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1.
Gene ; 715: 144005, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376410

RESUMO

Members of the highly conserved pleiotropic CK1 family of serine/threonine-specific kinases are tightly regulated in the cell and play crucial regulatory roles in multiple cellular processes from protozoa to human. Since their dysregulation as well as mutations within their coding regions contribute to the development of various different pathologies, including cancer and neurodegenerative diseases, they have become interesting new drug targets within the last decade. However, to develop optimized CK1 isoform-specific therapeutics in personalized therapy concepts, a detailed knowledge of the regulation and functions of the different CK1 isoforms, their various splice variants and orthologs is mandatory. In this review we will focus on the stress-induced CK1 isoform delta (CK1δ), thereby addressing its regulation, physiological functions, the consequences of its deregulation for the development and progression of diseases, and its potential as therapeutic drug target.


Assuntos
Caseína Quinase Idelta/química , Caseína Quinase Idelta/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Transdução de Sinais , Animais , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/genética , Sistemas de Liberação de Medicamentos/métodos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Relação Estrutura-Atividade
2.
Gene ; 716: 144032, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377316

RESUMO

Mitochondrial folate metabolism is central to the generation of nucleotides, fuelling methylation reactions, and redox homeostasis. Uniquely among the reactions of the mitochondrial folate pathway, the key step of the oxidation of 5,10-methylene-tetrahydrofolate (CH2-THF) can be catalysed by two isozymes, MTHFD2 and MTHFD2L. The MTHFD2 enzyme has recently received considerable attention as an oncogenic enzyme upregulated in several tumour types, which is additionally required by cancer cells in vitro and in vivo. However, much less is currently known about MTHFD2L and its expression in cancer. In this study, we examine and compare the expression and regulation of the two mitochondrial MTHFD isozymes in normal human and cancer cells. We found that normal and cancer cells express both enzymes, although MTHFD2 has a much higher baseline expression. Unlike MTHFD2, the MTHFD2L isozyme does not show an association with proliferation and growth factor stimulation. In addition, we did not find evidence of a compensatory increase of MTHFD2L following suppression of its isozyme. This study supports that MTHFD2L is unlikely to have an important function in increased proliferation or cancer. Furthermore, therapeutic strategies aiming to block the mitochondrial folate pathway in cancer should focus on MTHFD2, with MTHFD2L being unlikely to be involved in the development of chemoresistance to targeting of its mitochondrial isozyme.


Assuntos
Aminoidrolases/metabolismo , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Enzimas Multifuncionais/metabolismo , Neoplasias/enzimologia , Aminoidrolases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Isoenzimas/genética , Isoenzimas/metabolismo , Células MCF-7 , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Enzimas Multifuncionais/genética , Neoplasias/genética , Regulação para Cima
3.
Gene ; 716: 144025, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31394177

RESUMO

BACKGROUND: Existing meta-analysis have shown that the miR-200 family can be taken as a prognostic biomarker for many tumors. However, great heterogeneity was shown in predicting overall survival (OS) and progression-free survival (PFS). Emerging studies indicate that the expression levels of members of the miR-200 family are tissue-specific among various tumor tissues, which may be the main reason of the heterogeneity in predicting survival prognosis of tumor patients with the miR-200 family as biomarkers. By further analysis of heterogeneity of the miR-200 family as a biomarker for predicting survival prognosis of patients with different tumors, we expected to provide an accurate basis for the clinical application of the miR-200 family to predict the prognosis of patients with different tumors. METHODS: Eligible published studies were identified by searching the databases of PubMed, Embase and Web of Science. The clinical data of patients in the studies were pooled, and pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were used to calculate the strength of this association. The expressions of miRNAs were extracted from The Cancer Genome Atlas (TCGA). We presented the expressions of each member in miR-200 family in 15 types of cancer by boxplot, and analyzed the correlation among the members of miR-200 family by Spearman method. Different subgroup analyses were then performed based on the correlation among the members of miR-200 family, and the publication bias was assessed using the funnel plot of the Egger bias indicator test. RESULTS: Of 36 articles, including 15 tumor types and 4644 patients were included to perform meta-analysis. It was found that miR-200 family members can be used as independent protective factors in patients with various tumors but the miR-200 family has a higher heterogeneity in predicting prognosis: OS (HR = 0.82, 95% CI: 0.66-1.03, I2 = 85%, P < 0.01) and PFS (HR = 0.81, 95% CI: 0.57-1.16, I2 = 97%, P < 0.01). The data from TCGA database were used to analyze the expression levels of the miR-200 family and the results showed that the expression of miR-429 in different cancers is very different, and there are significant differences in expression levels compared with other miR-200 family members; the expression levels of miR-200a and miR-200b in various tumor tissues were similar to each other, respectively; miR-200c and miR-141 showed similar expression levels in each of most types of cancer tissues except ovarian cancer (OC). The expression levels of members of the miR-200 family in breast cancer (BRCA), cervical cancer (CESC), colon cancer (COAD), esophageal cancer (ESCA), head and neck cancer (HNSC), lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are relatively stable, but great variations can be found in the expression levels of miR-200 family members in ovarian cancer (OC), liver cancer (LIHC), renal clear cell carcinoma (KIRC) and renal papillary cell carcinoma (KIRP). Cluster analysis of expression of target genes of miR-200 family in different cancers yielded similar results to the expression level of the miR-200 family. Subgroup analysis of OC, LIHC, GC and LUAD based on expression levels and clustering results reduced or even eliminated the heterogeneity of miR-200 family members in predicting patient outcomes. CONCLUSIONS: Our results convincingly demonstrated that the miR-200 family could serve as a prognostic biomarker for cancers mentioned above and has potential value in clinical practice. MiR-200 family as prognostic biomarkers needs to be performed according to different tumor tissues and correlation between members in miR-200 family.


Assuntos
MicroRNAs/metabolismo , Neoplasias/mortalidade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mineração de Dados , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Análise de Sobrevida
4.
Adv Exp Med Biol ; 1121: 7-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392648

RESUMO

Common Non communicable diseases (NCDs), such as cardiovascular disease, cancer, schizophrenia, and diabetes, have become the major cause of death in the world. They result from an interaction between genetics, lifestyle and environmental factors. The prevalence of NCDs are increasing, and researchers hopes to find efficient strategies to predict, prevent and treat them. Given the role of epigenome in the etiology of NCDs, insight into epigenetic mechanisms may offer opportunities to predict, detect, and prevent disease long before its clinical onset.Epigenetic alterations are exerted through several mechanisms including: chromatin modification, DNA methylation and controlling gene expression by non-coding RNAs (ncRNAs). In this chapter, we will discuss about NCDs, with focus on cancer, diabetes and schizophrenia. Different epigenetic mechanisms, categorized into two main groups DNA methylation and chromatin modifications and non-coding RNAs, will be separately discussed for these NCDs.


Assuntos
Epigênese Genética , Doenças não Transmissíveis , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Humanos , Neoplasias/genética , Esquizofrenia/genética
6.
Anticancer Res ; 39(8): 4385-4391, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366534

RESUMO

BACKGROUND/AIM: To identify the reason for age and gender differences in cancer risk. PATIENTS AND METHODS: Age-standardized incidence rates for 17 cancer types were compared between genders in 50 populations. For each cancer type, the female/male rate ratio was listed in fixed order of population. Correlation coefficients were calculated between these lists in all pairwise combinations. For each population, the female/male rate ratio was listed in fixed order of cancer. Correlation coefficients were calculated between lists in all pairwise combinations. RESULTS: Only four pairwise combinations for cancer type gave a correlation coefficient greater than 0.700. For each population, the lowest correlation coefficient was 0.950. CONCLUSION: The reason for the differences in risk of cancer varies with each type of cancer, but remains fixed in all populations. It is suspected that species-specific genes control stem cell telomere dynamics in a fixed strategy at rates that vary among tissues and between genders.


Assuntos
Fatores Etários , Neoplasias/epidemiologia , Fatores Sexuais , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologia , Fatores de Risco
7.
Anticancer Res ; 39(8): 4475-4478, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366547

RESUMO

Chronic inflammation is involved in the development of cancer, lifestyle-related diseases, and autoimmune diseases. It also influences the severity of these diseases. Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues. The macrophage phenotype is believed to be important in mediating inflammatory changes in tissues. Recently, monocytes/macrophages activated with low-dose lipopolysaccharide (LPS) were demonstrated to suppress increased expression of monocyte chemotactic protein (MCP)-1 and inflammatory cytokines (interleukin (IL)-1 ß, IL-8, and tumor necrosis factor (TNF)-α). By suppressing the increased expression of chemotaxis-related and inflammation-related factors, monocytes/macrophages activated with low-dose LPS are considered to suppress the migration of macrophages into tissues and to regulate inflammatory changes in these tissues, respectively. The effects of macrophages activated with low-dose LPS were different from those of macrophages activated with high-dose LPS. In this review, we discuss the usefulness of monocytes/macrophages activation by low-dose LPS.


Assuntos
Inflamação/tratamento farmacológico , Lipopolissacarídeos/uso terapêutico , Neoplasias/tratamento farmacológico , Obesidade/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Quimiocina CCL2/genética , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Interleucina-1beta/genética , Interleucina-8/genética , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Neoplasias/genética , Obesidade/patologia , Fator de Necrose Tumoral alfa/genética
8.
Rinsho Ketsueki ; 60(6): 702-707, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281163

RESUMO

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes associated with DNA repair and telomere maintenance. In addition, mutations in ribosome-related genes cause defective hematopoiesis. Patients with IBMFS exhibit a predisposition to developing hematological malignancy or solid tumor because of the defect in cellular and molecular hemostasis. The SAMD9 mutation causes the multisystem disorder, MIRAGE syndrome, characterized by congenital adrenal hypoplasia and loss of chromosome 7, providing a novel insight into the correlation between the germline and somatic mutations of SAMD9/SAMD9L and myelodysplastic syndrome (MDS) with monosomy 7. Primary immunodeficiency diseases (PID) are caused by inborn errors of the immune system. PID patients with inadequate tumor immunity are at an elevated risk of developing malignancies such as lymphoma, leukemia, and gastrointestinal cancer. Recently, monocytopenia and mycobacterial infection (MonoMAC) syndrome with the GATA2 gene mutation have been reported as PID related to bone marrow failure. Patients with MonoMAC syndrome often develop MDS and acute myeloid leukemia. Here, we present the pediatric-onset IBMFS and/or PID with cancer predisposition and briefly discuss the tumorigenesis in each monogenic disease.


Assuntos
Anemia Aplástica/complicações , Doenças da Medula Óssea/complicações , Predisposição Genética para Doença , Hemoglobinúria Paroxística/complicações , Síndromes de Imunodeficiência/complicações , Neoplasias/genética , Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Criança , Hemoglobinúria Paroxística/genética , Humanos , Síndromes de Imunodeficiência/genética , Síndromes Mielodisplásicas
9.
Medicine (Baltimore) ; 98(27): e16087, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277104

RESUMO

Plasmacytoma variant translocation 1 (PVT1) is highly expressed in a variety of cancer tissues and is related to the clinicopathological features and prognosis. However, the prognostic value of PVT1 is still controversial. Therefore, this systematic evaluation and meta-analysis were performed to evaluate the relationship between PVT1 expression and clinicopathological features.PubMed, EMBASE, Web of science, and Cochrane library databases were searched for literature collection according to inclusion criteria and exclusion criteria. The pooled hazard ratios (HRs) or odds ratios (ORs) were used to evaluate the association between PVT1 expression and overall survival, tumor size, tumor-node-metastasis (TNM) stage, lymph node metastasis, and distant metastasis.A total of 39 articles including 3974 patients were included in the study. The results showed that the expression of PVT1 was closely related to the overall survival rate of cancers (HR = 1.64, 95% confidence interval [CI]: 1.50-1.78, P < .000001). Subgroup analysis showed that the high expression of PVT1 was closely related to the low overall survival rate of patients with clear cell renal cell carcinoma, breast cancer, cervical cancer, colon cancer, epithelial ovarian cancer, gastric cancer, lung cancer, and osteosarcoma. In addition, the high expression of PVT1 was positively correlated with tumor size (OR = 1.50, 95% CI: 1.14-1.96, P = .004), TNM stage (OR = 3.39, 95% CI: 2.73-4.20, P < .00001), lymph node metastasis (OR = 2.60, 95% CI: 1.76-3.84, P < .00001), and distant metastasis (OR = 2.94, 95% CI: 1.90-4.56, P < .00001).PVT1 could serve as a marker for the size, TNM stage, metastasis, and prognosis of different type of cancers.


Assuntos
Metástase Neoplásica/genética , Neoplasias/genética , Plasmocitoma/genética , RNA Longo não Codificante/metabolismo , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Estadiamento de Neoplasias , Neoplasias/mortalidade , Estudos Observacionais como Assunto , Análise de Sobrevida
10.
Yi Chuan ; 41(7): 567-581, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31307967

RESUMO

Cancer is a complex disease caused by the malignant cellular proliferation and metastasis. Elucidating its pathogenic mechanism is one of the major challenges that we face currently. Epigenetic mechanisms are essential for maintaining specific patterns of gene expression and normal development and growth of living individuals. Disorders of epigenetic markers, such as histone modification, DNA/RNA methylation, and changes in the three-dimensional conformation of chromatin, can interfere with gene expression to some extent, and result in cancers. This review provides a brief overview of epigenetics, focusing on their association with the genesis of cancers, and we look forward to the application of epigenetics in cancer clinical diagnosis and treatment.


Assuntos
Epigênese Genética , Neoplasias/genética , Cromatina , Metilação de DNA , Epigenômica , Humanos
11.
Vet Clin North Am Small Anim Pract ; 49(5): 809-818, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31256903

RESUMO

We introduce a next phase in the evolution of medicine affecting human and veterinary patients. This evolution, genomic cancer medicine (Pmed), involves expansion of genomic and molecular biology into clinical medicine. The implementation of these new technologies has already begun and is a commercial reality. We introduce the underpinnings for this evolution, and focus on application in complex disease states. Pet owners have begun requesting Pmed technologies. To meet this demand, it is important to be aware of the opportunities and obstacles associated with available Pmed offerings as well as the current state of the field.


Assuntos
Doenças do Gato/genética , Doenças do Gato/terapia , Doenças do Cão/genética , Doenças do Cão/terapia , Neoplasias/veterinária , Medicina de Precisão/veterinária , Animais , Gatos , Cães , Predisposição Genética para Doença , Genômica/métodos , Hemangiossarcoma/genética , Hemangiossarcoma/terapia , Hemangiossarcoma/veterinária , Humanos , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão/métodos , Análise de Sequência , Medicina Veterinária/métodos
12.
Vet Clin North Am Small Anim Pract ; 49(5): 781-791, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280902

RESUMO

Molecular diagnostics have revolutionized human oncology to allow early detection, targeted therapy, monitoring throughout treatment, and evidence of recurrence. By identifying genetic signatures associated with cancers, liquid biopsy techniques have been developed to diagnose and monitor cancer in noninvasive or minimally invasive ways. These techniques offer new opportunities for improving cancer screening, diagnosis, and monitoring the impact of therapy on the patients over time. Liquid biopsy also drives drug development programs. Similar diagnostics hold promise for comparable results in the veterinary field. Several noninvasive/minimally invasive techniques have been described in veterinary medicine that could be referred to as liquid biopsy.


Assuntos
Doenças do Cão/diagnóstico , Biópsia Líquida/veterinária , Neoplasias/veterinária , Animais , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/veterinária , Doenças do Cão/tratamento farmacológico , Doenças do Cão/genética , Cães , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/veterinária , Feminino , Humanos , Leucemia/diagnóstico , Leucemia/veterinária , Biópsia Líquida/métodos , Linfoma/diagnóstico , Linfoma/tratamento farmacológico , Linfoma/veterinária , Masculino , Terapia de Alvo Molecular/veterinária , Mutação , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias Uretrais/diagnóstico , Neoplasias Uretrais/genética , Neoplasias Uretrais/veterinária , Neoplasias da Bexiga Urinária/veterinária
13.
Anticancer Res ; 39(7): 3585-3593, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262883

RESUMO

BACKGROUND: The oncogenic role of epidermal growth factor receptor (EGFR) has been intensively studied. However, its emerging role in drug resistance has not been fully addressed. MATERIALS AND METHODS: This study systematically investigated the correlation of mRNA and protein expression of EGFR, as well as gene amplification and mutations with the log-transformed half-maximal inhibitory concentration (log10IC50) values obtained from the NCI panel of 60 human tumor cell lines against 83 standard anticancer agents and the top 10 natural cytotoxic products previously screened by us. RESULTS: EGFR protein expression, rather than other measurements, was most frequently associated with drug response. Log10IC50 and EGFR protein level were significantly positively correlated under all investigated DNA topoisomerase (TOPO) II inhibitors, followed by 81% of alkylating agents and platinum-based compounds, 71% of anti-hormones, 66% of TOPO I inhibitors and 50% of antibiotics. Furthermore, 60% of cytotoxic natural products did not reveal significant correlations. CONCLUSION: Collectively, we showed a broad-spectrum of cross-resistance towards clinical drugs mediated by EGFR. Natural cytotoxic products may be further developed as novel drugs to overcome EGFR-associated resistance to clinically established anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/fisiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , RNA Mensageiro/metabolismo
14.
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
16.
Nat Commun ; 10(1): 2569, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189880

RESUMO

Synonymous mutations have been viewed as silent mutations, since they only affect the DNA and mRNA, but not the amino acid sequence of the resulting protein. Nonetheless, recent studies suggest their significant impact on splicing, RNA stability, RNA folding, translation or co-translational protein folding. Hence, we compile 659194 synonymous mutations found in human cancer and characterize their properties. We provide the user-friendly, comprehensive resource for synonymous mutations in cancer, SynMICdb ( http://SynMICdb.dkfz.de ), which also contains orthogonal information about gene annotation, recurrence, mutation loads, cancer association, conservation, alternative events, impact on mRNA structure and a SynMICdb score. Notably, synonymous and missense mutations are depleted at the 5'-end of the coding sequence as well as at the ends of internal exons independent of mutational signatures. For patient-derived synonymous mutations in the oncogene KRAS, we indicate that single point mutations can have a relevant impact on expression as well as on mRNA secondary structure.


Assuntos
Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias/genética , Mutação Silenciosa/genética , Conjuntos de Dados como Assunto , Humanos , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Dobramento de RNA/genética , Processamento de RNA/genética , RNA Mensageiro/química , RNA Mensageiro/genética
17.
Nat Commun ; 10(1): 2701, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221965

RESUMO

One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Mutação com Ganho de Função , Perfilação da Expressão Gênica/métodos , Glicólise/efeitos dos fármacos , Glicólise/genética , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica/métodos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Serina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Nat Commun ; 10(1): 2702, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221991

RESUMO

Most cationic vectors are difficult to avoid the fate of small interfering RNA (siRNA) degradation following the endosome-lysosome pathway during siRNA transfection. In this study, the endoplasmic reticulum (ER) membrane isolated from cancer cells was used to fabricate an integrative hybrid nanoplexes (EhCv/siRNA NPs) for improving siRNA transfection. Compared to the undecorated Cv/siEGFR NPs, the ER membrane-decorated EhCv/siRNA NPs exhibits a significantly higher gene silencing effect of siRNA in vitro and a better antitumor activity in nude mice bearing MCF-7 human breast tumor in vivo. Further mechanistic studies demonstrate that functional proteins on the ER membrane plays important roles on improving cellular uptake and altering intracellular trafficking pathway of siRNA. It is worth to believe that the ER membrane decoration on nanoplexes can effectively transport siRNA through the endosome-Golgi-ER pathway to evade lysosomal degradation and enhance the silencing effects of siRNA.


Assuntos
Portadores de Fármacos/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Transfecção/métodos , Animais , Linhagem Celular Tumoral , Membrana Celular , Portadores de Fármacos/efeitos adversos , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Receptores ErbB/genética , Feminino , Terapia Genética/métodos , Complexo de Golgi/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/química , Neoplasias/genética , Neoplasias/terapia , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cancer Treat Res ; 178: 81-108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31209842

RESUMO

Rare cancers pose unique challenges for patients and their physicians arising from a lack of information regarding the best therapeutic options. Very often, a lack of clinical trial data leads physicians to choose treatments based on small case series or case reports. Precision medicine based on genomic analysis of tumors may allow for selection of better treatments with greater efficacy and less toxicity. Physicians are increasingly using genetics to identify patients at high risk for certain cancers to allow for early detection or prophylactic interventions. Genomics can be used to inform prognosis and more accurately establish a diagnosis. Genomic analysis may also expose therapeutic targets for which drugs are currently available and approved for use in other cancers. Notable successes in the treatment of previously refractory cancers have resulted. New more advanced sequencing technologies, tools for interpretation, and an increasing array of targeted drugs offer additional hope, but challenges remain.


Assuntos
Neoplasias , Medicina de Precisão , Genômica , Humanos , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/genética , Prognóstico
20.
Cancer Treat Res ; 178: 137-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31209844

RESUMO

Genomic information is increasingly being incorporated into clinical cancer care. Large-scale sequencing efforts have deepened our understanding of the genomic landscape of cancer and contributed to the expanding catalog of alterations being leveraged to aid in cancer diagnosis, prognosis, and treatment. Genomic profiling can provide clinically relevant information regarding somatic point mutations, copy number alterations, translocations, and gene fusions. Genomic features, such as mutational burden, can also be measured by more comprehensive sequencing strategies and have shown value in informing potential treatment options. Ongoing clinical trials are evaluating the use of molecularly targeted agents in genomically defined subsets of cancers within and across tumor histologies. Continued advancements in clinical genomics promise to further expand the application of genomics-enabled medicine to a broader spectrum of oncology patients.


Assuntos
Genômica , Neoplasias , Medicina de Precisão , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Neoplasias/genética , Prognóstico
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