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1.
PLoS Genet ; 16(3): e1008470, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203506

RESUMO

Cell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells. Anchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation. Taken together, our data have identified egl-43 Evi1 as an important factor coordinating cell invasion with cell cycle arrest.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Expressão Gênica/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Proto-Oncogenes/genética , Animais , Membrana Basal/metabolismo , Diferenciação Celular/genética , Proliferação de Células/genética , Proteínas Proto-Oncogênicas c-fos/genética , Receptores Notch/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética
2.
Cancer Sci ; 111(3): 869-880, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883160

RESUMO

Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer-related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR-493-5p, a major tumor suppressor miRNA that inactivates miR-483-3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR-493-5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR-493-5p given its significant inhibition through 3'-UTR targeting in miR-493-5p-rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR-493-5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR-493-5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR-493-5p activity. In summary, miR-493-5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Neoplasias Hepáticas/genética , Proteína Proto-Oncogênica N-Myc/genética , Oncogenes/genética , Regiões 3' não Traduzidas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs , Pessoa de Meia-Idade , Prognóstico , Proto-Oncogenes/genética
3.
Cancer Cell ; 36(3): 218-235, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31474570

RESUMO

Atypical protein kinase C (aPKC) isozymes, PKCλ/ι and PKCζ, are now considered fundamental regulators of tumorigenesis. However, the specific separation of functions that determine their different roles in cancer is still being unraveled. Both aPKCs have pleiotropic context-dependent functions that can translate into tumor-promoter or -suppressive functions. Here, we review early and more recent literature to discuss how the different tumor types, and their microenvironments, might account for the selective signaling of each aPKC isotype. This is of clinical relevance because a better understanding of the roles of these kinases is essential for the design of new anti-cancer treatments.


Assuntos
Isoenzimas/metabolismo , Neoplasias/patologia , Proteína Quinase C/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Polaridade Celular/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Camundongos Transgênicos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proto-Oncogenes/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Microambiente Tumoral/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
4.
Food Chem Toxicol ; 134: 110813, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31505237

RESUMO

Zinc is required for fetal development and is involved in key processes associated with breast carcinogenesis. We evaluated whether maternal zinc deficiency or supplementation during gestation influences female offspring susceptibility to breast cancer in adulthood. C57BL/6 mice consumed during gestation control (30 p.p.m. zinc), zinc-deficient (8 p.p.m) or zinc-supplemented (45 p.p.m.) diets. Maternal zinc supplementation increased in female mice offspring the incidence of chemically-induced mammary adenocarcinomas that were heavier, compared to control group. This was accompanied by a decreased number of terminal end buds, increased cell proliferation and apoptosis, and increased tumor suppressors p21, p53 and Rassf1, Zfp382 and Stat3 expression in mammary glands, as well as increased zinc status. Although maternal zinc deficiency did not alter the incidence of these lesions, it also induced heavier mammary adenocarcinomas, compared to control group. These effects were accompanied by a decreased number of terminal end buds, increased proto-oncogenes c-Myc and Lmo4 expression and H3K9Me3 and H4K20Me3 epigenetic marks in mammary glands of offspring, and decreased zinc status and increased levels of oxidative marker malondialdehyde. The data suggest that both maternal zinc deficiency and supplementation during gestation programmed increased breast cancer susceptibility in adult mice offspring following a J-shaped pattern through distinct mechanisms.


Assuntos
Deficiências Nutricionais/complicações , Suplementos Nutricionais , Neoplasias Mamárias Experimentais/etiologia , Zinco/administração & dosagem , Zinco/deficiência , Animais , Apoptose , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Masculino , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proto-Oncogenes , Proteína Supressora de Tumor p53/metabolismo
5.
Mutat Res ; 781: 88-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31416581

RESUMO

Mutations occur spontaneously, which can be induced by either chemicals (e.g. benzene) or biological factors (e.g. virus). Not all mutations cause noticeable changes in cellular functions. However, mutation in key cellular genes leads to developmental disorders. It is one of the main ways in which proto-oncogenes can be changed into their oncogenic state. The progressive accumulation of multiple mutations throughout life leads to cancer. In the past few decades, extensive research on cancer biology has discovered many genes and pathways having role in cancer development. In this review, we tried to summarize the current knowledge of mutational effect on different cancer types and its consequences in brief for future reference and guidance of researchers in cancer biology.


Assuntos
Mutação/genética , Neoplasias/genética , Animais , Carcinogênese/genética , Humanos , Proto-Oncogenes/genética
6.
Cancer Invest ; 37(4-5): 199-208, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31181967

RESUMO

Prostate cancer (PCa) is the most common malignant tumor for men. But the mechanism is unclear. EIF3C was shown to be overexpressed in PCa tissues and cell lines. EIF3C overexpression was correlated to age and tumor stage in PCa patients and indicated poor survival. The proliferation, migration, and invasiveness of PC3 cells were all inhibited after EIF3C knockdown. Additionally, the phosphorylation level of PI3K and Akt was downregulated while total NF-κB and Myc decreased after EIF3C knockdown. But the expression of IκB increased reversely. Therefore, EIF3C at least partially regulates the activity of PI3K/Akt/NF-κB signaling pathway in PC3 cells.


Assuntos
Carcinogênese/genética , Fator de Iniciação 3 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Fator de Iniciação 3 em Eucariotos/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/genética , Prognóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proto-Oncogenes , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Biomark ; 24(4): 383-393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909182

RESUMO

Cancer, a deadly disease is characterized by abnormal cell growth with the potential to invade to other parts of the body. Most cancers start due to changes at gene level that happen over a person's lifetime when DNA repair system becomes faulty. CCDC6, one of the players in DNA repair system acts as a tumor suppressor gene. It was originally identified in chimeric genes caused by chromosomal translocation involving RET proto-oncogene in some thyroid tumors. Different fusion chimers with different proto-oncogenes like RET are known for CCDC6 which hampered its function. Further, CCDC6 is recognized as a pro-apoptotic phosphoprotein, which is an ATM substrate responsive to genotoxic stress. In this article, we reviewed the published literature to characterize CCDC6 fusions with proto-oncogenes and the role of natural phytochemicals which can potentially alter CCDC6 activity and thus can prove beneficial for cancer patients.


Assuntos
Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proto-Oncogenes , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Proteínas do Citoesqueleto/química , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/química , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Relação Estrutura-Atividade
8.
Arch Endocrinol Metab ; 63(2): 142-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30916164

RESUMO

OBJECTIVE: To verify the physiological action of triiodothyronine T3 on the expression of transforming growth factor α (TGFA) mRNA in MCF7 cells by inhibition of RNA Polymerase II and the MAPK/ERK pathway. MATERIALS AND METHODS: The cell line was treated with T3 at a physiological dose (10-9M) for 10 minutes, 1 and 4 hour (h) in the presence or absence of the inhibitors, α-amanitin (RNA polymerase II inhibitor) and PD98059 (MAPK/ERK pathway inhibitor). TGFA mRNA expression was analyzed by RT-PCR. For data analysis, we used ANOVA, complemented with the Tukey test and Student t-test, with a minimum significance of 5%. RESULTS: T3 increases the expression of TGFA mRNA in MCF7 cells in 4 h of treatment. Inhibition of RNA polymerase II modulates the effect of T3 treatment on the expression of TGFA in MCF7 cells. Activation of the MAPK/ERK pathway is not required for T3 to affect the expression of TGFA mRNA. CONCLUSION: Treatment with a physiological concentration of T3 after RNA polymerase II inhibition altered the expression of TGFA. Inhibition of the MAPK/ERK pathway after T3 treatment does not interfere with the TGFA gene expression in a breast adenocarcinoma cell line.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , Sistema de Sinalização das MAP Quinases/genética , Fator de Crescimento Transformador alfa/genética , Tri-Iodotironina/genética , Adenocarcinoma/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral/metabolismo , Feminino , Humanos , Células MCF-7/metabolismo , Proto-Oncogenes/genética , RNA Mensageiro/genética , Fator de Crescimento Transformador alfa/efeitos dos fármacos , Fator de Crescimento Transformador alfa/metabolismo , Tri-Iodotironina/metabolismo , Tri-Iodotironina/farmacologia
9.
Endocrinol Metab (Seoul) ; 34(1): 11-22, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30784243

RESUMO

The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of thyroid cancers. The NGS studies have confirmed the previously reported high frequency of mutually-exclusive oncogenic alterations affecting BRAF and RAS proto-oncogenes in all stages of thyroid cancer. Initially identified by traditional sequencing approaches, the NGS studies also confirmed the acquisition of alterations that inactivate tumor protein p53 (TP53) and activate phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced thyroid cancers. Novel alterations, such as those in telomerase reverse transcriptase (TERT) promoter and mating-type switching/sucrose non-fermenting (SWI/SNF) complex, are also likely to promote progression of the BRAFV600E-driven thyroid cancers. A number of genetically engineered mouse models (GEMM) of BRAFV600E-driven thyroid cancer have been developed to investigate thyroid tumorigenesis mediated by oncogenic BRAF and to explore the role of genetic alterations identified in the genomic analyses of advanced thyroid cancer to promote tumor progression. This review will discuss the various GEMMs that have been developed to investigate oncogenic BRAFV600E-driven thyroid cancers.


Assuntos
Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proto-Oncogenes/genética , Neoplasias da Glândula Tireoide/genética , Animais , Carcinoma Papilar/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Progressão da Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Camundongos , Camundongos Transgênicos/genética , Mutação , Telomerase/genética , Neoplasias da Glândula Tireoide/veterinária , Proteína Supressora de Tumor p53/metabolismo
10.
PLoS One ; 14(2): e0208287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30726209

RESUMO

The molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal versus cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic analysis of the impact of three chemically different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabolism. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Humanos , Camundongos , Chaperonas Moleculares/genética , Células NIH 3T3 , Proto-Oncogenes/genética , Transdução de Sinais/efeitos dos fármacos
11.
Clin Exp Dermatol ; 44(6): 620-624, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30793382

RESUMO

BACKGROUND: Despite its high contagiousness, high recurrence rate and potential for malignant transformation, effective treatments for condyloma acuminatum (CA) have not yet been developed. Accordingly, it is necessary to clarify the mechanisms underlying CA development. AIM: To investigate the expression and significance of the proteins Wnt-1 and TSLC1 in patients with CA and in normal foreskin controls. METHODS: Wnt-1 and TSLC1 were assessed by immunohistochemistry in 45 patients with CA. RESULTS: Positive expression rates of Wnt-1 and TSLC1 were 82.22% (37/45) and 37.78% (17/45), respectively, in CA tissues, and 29.17% (7/24) and 91.67% (22/24), respectively, in normal foreskin controls. Wnt-1 expression intensity in CA was markedly higher (positive to strongly positive) than that in normal controls (negative to weakly positive), whereas TSLC1 expression intensity ranged from weakly positive to positive in CA, and nearly strongly positive in the normal control group. The differences in the positive expression rate and expression intensity of Wnt-1 and TSLC1 between the two groups were statistically significant (P < 0.05). In addition, Wnt-1 and TSLC1 were negatively correlated. (r = -0.336, P < 0.05). CONCLUSIONS: Overexpression of Wnt-1 and low expression of TSLC1 may be associated with the growth of CA. These findings may provide a basis for the development of therapies to prevent recurrence or malignant transformation of CA.


Assuntos
Molécula 1 de Adesão Celular/metabolismo , Condiloma Acuminado/metabolismo , Proteína Wnt1/metabolismo , Adolescente , Adulto , Condiloma Acuminado/patologia , Feminino , Genes Supressores de Tumor , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Infecções por Papillomavirus/metabolismo , Proto-Oncogenes , Proteínas Supressoras de Tumor , Adulto Jovem
13.
Carcinogenesis ; 40(2): 349-359, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30325408

RESUMO

Liver cancer results in a high degree of mortality, especially among men. As fatty liver disease is a risk factor for development of hepatocellular carcinoma, we investigated the role of dietary fat type in tumor promotion by high-fat diets in mice after initiation with the chemical carcinogen diethyl nitrosamine. Tumor incidence and multiplicity were significantly greater in males than those in females. In males, fat type had complex effects on tumorigenesis. Preneoplastic foci were most prevalent in mice fed a polyunsaturated fat diet enriched in docosahexaenoic acid, whereas carcinomas and large visible liver tumors were significantly greater in mice fed a saturated fat diet made with cocoa butter relative to mice fed mono- or polyunsaturated fats. Different mechanisms thus seemed involved in early and late tumor promotion. The hepatic transcriptome and gut microbiome were assessed for traits associated with tumorigenesis. Hepatic expression of more than 20% of all genes was affected by sex, whereas fat type affected fewer genes. In males, the saturated fat diet induced expression of the proto-oncogene Agap2 and affected the expression of several cytochrome P450 genes, and genes involved in lipid, bile acid and fatty acid metabolism. The gut microbiome had a higher level of genus Akkermansia and a lower level of Firmicutes in females than in males. Males fed saturated fat had an altered microbiome, including an enrichment of the genus Coprococcus. In conclusion, sex and the dietary fat type affect the gut microbiome, the hepatic transcriptome and ultimately hepatic tumor growth.


Assuntos
Carcinogênese/patologia , Dieta Hiperlipídica/efeitos adversos , Proteínas de Ligação ao GTP/metabolismo , Microbioma Gastrointestinal/fisiologia , Neoplasias Hepáticas/etiologia , Proto-Oncogenes/fisiologia , Animais , Ácidos e Sais Biliares/metabolismo , Carcinogênese/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/patologia , Gorduras na Dieta/efeitos adversos , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos/metabolismo , Feminino , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Fígado/microbiologia , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
BMC Genomics ; 19(1): 881, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522435

RESUMO

BACKGROUND: The eukaryotic unicellular protist Plasmodiophora brassicae is an endocellular parasite of cruciferous plants. In host cortical cells, this protist develops a unicellular structure that is termed the plasmodium. The plasmodium is actually a multinucleated cell, which subsequently splits and forms resting spores. The mechanism for the growth of this endocellular parasite in host cell is unclear. RESULTS: Here, combining de novo genome sequence and transcriptome analysis of strain ZJ-1, we identified top five significant enriched KEGG pathways of differentially expressed genes (DEGs), namely translation, cell growth and death, cell communication, cell motility and cancers. We detected 171 proto-oncogenes from the genome of P. brassicae that were implicated in cancer-related pathways, of which 46 were differential expression genes. Three predicted proto-oncogenes (Pb-Raf1, Pb-Raf2, and Pb-MYB), which showed homology to the human proto-oncogenes Raf and MYB, were specifically activated during the plasmodial growth in host cortical cells, demonstrating their involvement in the multinucleate development stage of the unicellular protist organism. Gene networks involved in the tumorigenic-related signaling transduction pathways and the activation of 12 core genes were identified. Inhibition of phosphoinositol-3-kinase relieved the clubroot symptom and significantly suppressed the development process of plasmodia. CONCLUSIONS: Proto-oncogene-related regulatory mechanisms play an important role in the plasmodial growth of P. brassicae.


Assuntos
Genoma de Protozoário , Plasmodioforídeos/genética , Proto-Oncogenes/genética , Sequência de Aminoácidos , Brassica napus/metabolismo , Brassica napus/parasitologia , Perfilação da Expressão Gênica , Genes myb/genética , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Oxazepinas/farmacologia , Oxazepinas/uso terapêutico , Doenças das Plantas/parasitologia , Doenças das Plantas/terapia , Raízes de Plantas/citologia , Raízes de Plantas/metabolismo , Raízes de Plantas/parasitologia , Plasmodioforídeos/crescimento & desenvolvimento , Alinhamento de Sequência , Esporos de Protozoários/efeitos dos fármacos , Esporos de Protozoários/genética , Transcriptoma/efeitos dos fármacos , Quinases raf/genética
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(5): 1323-1329, 2018 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30295245

RESUMO

OBJECTIVE: To explore the expression of EVI1 gene in AML and the ALL patients' bone marrow cells, and its correlation with the leukemic typing, clinical characteristics and prognosis. METHODS: Three hundred and thirty-three cases of leukemia in our hospital from 2012 to 2016 were enrolled in this study. Among them there were 263 cases of AML, 70 cases of ALL, and 13 volunteers were selected as normal controls. The bone marrow samples of the patients and volunteers were aspirated. Firstly, the blood mononuclear cells(PBMNC) were separated from the samples through the Ficoll-Hypaque density gradient centrifugation. Secondly, the total DNA was extracted, and the expression of EVI1 mRNA were assayed by real-ime quantitative PCR, which help to find out the EVI1 mRNA expression difference between AML and ALL. Finally, the correlation of EVI1 expression with the acute leukemia typing, clinical characteristics and prognosis were analyzed by a series of statistical method. RESULTS: Based on the expression levels of the EVI1 mRNA determined by real-time quantitative PCR, the expression levels in AML and ALL were both higher, but without significant difference. The rates of both EVI1 mRNA overexpression and low expression of the EVI1 mRNA in AML patients were higher than those in AML group, however, the rate of normal expression in ALL group was statistically significantly lower than that in the AML. The level of Plt in patients with AML-M1 and T-ALL positively correlated with the level of EVI1 expression(r=0.393,P<0.05;ρ=0.442,P<0.05)while the level of blasts(%) in patients with AML-M3 negatively correlated with the level of EVI1 expression. The expression of EVI1 correlated with the age of patients(χ2 =6.684,P<0.05). The prognosis of AML patients with high expression of EVI1 mRNA was poor(Log-Rank test,P<0.05)and AML-M3 patients with high expression of EVI1 had a significantly poorer prognosis than that of patients without high expression(Log-Rank test,P<0.01). CONCLUSION: In expression level of EVI1 no difference has been found in AML and ALL, but the distribution of EVI1 expression shows obvious difference and the difference correlats with the age of patients, at the same time, the some clinical features and subtype of acute leukemia correlate with the expression level of EVI1.


Assuntos
Medula Óssea , Leucemia Mieloide Aguda , Proteínas de Ligação a DNA , Humanos , Proteína do Locus do Complexo MDS1 e EVI1 , Prognóstico , Proto-Oncogenes , Fatores de Transcrição
16.
Mol Cell ; 72(3): 413-425.e5, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30293784

RESUMO

c-Kit is a classic proto-oncogene either mutated or upregulated in cancer cells, and this leads to its constitutive kinase activation and, thus, to uncontrolled proliferation. Although the pro-oncogenic role of c-Kit is of no doubt, some observations do not fit well with c-Kit solely as a tumor-promoting moiety. We show here that c-Kit actively triggers cell death in various cancer cell lines unless engaged by its ligand stem cell factor (SCF). This pro-death activity is enhanced when the kinase activation of c-Kit is silenced and is due to c-Kit intracellular cleavage by caspase-like protease at D816. Moreover, in vivo, overexpression of a c-Kit kinase-dead mutant inhibits tumor growth, and this intrinsic c-Kit tumor-suppressive activity is dependent on the D816 cleavage. Thus, c-Kit acts both as a proto-oncogene via its kinase activity and as a tumor suppressor via its dependence receptor activity.


Assuntos
Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/fisiologia , Animais , Apoptose , Divisão Celular , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos SCID , Fosforilação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proto-Oncogenes , Fator de Células-Tronco/metabolismo
17.
Cancer Lett ; 438: 10-16, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217565

RESUMO

Krüppel-like factor 4 (KLF4) is an important transcription factor that is expressed in a variety of tissues and regulates many critical physiologic and cellular processes, including cell proliferation, differentiation, stem cell reprogramming, maintenance of genomic stability, and normal tissue homeostasis. KLF4 has both tumor suppressive and oncogenic functions in gastrointestinal and other cancers. These functions are thought to be context dependent, but how KLF4 exerts these differential functions and the molecular mechanisms behind them remain poorly understood. Recent studies have shown that the KLF4 gene undergoes alternative splicing, and the protein products of certain transcripts antagonize wild-type KLF4 function, suggesting an additional layer of regulation of KLF4 function. Therefore, detailed study of KLF4 alternative splicing may not only provide new insights into the complexity of KLF4 functions but also lead to rational targeting of KLF4 for cancer prevention and therapy.


Assuntos
Fatores de Transcrição Kruppel-Like/genética , Neoplasias/genética , Proto-Oncogenes/genética , Proteínas Supressoras de Tumor/genética , Processamento Alternativo , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias/classificação , Neoplasias/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Análise de Sobrevida , Proteínas Supressoras de Tumor/metabolismo
18.
J BUON ; 23(3): 604-610, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30003726

RESUMO

PURPOSE: To identify microRNAs (miRNAs) directly regulating the proto-oncogene Bmi-1 expression in the development of hepatocellular carcinoma (HCC) and to explore the underlying molecular mechanisms. METHODS: Four HCC cell lines, including HepG2, Bel7404, Huh7, and PLC5, the normal hepatocellular cell line MIHA, and 30 HCC biopsies were included in this study. Potential miRNAs, which interact with Bmi-1 and are involved in the development of HCC were identified through bioinformatic analyses. The expression of miRNA and Bmi-1 in HCC cell lines and HCC tissues was analyzed using fluorescence protein analysis, real-time quantitative PCR (RT-qPCR), and Western blotting. RESULTS: Bioinformatic analysis suggested that miR-218 is a potential miRNA regulating Bmi-1 expression. Fluorescence protein analysis, RT-qPCR, and Western blotting confirmed the direct interaction between miR-218 and Bmi-1. In addition, increased expression of Bmi-1 was detected in HCC cell lines and HCC tissues. In most HCC tissues, the expression of miR-218 was decreased and was associated with increased expression of Bmi-1. CONCLUSION: miR-p218 downregulates the expression of the proto-oncogene Bmi-1 in HCC, and it may be an effective target for the treatment of this disease.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Proteína Quinase 7 Ativada por Mitógeno/biossíntese , Proteína Quinase 7 Ativada por Mitógeno/genética , Proto-Oncogenes , Transfecção
19.
J Cell Biochem ; 119(11): 8830-8840, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30011084

RESUMO

Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2Tg ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2TgOb ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals.


Assuntos
Calcificação Fisiológica/fisiologia , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proto-Oncogenes/fisiologia , Análise de Variância , Animais , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Osso Esponjoso/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/fisiologia
20.
Cancer Lett ; 434: 120-129, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30031758

RESUMO

Cholangiocarcinoma (CCA) is a destructive malignancy with limited responsiveness to conventional chemotherapy. Although angiotensin receptor blockers (ARBs) have gained attention for their potential anticancer activity, little is known about their effects on CCA. The transcriptional co-activator, Yes-associated protein (YAP) is a critical oncogene in several cancers, including CCA. Following recent evidence showing that YAP is regulated by angiotensin II (AT-II), we investigated the effects of an ARB, losartan, on two human CCA cell lines (KKU-M213 and HuCCT-1) with regards to YAP oncogenic regulation. Losartan suppressed AT-II-induced CCA cell proliferation in a dose-dependent manner, induced apoptosis, decreased YAP (Ser127), and downregulated the YAP target genes CTGF, CYR61, ANKRD1, and MFAP5. However, losartan did not affect epithelial-mesenchymal transition, differentiation, or stemness in the CCA cells. Xenograft tumor growth assay showed that oral administration of a low clinical dose of losartan considerably reduced subcutaneous tumor burden and attenuated intratumor vascularization in CCA cell-derived xenograft tumors in BALB/c nude mice. These results indicate that ARB therapy could serve as a potential novel strategy for CCA treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Neoplasias dos Ductos Biliares/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Losartan/farmacologia , Fosfoproteínas/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfoproteínas/metabolismo , Proto-Oncogenes , Fatores de Transcrição
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