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1.
J Thorac Oncol ; 16(4): 583-600, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388477

RESUMO

INTRODUCTION: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. METHODS: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. RESULTS: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. CONCLUSIONS: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenosina , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Mutação , Microambiente Tumoral
2.
Cancer Res ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33495232

RESUMO

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in SCLC patients. This may reflect defects in immune surveillance. Here we illustrate that evading NK surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. ChIP-Seq showed NKG2DL loci in SCLC are inaccessible compared to NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Likewise, HDAC inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma.

3.
Database (Oxford) ; 20202020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33181824

RESUMO

Accumulating evidences have shown that the deregulation of circRNA has close association with many human cancers. However, these experimental verified circRNA-cancer associations are not collected in any database. Here, we develop a manually curated database (circR2Cancer) that provides experimentally supported associations between circRNAs and cancers. The current version of the circR2Cancer contains 1439 associations between 1135 circRNAs and 82 cancers by extracting data from existing literatures and databases. In addition, circR2Cancer contains the information of cancer exacted from Disease Ontology and basic biological information of circRNAs from circBase. At the same time, circR2Cancer provides a simple and friendly interface for users to conveniently browse, search and download the data. It will be a useful and valuable resource for researchers to understanding the regulation mechanism of circRNA in cancers. DATABASE URL: http://www.biobdlab.cn:8000.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33108298

RESUMO

Significant progress has been made with face photo-sketch synthesis in recent years due to the development of deep convolutional neural networks, particularly generative adversarial networks (GANs). However, the performance of existing methods is still limited because of the lack of training data (photo-sketch pairs). To address this challenge, we investigate the effect of knowledge distillation (KD) on training neural networks for the face photo-sketch synthesis task and propose an effective KD model to improve the performance of synthetic images. In particular, we utilize a teacher network trained on a large amount of data in a related task to separately learn knowledge of the face photo and knowledge of the face sketch and simultaneously transfer this knowledge to two student networks designed for the face photo-sketch synthesis task. In addition to assimilating the knowledge from the teacher network, the two student networks can mutually transfer their own knowledge to further enhance their learning. To further enhance the perception quality of the synthetic image, we propose a KD+ model that combines GANs with KD. The generator can produce images with more realistic textures and less noise under the guide of knowledge. Extensive experiments and a user study demonstrate the superiority of our models over the state-of-the-art methods.

5.
J Agric Food Chem ; 68(44): 12413-12420, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33104344

RESUMO

Fungicides are commonly used to prevent and treat grape (Vitis vinifera L.) diseases; however, they are potentially toxic to humans. Herein, we show that the application of S-adenosyl-l-methionine (SAM) accelerated the metabolism of various fungicides in Cabernet Sauvignon berries. The substances and enzymes involved in the metabolism of fungicides were analyzed to elucidate the effects of SAM. Results showed that SAM improved the production rate of superoxide anion, the hydrogen peroxide content, and the activities of superoxide dismutase, catalase, and peroxidase in azoxystrobin-treated berries. Additionally, SAM had a positive effect on the content of reduced glutathione and on the activities of glutathione S-transferase, glutathione reductase, and glutathione peroxidase. Importantly, the stimulatory effect of SAM on fungicide metabolism was also observed for metalaxyl and thiophanate-methyl. These results suggest that SAM can be used to improve food safety.

6.
Adv Sci (Weinh) ; 7(14): 2000098, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32714746

RESUMO

The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well-characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well-conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC-Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC-Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC-Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti-metastasis drug development, and also provides a novel strategy for inhibitor discovery toward "undruggable" protein targets.

7.
J Biol Chem ; 295(32): 11144-11160, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32540968

RESUMO

Defective DNA damage response (DDR) signaling is a common mechanism that initiates and maintains the cellular senescence phenotype. Dysfunctional telomeres activate DDR signaling, genomic instability, and cellular senescence, but the links among these events remains unclear. Here, using an array of biochemical and imaging techniques, including a highly regulatable CRISPR/Cas9 strategy to induce DNA double strand breaks specifically in the telomeres, ChIP, telomere immunofluorescence, fluorescence in situ hybridization (FISH), micronuclei imaging, and the telomere shortest length assay (TeSLA), we show that chromosome mis-segregation due to imperfect DDR signaling in response to dysfunctional telomeres creates a preponderance of chromatin fragments in the cytosol, which leads to a premature senescence phenotype. We found that this phenomenon is caused not by telomere shortening, but by cyclic GMP-AMP synthase (cGAS) recognizing cytosolic chromatin fragments and then activating the stimulator of interferon genes (STING) cytosolic DNA-sensing pathway and downstream interferon signaling. Significantly, genetic and pharmacological manipulation of cGAS not only attenuated immune signaling, but also prevented premature cellular senescence in response to dysfunctional telomeres. The findings of our study uncover a cellular intrinsic mechanism involving the cGAS-mediated cytosolic self-DNA-sensing pathway that initiates premature senescence independently of telomere shortening.

8.
J Proteomics ; 210: 103545, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31626998

RESUMO

Targeting specific ubiquitin E3 ligase for degradation of disease-driven protein has recently been an important concept for cancer therapy, as exemplified by the case of thalidomide for the treatment of multiple myeloma. E7070, an aryl sulfonamide drug, exhibited anticancer activity by targeting the E3 ligase receptor DCAF15, with RBM39 as the only known substrate. Exploration of additional substrates of E7070 would facilitate elucidation of its mechanism of actions. To this end, we used a strategy combing pSILAC method with two complementary digestion approaches (LysC-Trypsin and LysN-LysArgiNase) to accurately monitor the protein turnover and increase the depth of proteome profiling. Systematically, we showed that E7070 treatment changed turnover rates of 868 proteins (1.5 fold change and p-value <.05). Several proteins displayed accelerated turnover indicating they were potential new substrates of E7070, among which, pre-mRNA splicing factor 39 (PRPF39) had been reported to be overexpressed in certain cancers. We further demonstrated that PRPF39 was ubiquitinated and degraded by E7070 in a DCAF15-dependent manner, and represented a new bona fide substrate of E7070. The degradation of PRPF39 might also be contributed to the anticancer activity of E7070. SIGNIFICANCE: Identification of degraded substrates is difficult because protein abundance is a comprehensive result regulated by protein production and degradation at the same time. Pulsed SILAC (pSILAC), a method to measure protein turnover, would provide higher sensitivity than total protein quantification. In addition, some peptide sequences are not amenable to MS analysis after LysC-Trypsin digestion. LysN-LysargiNase, as a mirror protease combination of LysC-Trypsin, can be complementary for peptide identification with LysC-Trypsin. By combining pSILAC with two complementary digestion approaches (LysC-Trypsin and LysN-LysArgiNase), we systematically investigated E7070-dependent protein degradation. As a result, we found several potential degradation substrates of E7070 including PRPF39. Further, by exploiting a series of biological assays, we demonstrated that E7070 can lead to the ubiquitination and proteasomal degradation of PRPF39 by promoting the recruitment of PRPF39 to the CUL4-DCAF15 E3 ubiquitin ligase.

9.
J Med Chem ; 62(16): 7473-7488, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31335138

RESUMO

Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15, which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15 as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery.


Assuntos
Desenho de Fármacos , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Sequência de Aminoácidos , Humanos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade
10.
J Immunother Cancer ; 7(1): 32, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728077

RESUMO

BACKGROUND: Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models. METHODS: RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent KrasG12D GEMM of lung adenocarcinoma model. RESULTS: Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of KrasG12D GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro. CONCLUSIONS: We show that arginase expression is elevated in mouse and patient lung tumors. In a KRASG12D GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.


Assuntos
Arginase/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Células Mieloides/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Arginase/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Camundongos , Pessoa de Meia-Idade , RNA-Seq
11.
IEEE Trans Neural Netw Learn Syst ; 30(10): 3096-3108, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30676981

RESUMO

Great breakthroughs have been made in the accuracy and speed of face photo-sketch synthesis in recent years. Regression-based methods have gained increasing attention, which benefit from deeper and faster end-to-end convolutional neural networks. However, most of these models typically formulate the mapping from photo domain X to sketch domain Y as a unidirectional feedforward mapping, G: X → Y , and vice versa, F: Y → X ; thus, the utilization of mutual interaction between two opposite mappings is lacking. Therefore, we proposed a collaborative framework for face photo-sketch synthesis. The concept behind our model was that a middle latent domain ~Z between the photo domain X and the sketch domain Y can be learned during the learning procedure of G: X → Y and F: Y → X by introducing a collaborative loss that makes full use of two opposite mappings. This strategy can constrain the two opposite mappings and make them more symmetrical, thus making the network more suitable for the photo-sketch synthesis task and obtaining higher quality generated images. Qualitative and quantitative experiments demonstrated the superior performance of our model in comparison with the existing state-of-the-art solutions.

12.
Nat Commun ; 9(1): 4770, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425250

RESUMO

Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis. However, substrates of USP14 remain largely unknown, hindering the understanding of its functional roles. Here we conduct a comprehensive proteome, ubiquitinome and interactome analysis for USP14 substrate screening. Bioinformatics analysis reveals broad new potential roles of USP14, especially in lipid and carbohydrate metabolism. Among the potential substrates identified, we show that fatty acid synthase (FASN), a key enzyme involved in hepatic lipogenesis, is a bona fide substrate of USP14. USP14 directly interacts with and increases FASN stability. As a result, overexpression of USP14 promotes liver triglyceride accumulation in C57BL/6 mice, whereas genetic ablation or pharmacological inhibition of USP14 ameliorates hepatosteatosis, hyperglycemia and insulin resistance in obese mice. In conclusion, our findings reveal for the first time an indispensable role of USP14 in hepatosteatosis through FASN stabilization.


Assuntos
Ácido Graxo Sintases/metabolismo , Proteoma , Ubiquitina Tiolesterase/metabolismo , Animais , Metabolismo dos Carboidratos , Biologia Computacional , Técnicas de Silenciamento de Genes , Homeostase , Humanos , Hiperglicemia , Resistência à Insulina , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Triglicerídeos/análise , Ubiquitina Tiolesterase/genética , Regulação para Cima
13.
Cell Rep ; 24(13): 3477-3487.e6, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257209

RESUMO

Nuclear protein in testis (Nut) is a universal oncogenic driver in the highly aggressive NUT midline carcinoma, whose physiological function in male germ cells has been unclear. Here we show that expression of Nut is normally restricted to post-meiotic spermatogenic cells, where its presence triggers p300-dependent genome-wide histone H4 hyperacetylation, which is essential for the completion of histone-to-protamine exchange. Accordingly, the inactivation of Nut induces male sterility with spermatogenesis arrest at the histone-removal stage. Nut uses p300 and/or CBP to enhance acetylation of H4 at both K5 and K8, providing binding sites for the first bromodomain of Brdt, the testis-specific member of the BET family, which subsequently mediates genome-wide histone removal. Altogether, our data reveal the detailed molecular basis of the global histone hyperacetylation wave, which occurs before the final compaction of the male genome.


Assuntos
Histonas/metabolismo , Infertilidade Masculina/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Espermatozoides/metabolismo , Acetilação , Animais , Código das Histonas , Histonas/química , Masculino , Camundongos , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Ligação Proteica , Espermatogênese , Xenopus , Fatores de Transcrição de p300-CBP/metabolismo
15.
Mol Cell Proteomics ; 16(7): 1324-1334, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28450421

RESUMO

Type 2 diabetes (T2D) is a major chronic healthcare concern worldwide. Emerging evidence suggests that a histone-modification-mediated epigenetic mechanism underlies T2D. Nevertheless, the dynamics of histone marks in T2D have not yet been carefully analyzed. Using a mass spectrometry-based label-free and chemical stable isotope labeling quantitative proteomic approach, we systematically profiled liver histone post-translational modifications (PTMs) in a prediabetic high-fat diet-induced obese (DIO) mouse model. We identified 170 histone marks, 30 of which were previously unknown. Interestingly, about 30% of the histone marks identified in DIO mouse liver belonged to a set of recently reported lysine acylation modifications, including propionylation, butyrylation, malonylation, and succinylation, suggesting possible roles of these newly identified histone acylations in diabetes and obesity. These histone marks were detected without prior affinity enrichment with an antibody, demonstrating that the histone acylation marks are present at reasonably high stoichiometry. Fifteen histone marks differed in abundance in DIO mouse liver compared with liver from chow-fed mice in label-free quantification, and six histone marks in stable isotope labeling quantification. Analysis of hepatic histone modifications from metformin-treated DIO mice revealed that metformin, a drug widely used for T2D, could reverse DIO-stimulated histone H3K36me2 in prediabetes, suggesting that this mark is likely associated with T2D development. Our study thus offers a comprehensive landscape of histone marks in a prediabetic mouse model, provides a resource for studying epigenetic functions of histone modifications in obesity and T2D, and suggest a new epigenetic mechanism for the physiological function of metformin.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Histonas/metabolismo , Fígado/metabolismo , Obesidade/induzido quimicamente , Proteômica/métodos , Acilação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Epigênese Genética , Código das Histonas , Histonas/efeitos dos fármacos , Marcação por Isótopo , Espectrometria de Massas , Metformina/farmacologia , Camundongos , Camundongos Obesos , Obesidade/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
16.
J Cell Biol ; 216(2): 409-424, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28122957

RESUMO

Glycolytic enzymes are known to play pivotal roles in cancer cell survival, yet their molecular mechanisms remain poorly understood. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that coordinates glycolysis, pentose phosphate pathway, and serine biosynthesis in cancer cells. Herein, we report that PGAM1 is required for homologous recombination (HR) repair of DNA double-strand breaks (DSBs) caused by DNA-damaging agents. Mechanistically, PGAM1 facilitates DSB end resection by regulating the stability of CTBP-interacting protein (CtIP). Knockdown of PGAM1 in cancer cells accelerates CtIP degradation through deprivation of the intracellular deoxyribonucleotide triphosphate pool and associated activation of the p53/p73 pathway. Enzymatic inhibition of PGAM1 decreases CtIP protein levels, impairs HR repair, and hence sensitizes BRCA1/2-proficient breast cancer to poly(ADP-ribose) polymerase (PARP) inhibitors. Together, this study identifies a metabolically dependent function of PGAM1 in promoting HR repair and reveals a potential therapeutic opportunity for PGAM1 inhibitors in combination with PARP inhibitors.


Assuntos
Quebras de DNA de Cadeia Dupla , Desoxirribonucleotídeos/metabolismo , Neoplasias/enzimologia , Fosfoglicerato Mutase/metabolismo , Reparo de DNA por Recombinação , Células A549 , Animais , Apoptose , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Proteínas de Transporte/metabolismo , Ciclo Celular , Proliferação de Células , Sobrevivência Celular , Relação Dose-Resposta a Droga , Endodesoxirribonucleases , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Espectrometria de Massas , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Fosfoglicerato Mutase/antagonistas & inibidores , Fosfoglicerato Mutase/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Estabilidade Proteica , Proteômica/métodos , Interferência de RNA , Fatores de Tempo , Transfecção , Carga Tumoral , Proteína Tumoral p73/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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