNEL staining were used to detect chemoresistance. We confirmed that NET1 was targeted by miR-206 using Western blot and luciferase reporter assays. We identified NET1 gene as one of the most significantly elevated genes in pediatric B-ALL. MTT and colony formation assays demonstrated that NET1 overexpression increases B-ALL cell proliferation in Nalm-6 cells. ELISA assays, Western blot analyses, and TUNEL staining showed that NET1 contributes to ALL cell doxorubicin resistance, whereas NET1 inhibition reduces resistance. Using the TargetScan database, we found that several microRNAs (miRNAs) were predicted to target NET1, including microRNA-206 (miR-206), which has been shown to regulate cancer development. To determine whether miR-206 targets NET1 in vitro, we transfected Nalm-6 cells with miR-206 or its inhibitor miR-206-in. Western blot assays showed that miR-206 inhibits NET1 expression and miR-206-in increases NET1 expression. Luciferase assays using wild-type or mutant 3'-untranslated region (3'-UTR) of NET1 confirmed these findings. We ultimately found that miR-206 inhibits B-ALL cell proliferation and chemoresistance induced by NET1. Taken together, our results provide the first evidence that NET1 enhances proliferation and chemoresistance in B-ALL cells and that miR-206 regulates these effects by targeting NET1. This study therefore not only contributes to a greater understanding of the molecular mechanisms underlying B-ALL progression but also opens the possibility for developing curative interventions.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Proteínas Oncogênicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Criança , Pré-Escolar , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
14.
BMC Cancer ; 19(1): 422, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060523

RESUMO

BACKGROUND: Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonged platinum sensitivity. METHODS: In this retrospective study (2005 to 2014), we selected 31 patients with platinum resistant ovarian cancer retreated with platinum therapy. Copy number alterations and HR scores were evaluated using the OncoScan® FFPE platform in 15 cases. The mutational profile of 24 genes was investigated by targeted-NGS. RESULTS: The median values of the four HRD scores were higher in responders (LOH = 15, LST = 28, tAI = 33, CS = 84) compared with non-responders (LOH = 7.5, LST = 17.5, tAI = 23, CS = 47). Patients with high LOH, LST, tAI and CS scores had better response rates, although these differences were not statistically significant. Response rate to platinum retreatment was 22% in patients with CCNE1 gains and 83.5% in patients with no CCNE1 gains (p = 0.041). Furthermore, response rate was 54.5% in patients with RB1 loss and 25% in patients without RB1 loss (p = 0.569). Patients with CCNE1 gains showed a worse progression free survival (PFS = 11.1 months vs 3.7 months; p = 0.008) and a shorter overall survival (OS = 39.3 months vs 7.1 months; p = 0.007) in comparison with patients with no CCNE1 gains. Patients with RB1 loss had better PFS (9.0 months vs 2.6 months; p = 0.093) and OS (27.4 months vs 3.6 months; p = 0.025) compared with cases with no RB1 loss. Four tumor samples were BRCA mutated and tumor mutations were not associated with response to treatment. CONCLUSIONS: HR deficiency was found in 60% of our cases and HRD medium values were higher in responders than in non-responders. Despite the small number of patients tested, CCNE1 gain and RB1 loss discriminate patients with tumors extremely sensitive to platinum retreatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclina E/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/genética , Compostos de Platina/farmacologia , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brasil/epidemiologia , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Análise Mutacional de DNA , Feminino , Recombinação Homóloga/genética , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Compostos de Platina/uso terapêutico , Intervalo Livre de Progressão , Retratamento , Estudos Retrospectivos , Análise de Sobrevida
15.
Oncol Rep ; 42(1): 3-19, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059069

RESUMO

Runt­related transcription factor (RUNX) proteins belong to a transcription factors family known as master regulators of important embryonic developmental programs. In the last decade, the whole family has been implicated in the regulation of different oncogenic processes and signaling pathways associated with cancer. Furthermore, a suppressor tumor function has been also reported, suggesting the RUNX family serves key role in all different types of cancer. In this review, the known biological characteristics, specific regulatory abilities and experimental evidence of RUNX proteins will be analyzed to demonstrate their oncogenic potential and tumor suppressor abilities during oncogenic processes, suggesting their importance as biomarkers of cancer. Additionally, the importance of continuing with the molecular studies of RUNX proteins' and its dual functions in cancer will be underlined in order to apply it in the future development of specific diagnostic methods and therapies against different types of cancer.


Assuntos
Subunidades alfa de Fatores de Ligação ao Core/genética , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Neoplasias/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias/genética , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
16.
J Ovarian Res ; 12(1): 41, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077237

RESUMO

BACKGROUND AND OBJECTIVE: Ovarian cancer is a common gynaecological cancer with a poor prognosis that poses a serious threat to human life and health. It is essential to explore the possible prognostic biomarkers of ovarian cancer. As an important tumour suppressor gene, BCL7A actively participates in the growth of tumours. We aimed to study the prognostic role of BCL7A in ovarian cancer. RESULTS: Through data mining of RNAseq data from the Cancer Genome Atlas database (TCGA), we explored the clinical relevance of BCL7A mRNA expression. As a result, we found that BCL7A is expressed at low levels in ovarian cancer tissues and is correlated with survival status. Survival analysis showed that, compared with those who had higher levels of BCL7A expression, patients with ovarian cancer and low levels of BCL7A generally had shorter overall/relapse-free survival times. Cox regression models showed that low BCL7A expression could be used as an independent prognostication factor for ovarian cancer patients. CONCLUSIONS: Low BCL7A expression is an independent risk factor for poor prognosis in ovarian cancer patients.


Assuntos
Proteínas dos Microfilamentos/biossíntese , Proteínas Oncogênicas/biossíntese , Neoplasias Ovarianas/genética , Feminino , Humanos , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , RNA Mensageiro/metabolismo , Fatores de Risco , Análise de Sobrevida
17.
Nat Commun ; 10(1): 2126, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073164

RESUMO

Repair of the endothelial cell barrier after inflammatory injury is essential for tissue fluid homeostasis and normalizing leukocyte transmigration. However, the mechanisms of endothelial regeneration remain poorly understood. Here we show that the endothelial and hematopoietic developmental transcription factor Sox17 promotes endothelial regeneration in the endotoxemia model of endothelial injury. Genetic lineage tracing studies demonstrate that the native endothelium itself serves as the primary source of endothelial cells repopulating the vessel wall following injury. We identify Sox17 as a key regulator of endothelial cell regeneration using endothelial-specific deletion and overexpression of Sox17. Endotoxemia upregulates Hypoxia inducible factor 1α, which in turn transcriptionally activates Sox17 expression. We observe that Sox17 increases endothelial cell proliferation via upregulation of Cyclin E1. Furthermore, endothelial-specific upregulation of Sox17 in vivo enhances lung endothelial regeneration. We conclude that endotoxemia adaptively activates Sox17 expression to mediate Cyclin E1-dependent endothelial cell regeneration and restore vascular homeostasis.


Assuntos
Ciclina E/genética , Endotélio Vascular/fisiopatologia , Endotoxemia/patologia , Proteínas HMGB/metabolismo , Proteínas Oncogênicas/genética , Regeneração/imunologia , Fatores de Transcrição SOXF/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Ciclina E/metabolismo , Modelos Animais de Doenças , Células Endoteliais/fisiologia , Endotoxemia/imunologia , Células HEK293 , Proteínas HMGB/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Oncogênicas/metabolismo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição SOXF/genética , Transdução de Sinais/fisiologia , Regulação para Cima
18.
Nat Commun ; 10(1): 2146, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086175

RESUMO

Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP 'oncohistone-mimic', that dysregulate gene silencing to promote tumorigenesis.


Assuntos
Neoplasias Encefálicas/genética , Ependimoma/genética , Glioma/genética , Proteínas Oncogênicas/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Animais , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/metabolismo , Ilhas de CpG , Fossa Craniana Posterior , Conjuntos de Dados como Assunto , Embrião de Mamíferos , Ependimoma/patologia , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Células HEK293 , Histonas , Humanos , Camundongos , Proteínas Oncogênicas/genética , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
19.
DNA Cell Biol ; 38(6): 541-548, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31140864

RESUMO

The aim of this research was to verify the mutation rate of the ring finger protein 43 (RNF43) of the transmembrane E3 ubiquitin ligase and investigate the influence of single nucleotide polymorphisms (SNPs) rs2257205 in RNF43 in a Chinese colorectal cancer (CRC) cohort. DNA from 177 diagnosed CRC patients' tissues or blood samples were extracted, amplified, and sequenced. Clinicopathological features, including age, gender, tumor location, tumor-lymph node-metastasis stage, and survival information, were analyzed. Four novel RNF43 mutations (including G659 and R117 sites) were validated in 177 CRC patients; all events were somatic frameshift mutations. Furthermore, we also found that an SNP (rs2257205) of the RNF43 X117 site was associated with overall survival (OS) instead of disease-free survival. G homozygote subjects were significantly correlated with poor OS compared with another group. Then we rescued RNF43 R117R (encoded by nucleotide CGC) and R117H (encoded by nucleotide CAC) expression in the HCT116 cells and analyzed the targets of the Wnt/ß-catenin pathway. The expression of CCND1 and c-Myc were decreased. The prognosis of CRC patients could be affected by the different functions of SNPs of RNF43.


Assuntos
Neoplasias Colorretais/mortalidade , Proteínas de Ligação a DNA/genética , Proteínas Oncogênicas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Linhagem Celular Tumoral , China , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Prognóstico , Estudos Retrospectivos
20.
Int J Cancer ; 145(5): 1299-1311, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31093963

RESUMO

Molecular subtypes of breast cancer are defined on the basis of gene expression and genomic/epigenetic pattern differences. Different subtypes are thought to originate from distinct cell lineages, but the early activation of an oncogene could also play a role. It is difficult to discriminate the respective inputs of oncogene activation or cell type of origin. In this work, we wished to determine whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. To this aim, we transduced shp53 immortalized HMECs in parallel with the CCNE1, WNT1 and RASv12 oncogenes which activate distinct oncogenic pathways and characterized them at sequential stages of transformation for changes in their genetic and epigenetic profiles. We show that initial activation of CCNE1, WNT1 and RASv12, in shp53 HMECs results in different and reproducible changes in mRNA and micro-RNA expression, copy number alterations (CNA) and DNA methylation profiles. Noticeably, HMECs transformed by RAS bore very specific profiles of CNAs and DNA methylation, clearly distinct from those shown by CCNE1 and WNT1 transformed HMECs. Genes impacted by CNAs and CpG methylation in the RAS and the CCNE1/WNT1 clusters showed clear differences, illustrating the activation of distinct pathways. Our data show that early activation of distinct oncogenic pathways leads to active adaptive events resulting in specific sets of CNAs and DNA methylation changes. We, thus, propose that activation of different oncogenes could have a role in reshaping the genetic landscape of breast cancer subtypes.


Assuntos
Neoplasias da Mama/genética , Glândulas Mamárias Humanas/fisiologia , Oncogenes , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Ciclina E/biossíntese , Ciclina E/genética , Metilação de DNA , Epigênese Genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/fisiologia , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Xenoenxertos , Humanos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Camundongos , Camundongos Nus , Camundongos SCID , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Wnt1/biossíntese , Proteína Wnt1/genética
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