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1.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206240

RESUMO

The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos , Fosfolipídeos/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Idoso , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Células Epiteliais/enzimologia , Células Epiteliais/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Lipidômica , Lipogênese , Masculino , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
2.
Anticancer Res ; 41(4): 1831-1840, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813388

RESUMO

BACKGROUND/AIM: Peroxiredoxin V (Prx V) plays crucial roles in cellular apoptosis and proliferation in various cancer cells by regulating the cellular reactive oxygen species (ROS) levels. MATERIALS AND METHODS: Here, we examined the possible regulatory effects of Prx V on doxorubicin (DOX)-induced cellular apoptosis and its mechanisms in the human gastric adenocarcinoma cell line (AGS cells). RESULTS: Our findings suggest that Prx V knockdown may significantly increase the DOX-induced apoptosis by aggravating intracellular ROS accumulation. We also found that DOX-induced mitochondrial ROS levels and membrane permeability were significantly higher in short hairpin Prx V cells than in mock cells, and these phenomena were dramatically reversed by ROS scavenger treatment. Prx V knockdown also significantly upregulated the cleaved caspase 9, 3, and B-cell lymphoma 2 (Bcl2)-associated agonist of cell death/Bcl2 protein expression levels, suggesting that Prx V knockdown activates mitochondria-dependent apoptotic signaling pathways. CONCLUSION: Taken together, this study suggests that Prx V may be a strong molecular target for gastric cancer (GC) chemotherapy, and further elucidates the role of Prx V in oxidative stress-induced cell apoptosis.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Inativação Gênica , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Peroxirredoxinas/genética , Transdução de Sinais , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
3.
Methods Mol Biol ; 2294: 275-293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33742409

RESUMO

It is becoming increasingly evident that progression and metastasis of solid cancers is driven by the interaction of oncogene-transformed cancer cells and non-malignant host cells in the tumor stroma. In this process, the immune system contributes a complex set of highly important pro- and antitumor effects, which are not readily recapitulated by commonly used xenograft cancer models in immunodeficient mice.Therefore, we provide protocols for isolation of primary tumor cells from the MMTV-PymT mouse model for metastasizing breast cancer and their resubmission to congenic immunocompetent mice by orthotopic transplantation into the mammary gland or different routes of injection to induce organ-specific experimental metastasis, including intravenous, intracardiac, and caudal artery injection of tumor cells. Moreover, we describe protocols for sensitive detection and quantification of the metastatic burden.


Assuntos
Adenocarcinoma/patologia , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Peptídeo Hidrolases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Adenocarcinoma/enzimologia , Animais , Feminino , Neoplasias Mamárias Experimentais/enzimologia , Camundongos , Transgenes , Células Tumorais Cultivadas
4.
J Pathol ; 253(1): 106-118, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33009820

RESUMO

Neuroendocrine prostate cancer (NEPC) is a more aggressive subtype of castration-resistant prostate cancer (CRPC). Although it is well established that PHF8 can enhance prostate cancer cell proliferation, whether PHF8 is involved in prostate cancer initiation and progression is relatively unclear. By comparing the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with or without Phf8 knockout, we systemically examined the role of PHF8 in prostate cancer development. We found that PHF8 plays a minimum role in initiation and progression of adenocarcinoma. However, PHF8 is essential for NEPC because not only is PHF8 highly expressed in NEPC but also animals without Phf8 failed to develop NEPC. Mechanistically, PHF8 transcriptionally upregulates FOXA2 by demethylating and removing the repressive histone markers on the promoter region of the FOXA2 gene, and the upregulated FOXA2 subsequently regulates the expression of genes involved in NEPC development. Since both PHF8 and FOXA2 are highly expressed in NEPC tissues from patients or patient-derived xenografts, the levels of PHF8 and FOXA2 can either individually or in combination serve as NEPC biomarkers and targeting either PHF8 or FOXA2 could be potential therapeutic strategies for NEPC treatment. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Adenocarcinoma/enzimologia , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/enzimologia , Epigênese Genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Histona Desmetilases/metabolismo , Neoplasias da Próstata/enzimologia , Fatores de Transcrição/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/secundário , Animais , Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/secundário , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/genética , Histona Desmetilases/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores de Transcrição/genética , Transcrição Genética , Regulação para Cima
5.
Eur J Pharmacol ; 891: 173687, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33130276

RESUMO

Esophageal cancer is a prominent worldwide illness that is divided into two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Mortality rates are alarming, and the understanding of the mechanisms involved in esophageal cancer development, becomes essential. Purinergic signaling is related to many diseases and among these various types of tumors. Here we studied the effects of the P2Y2 receptor activation in different types of esophageal cancer. Esophageal tissue samples of healthy controls were used for P2Y2R expression quantification. Two human esophageal cancer cell lines Kyse-450 (squamous cell carcinoma) and OE-33 (adenocarcinoma) were used to perform in vitro analysis of cell proliferation, migration, adhesion, and the signaling pathways involved in P2Y2R activation. Data showed that P2Y2R was expressed in biopsies of patients with ESCC and adenocarcinoma, as well as in the two human esophageal cancer cell lines studied. The RT-qPCR analysis demonstrated that OE-33 cells have higher P2RY2 expression than Kyse-450 squamous cell line. Results showed that P2Y2R activation, induced by ATP or UTP, promoted esophageal cancer cells proliferation and colony formation. P2Y2R blockage with the selective antagonist, AR-C 118925XX, led to decreased proliferation, colony formation and adhesion. Treatments with ATP or UTP activated ERK 1/2 pathway in ESCC and ECA cells. The P2Y2R antagonism did not alter the migration of esophageal cancer cells. Interestingly, the esophageal cancer cell lines presented a distinct profile of nucleotide hydrolysis activity. The modulation of P2Y2 receptors may be a promising target for esophageal cancer treatment.


Assuntos
Adenocarcinoma/enzimologia , Carcinoma de Células Escamosas/enzimologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Agonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y2/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Trifosfato de Adenosina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y2/metabolismo , Transdução de Sinais , Uridina Trifosfato/farmacologia
6.
Front Immunol ; 11: 576310, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133093

RESUMO

Shp1, encoded by the gene Ptpn6, is a protein tyrosine phosphatase that transduces inhibitory signals downstream of immunoreceptors in many immune cell types. Blocking Shp1 activity represents an exciting potential immunotherapeutic strategy for the treatment of cancer, as Shp1 inhibition would be predicted to unleash both innate and adaptive immunity against tumor cells. Antibodies blocking the interaction between CD47 on tumor cells and SIRPα on macrophages enhance macrophage phagocytosis, show efficacy in preclinical tumor models, and are being evaluated in the clinic. Here we found that Shp1 bound to phosphorylated peptide sequences derived from SIRPα and transduced the anti-phagocytic signal, as Shp1 loss in mouse bone marrow-derived macrophages increased phagocytosis of tumor cells in vitro. We also generated a novel mouse model to evaluate the impact of global, inducible Ptpn6 deletion on anti-tumor immunity. We found that inducible Shp1 loss drove an inflammatory disease in mice that was phenotypically similar to that seen when Ptpn6 is knocked out from birth. This indicates that acute perturbation of Shp1 in vivo could drive hyperactivation of immune cells, which could be therapeutically beneficial, though at the risk of potential toxicity. In this model, we found that Shp1 loss led to robust anti-tumor immunity against two immune-rich syngeneic tumor models that are moderately inflamed though not responsive to checkpoint inhibitors, MC38 and E0771. Shp1 loss did not promote anti-tumor activity in the non-inflamed B16F10 model. The observed activity in MC38 and E0771 tumors was likely due to effects of both innate and adaptive immune cells. Following Shp1 deletion, we observed increases in intratumoral myeloid cells in both models, which was more striking in E0771 tumors. E0771 tumors also contained an increased ratio of effector to regulatory T cells following Shp1 loss. This was not observed for MC38 tumors, though we did find increased levels of IFNγ, a cytokine produced by effector T cells, in these tumors. Overall, our preclinical data suggested that targeting Shp1 may be an attractive therapeutic strategy for boosting the immune response to cancer via a mechanism involving both innate and adaptive leukocytes.


Assuntos
Adenocarcinoma/enzimologia , Neoplasias da Mama/enzimologia , Neoplasias do Colo/enzimologia , Melanoma Experimental/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/deficiência , Neoplasias Cutâneas/enzimologia , Macrófagos Associados a Tumor/enzimologia , Imunidade Adaptativa , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Animais , Antígenos de Diferenciação/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Feminino , Humanos , Imunidade Inata , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Células THP-1 , Carga Tumoral , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia
7.
Int J Mol Sci ; 21(21)2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33126685

RESUMO

Bile acids (BAs) have been implicated in the development of oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma (OAC). However, whether BAs promote cancer invasiveness has not been elucidated. We evaluated the role of BAs, in particular deoxycholic acid (DCA), in OAC invasion. Migration and invasiveness in untreated and BA-treated oesophageal SKGT-4 cancer cells were evaluated. Activity and expression of different matrix metalloproteinases (MMPs) were determined by zymography, ELISA, PCR and Western blot. Finally, human OAC tissues were stained for MMP-10 by immunohistochemistry. It was found that SKGT-4 cells incubated with low concentrations of DCA had a significant increase in invasion. In addition, MMP-10 mRNA and protein expression were also increased in the presence of DCA. MMP-10 was found to be highly expressed both in-vitro and in-vivo in neoplastic OAC cells relative to non-neoplastic squamous epithelial cells. Our results show that DCA promotes OAC invasion and MMP-10 overexpression. This study will advance our understanding of the pathophysiological mechanisms involved in human OAC and shows promise for the development of new therapeutic strategies.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Ácido Desoxicólico/farmacologia , Neoplasias Esofágicas/patologia , Esôfago/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 10 da Matriz/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Apoptose , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Colagogos e Coleréticos/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/enzimologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/enzimologia , Carcinoma de Células Escamosas do Esôfago/patologia , Esôfago/efeitos dos fármacos , Esôfago/enzimologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Prognóstico , Células Tumorais Cultivadas
8.
Dokl Biochem Biophys ; 493(1): 208-210, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32894467

RESUMO

Human colorectal adenocarcinoma cell line Caco-2 is often used as a model of healthy intestinal epithelium, in particular, in miRNA studies. The work of the enzymes Drosha and Dicer is an integral part of the process of miRNA formation. Inaccuracies in the work of these enzymes lead to a change in the nucleotide sequences of miRNAs with the formation of new isoforms, which, in turn, can change intracellular regulatory mechanisms. In the framework of this study, it was shown that the quantitative estimates of inaccuracies in Drosha and Dicer activity significantly differ between the specimens of normal colon tissue and malignant colorectal tumors.


Assuntos
Adenocarcinoma/metabolismo , Colo/metabolismo , Neoplasias Colorretais/metabolismo , RNA Helicases DEAD-box/metabolismo , MicroRNAs/metabolismo , Ribonuclease III/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Estudos de Casos e Controles , Colo/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Biologia Computacional , RNA Helicases DEAD-box/genética , Bases de Dados Genéticas , Humanos , MicroRNAs/genética , Ribonuclease III/genética
9.
Cancer Control ; 27(1): 1073274820954458, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32959672

RESUMO

INTRODUCTION: Using the TMN classification alone to predict survival in patients with gastric cancer has certain limitations, we conducted this study was to develop an effective nomogram based on aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio to predict overall survival (OS) in surgically treated gastric cancer. METHODS: we retrospectively analyzed 190 cases of gastric cancer and used Cox regression analysis to identify the significant prognostic factors for OS in patients with resectable gastric cancer. The predictive accuracy of nomogram was assessed using a calibration plot, concordance index (C-index) and decision curve. This was then compared with a traditional TNM staging system. Based on the total points (TPS) by nomogram, we further divided patients into different risk groups. RESULTS: multivariate analysis of the entire cohort revealed that independent risk factors for survival were age, clinical stage and AST/ALT ratio, which were entered then into the nomogram. The calibration curve for the probability of OS showed that the nomogram-based predictions were in good agreement with actual observations. Additionally, the C-index of the established nomogram for predicting OS had a superior discrimination power compared to the TNM staging system [0.794 (95% CI: 0.749-0.839) vs 0.730 (95% CI: 0.688-0.772), p < 0.05]. Decision curve also demonstrated that the nomogram was better than the TNM staging system. Based on TPS of the nomogram, we further subdivided the study cohort into 3 groups including low risk (TPS ≤ 158), middle risk (158 < TPS ≤ 188) and high risk (TPS > 188) categories. The differences in OS rate were significant among the groups. CONCLUSION: the established nomogram is associated with a more accurate prognostic prediction for individual patients with resectable gastric cancer.


Assuntos
Adenocarcinoma/secundário , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores Tumorais/sangue , Gastrectomia/mortalidade , Nomogramas , Neoplasias Gástricas/patologia , Adenocarcinoma/sangue , Adenocarcinoma/enzimologia , Adenocarcinoma/cirurgia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida
10.
J Cancer Res Clin Oncol ; 146(11): 2843-2850, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32725356

RESUMO

PURPOSE: Demethylation of DNA through enzymes like LSD1 showed a crucial impact on different kind of cancers. Epigenetic modifications in cervical cancer are still not fully investigated nevertheless of high interest for a therapeutic use. METHODS: Tumor samples of 250 cervical cancer patients were immunochemically stained and evaluated based on Immunoreactive Score. Results were statistically analyzed for clinical and pathological parameters. RESULTS: Our patient collective showed a disadvantage for 10-year survival for patients with a strong expression of LSD1 in the cytoplasm of cervical cancer cells. The results of the correlational analysis further revealed a negative correlation of LSD1 to G-protein coupled estrogen receptor (GPER). CONCLUSIONS: Epigenetic changes through enzymes like LSD1 may also be of interest for patients with cervical cancer. A combined therapy with other proteins relayed to cervical cancer like GPER might be of interest for future investigations.


Assuntos
Adenocarcinoma/enzimologia , Carcinoma de Células Escamosas/enzimologia , Histona Desmetilases/metabolismo , Neoplasias do Colo do Útero/enzimologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Feminino , Histona Desmetilases/análise , Humanos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/patologia
11.
Gene ; 754: 144859, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32535049

RESUMO

DNA topoisomerases essentially remove topological strains generated during DNA replication, transcription, DNA repair, and other cytogenetic processes. However, distinct expression level and prognostic significance of individual topoisomerase isoforms in gastric cancer (GC) remain largely unexplored. In this study, we utilized Oncomine and Kaplan-Meier plotter database to detect the mRNA expression level of individual topoisomerase isoforms as well as assess their prognostic significance in GC patients. With the exception of TOP3B and TOP2B, levels of all topoisomerase isoforms were found to be elevated in GC patients when compared to the normal tissues. Elevated expression of TOP1 and TOP1MT was relevant to longer overall survival (OS) in GC and gastric intestinal type adenocarcinoma (GITA) patients, but not in diffuse gastric adenocarcinoma (DFA) patients. Increased expression of TOP2A and TOP2B was related to better OS in GC, as well as in GITA and DFA patients. In contrast, increased expression TOP3A and TOP3B was associated with shorter OS in GC, as well as in GITA and DFA patients. We also applied the Tumor IMmune Estimation Resource (TIMER) tool to assess the correlations between distinct topoisomerase isoforms and the infiltrating immune cell landscape. Furthermore, we found that down-regulating the expression of TOP3A by shRNA significantly inhibited the proliferation and colony formation in GC cells compared to control shRNA treated cells. Thus our study lays the framework for utilizing topoisomerases in better understanding the complexity and heterogeneity of GC and for developing strategies for novel customized therapy in GC patients.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Neoplasias Gástricas/patologia , Adenocarcinoma/enzimologia , Biomarcadores Tumorais/genética , DNA Topoisomerases Tipo II/genética , Precursores Enzimáticos , Perfilação da Expressão Gênica , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prognóstico , Neoplasias Gástricas/enzimologia , Taxa de Sobrevida
12.
Medicine (Baltimore) ; 99(26): e20950, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590806

RESUMO

BACKGROUND: Glioma-associated oncogene homolog 1(GLI1) expression correlates with the clinical significance and prognosis of several cancers. However, the evaluation of the role GLI1 expression plays in pancreatic ductal adenocarcinoma (PDAC) clinicopathological features and outcomes still lacks. OBJECTIVE: The present study systemic reviewed the association of GLI1 expression and clinical significance as well as patients survival in PDAC. METHODS: We systematically searched the database of The Cochrane Library, PubMed, Embase, CNKI, Weipu data, and Wanfang data according to the inclusion and exclusion criteria. (The search ended on January 1, 2019; no language restrictions). The Newcastle-Ottawa Scale (NOS) scale was implemented to assess the quality of the literature and the Review Manager 5.3 Software was used to conduct a meta-analysis. Finally, 9 studies, a total of 1058 patients, have been included. RESULTS: GLI1 is more likely expressed in PDAC tissue rather than para-carcinoma tissue (OR = 2.86, 95%CI = 1.87-4.36, P < .00001). GLI1 expression is associated with the TNM stage (OR = 3.11, 95%CI = 2.01-4.79, P < .00001), perineural invasion (OR = 2.50, 95%CI = 1.28-4.91, P = .008), and lymphatic metastasis (OR = 2.73, 95%CI = 1.71-4.36, P < .0001). But the association with differentiation (OR = 1.20, 95%CI = 0.74-1.96, P = .46) and tumor size (OR = 2.41, 95%CI = 0.97-6.00, P = .06) was not significant. GLI1 expression is related to the worse overall survival in PDACs (HR = 1.68, 95%CI = 1.40-2.02, P < .00001). CONCLUSION: Positive GLI1 expression promotes the progression and metastasis of PDACs and plays an important role in the clinical significance and the patients survival.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Prognóstico , Proteína GLI1 em Dedos de Zinco/análise , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/genética , Humanos
13.
Int J Biochem Cell Biol ; 125: 105777, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32504672

RESUMO

OBJECTIVE: Fraxetin, extracted from the bark of Fraxinus rhynchophylla, has been shown to exhibit antitumour and anti-inflammatory pharmacological properties. However, the mechanism underlying its anticancer activity towards colon adenocarcinoma (COAD) is not well understood. We aimed to determine the antitumour effect of fraxetin on COAD cell lines and elucidate its biochemical and molecular targets. METHODS: The cell lines HCT116 and DLD-1 were used to evaluate the in vitro antitumour efficacy of fraxetin. Cytotoxicity and viability were assessed by CCK-8 and plate colony formation assays. Flow cytometry was used to assess apoptosis and cell cycle progression in fraxetin-treated COAD cells. Western blot, RT-qPCR, molecular docking, immunohistochemical, and immunofluorescence analyses were used to gain insights into cellular and molecular mechanisms. Preclinical curative effects were evaluated in nude mouse xenograft models. RESULTS: Fraxetin significantly inhibited COAD cell proliferation in both dose- and time-dependent manners, specifically by inducing S-phase cell cycle arrest and triggering intrinsic apoptosis. Additionally, the level of p-JAK2 was decreased by fraxetin via the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway. Interestingly, in COAD cells, fraxetin directly targeted the Y1007 and Y1008 residues of JAK2 to suppress its auto- or transphosphorylation, leading to decreased activation of its downstream effector STAT3 and blocking its nuclear translocation. Finally, fraxetin exhibited good tumour growth suppression activity and low toxicity. CONCLUSIONS: Fraxetin inhibits the proliferation of COAD cells by regulating the JAK2/STAT3 signalling pathway, providing evidence that targeting JAK2 with fraxetin may offer a novel potential auxiliary therapy for COAD treatment.


Assuntos
Adenocarcinoma/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Colo/metabolismo , Cumarínicos/farmacologia , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Cumarínicos/química , Cumarínicos/uso terapêutico , Fraxinus/química , Humanos , Janus Quinase 2/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Fosforilação , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
BMC Med Genet ; 21(1): 130, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539715

RESUMO

BACKGROUND: Colon adenocarcinoma (COAD) is the most common form of colon cancer. The glutathione S-transferase Mu (GSTM) gene belongs to the GST gene family, which functions in cell metabolism and detoxification. The relationship between GSTM and COAD and the underlying mechanism remain unknown. METHODS: Data extracted from The Cancer Genome Atlas included mRNA expression and clinical information such as gender, age, and tumor stage. Prognostic values of GSTM genes were identified by survival analysis. Function and mechanism of prognostic GSTM genes were identified by gene set enrichment analysis. A nomogram was used to predict the contribution of risk factors to the outcome of COAD patients. RESULTS: Low expression of GSTM1 and GSTM2 was related to favorable OS (adjusted P = 0.006, adjusted HR = 0.559, 95% CI = 0.367-0.849 and adjusted P = 0.002, adjusted HR = 0.519, 95% CI = 0.342-0.790, respectively) after adjusting for tumor stage. Enrichment analysis also showed that genes involved were related to cell cycle, metabolism, and detoxification processes, as well as the Wnt signaling and NF-κB pathways. CONCLUSIONS: In conclusion, low expression of GSTM1 and GSTM2 were significantly associated with favorable prognosis in COAD. These two genes may serve as potential biomarkers of COAD prognosis.


Assuntos
Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Glutationa Transferase/genética , Família Multigênica , Análise de Dados , Regulação Enzimológica da Expressão Gênica , Ontologia Genética , Humanos , Prognóstico , Análise de Sobrevida
15.
Pathol Res Pract ; 216(6): 152965, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32360251

RESUMO

BACKGROUND: In the United States endometrial carcinoma is the most common female gynecologic malignancy. An average of more than 60,000 new cases of endometrial carcinomas have been diagnosed yearly over the past 5 years, with a higher incidence occurring in the central Appalachian states of Ohio and West Virginia. In the U.S., the national average of newly diagnosed endometrial carcinomas is 26.8 in every 100,000 women, while in the states of Ohio and West Virginia the average is 30.5 and 31.1 in every 100,000 women, respectively. This notable increase in the incidence of endometrial carcinomas may be due a variety of elevated risk factors including but not limited to: tobacco use, obesity, and genetic predisposition of the predominant demographic. The American Cancer Society estimates that approximately 55,000 new cases of endometrial carcinoma will be diagnosed in 2020 yet, this disease is widely considered understudied and under-represented in mainstream cancer research circles. METHODS: The aim of this study was to quantitate the co-expression of two DNA repair proteins poly-ADP-ribose polymerase 1 and 2 (Parp-1 and Parp-2) by enzyme- linked immuno-sorbent assay (ELISA) in 60 endometrioid endometrial tumor samples and compare their expression to matched non-malignant endometrial tissue from the same corresponding donors from central Appalachia. RESULTS: We found that Parp-1 was significantly overexpressed in endometrial carcinoma relative to corresponding normal tissue. This overexpression implicates Parp inhibition therapy as a possible treatment for the disease. Our results also found a protective effect of native Parp-2 expression in non-malignant endometrial tissue with each 1 ng/mL increase in PARP-2 concentration in normal tissue was associated with a 10 % reduction in the hazard of tumor progression (HR = 0.90; p = 0.039) and a 21 % reduction in the hazard of death (HR = 0.79; p = 0.044). CONCLUSIONS: This study demonstrated the over-expression of the druggable target Parp-1 in endometrial adenocarcinoma and observed a strong negative correlation of native Parp-2 expression and disease progression via the quantification of the Parp proteins using enzyme- linked immuno-sorbent assay (ELISA) assays.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias do Endométrio/patologia , Poli(ADP-Ribose) Polimerase-1/biossíntese , Poli(ADP-Ribose) Polimerases/biossíntese , Adenocarcinoma/enzimologia , Idoso , Neoplasias do Endométrio/enzimologia , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico
16.
PLoS One ; 15(5): e0233208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428030

RESUMO

To facilitate functional investigation of the role of NADPH oxidase 1 (NOX1) and associated reactive oxygen species in cancer cell signaling, we report herein the development and characterization of a novel mouse monoclonal antibody that specifically recognizes the C-terminal region of the NOX1 protein. The antibody was validated in stable NOX1 overexpression and knockout systems, and demonstrates wide applicability for Western blot analysis, confocal microscopy, flow cytometry, and immunohistochemistry. We employed our NOX1 antibody to characterize NOX1 expression in a panel of 30 human colorectal cancer cell lines, and correlated protein expression with NOX1 mRNA expression and superoxide production in a subset of these cells. Although a significant correlation between oncogenic RAS status and NOX1 mRNA levels could not be demonstrated in colon cancer cell lines, RAS mutational status did correlate with NOX1 expression in human colon cancer surgical specimens. Immunohistochemical analysis of a comprehensive set of tissue microarrays comprising over 1,200 formalin-fixed, paraffin-embedded tissue cores from human epithelial tumors and inflammatory disease confirmed that NOX1 is overexpressed in human colon and small intestinal adenocarcinomas, as well as adenomatous polyps, compared to adjacent, uninvolved intestinal mucosae. In contradistinction to prior studies, we did not find evidence of NOX1 overexpression at the protein level in tumors versus histologically normal tissues in prostate, lung, ovarian, or breast carcinomas. This study constitutes the most comprehensive histopathological characterization of NOX1 to date in cellular models of colon cancer and in normal and malignant human tissues using a thoroughly evaluated monoclonal antibody. It also further establishes NOX1 as a clinically relevant therapeutic target in colorectal and small intestinal cancer.


Assuntos
Adenocarcinoma/enzimologia , Neoplasias do Colo/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Intestino Delgado/enzimologia , NADPH Oxidase 1/biossíntese , Proteínas de Neoplasias/biossíntese , Adenocarcinoma/genética , Adenocarcinoma/patologia , Células CACO-2 , Neoplasias do Colo/genética , Células HT29 , Humanos , Intestino Delgado/patologia , Modelos Biológicos , NADPH Oxidase 1/genética , Proteínas de Neoplasias/genética
17.
Mol Cell Biochem ; 470(1-2): 115-129, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32415418

RESUMO

Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.


Assuntos
Adenocarcinoma/enzimologia , Glicólise , Pâncreas/enzimologia , Neoplasias Pancreáticas/enzimologia , Fosfofrutoquinase-2/fisiologia , Adenocarcinoma/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Citoplasma/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células HeLa , Humanos , Isoenzimas/genética , Isoenzimas/fisiologia , Neoplasias Pancreáticas/patologia , Fenótipo , Fosfofrutoquinase-2/genética , Splicing de RNA , RNA Mensageiro/metabolismo
18.
Mol Biol (Mosk) ; 54(1): 146-152, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32163398

RESUMO

Migration of cancer cells from the primary tumor site to nearby tissues is the starting point of the metastatic process. The invasive properties of cells are especially important for carcinomas, since tumor cells need to overcome the basement membrane and go beyond its boundaries to the underlying tissues. Substances that reduce the invasive ability of malignant cells are promising as antimetastatic agents. In the present work, the possibility of inhibiting the ability of different cancer cell lines to migrate under the influence of the Bacillus pumilus ribonuclease (binase) was analyzed using the scratch-wound assay. It was established that binase at non-toxic concentrations (10 µg/mL) reliably suppressed the migratory ability of HuTu 80 human duodenum adenocarcinoma cells incubated with RNase for 48-72 h. The antimetastatic potential of binase is confirmed by molecular modeling data demonstrating the ability of binase to inhibit cellular metalloproteinases that determine the migration of tumor cells.


Assuntos
Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Movimento Celular/efeitos dos fármacos , Duodeno/patologia , Ribonucleases/metabolismo , Ribonucleases/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Metaloproteases/antagonistas & inibidores , Metaloproteases/metabolismo
19.
JCI Insight ; 5(3)2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32051337

RESUMO

Lung cancer (LC) is a leading cause of cancer-related deaths worldwide. Its rapid growth requires hyperactive catabolism of principal metabolic fuels. It is unclear whether fructose, an abundant sugar in current diets, is essential for LC. We demonstrated that, under the condition of coexistence of metabolic fuels in the body, fructose was readily used by LC cells in vivo as a glucose alternative via upregulating GLUT5, a major fructose transporter encoded by solute carrier family 2 member 5 (SLC2A5). Metabolomic profiling coupled with isotope tracing demonstrated that incorporated fructose was catabolized to fuel fatty acid synthesis and palmitoleic acid generation in particular to expedite LC growth in vivo. Both in vitro and in vivo supplement of palmitoleic acid could restore impaired LC propagation caused by SLC2A5 deletion. Furthermore, molecular mechanism investigation revealed that GLUT5-mediated fructose utilization was required to suppress AMPK and consequently activate mTORC1 activity to promote LC growth. As such, pharmacological blockade of in vivo fructose utilization using a GLUT5 inhibitor remarkably curtailed LC growth. Together, this study underscores the importance of in vivo fructose utilization mediated by GLUT5 in governing LC growth and highlights a promising strategy to treat LC by targeting GLUT5 to eliminate those fructose-addicted neoplastic cells.


Assuntos
Adenilato Quinase/metabolismo , Ácidos Graxos/biossíntese , Frutose/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Neoplasias Pulmonares/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transdução de Sinais , Células A549 , Adenocarcinoma/enzimologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Estudos de Coortes , Glucose/metabolismo , Xenoenxertos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Análise de Sobrevida
20.
Medicine (Baltimore) ; 99(3): e18726, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011450

RESUMO

Immune-checkpoint inhibitor (ICI) efficacy in patients with non-small cell lung cancer (NSCLC) harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against epidermal growth-factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1)-mutated NSCLC patients in the real-world setting.In this retrospective, multicenter study on adults with ICI-treated EGFR-mutated or ALK- or ROS1-translated NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, and progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS) from immunotherapy initiation.Fifty-one NSCLC patients (mean age, 58.0 years) were included from 20 French centers: 61% were never-smokers and 59% were women. Among them, 82% had EGFR-activating mutations, 16% ALK translocations, or 2% ROS1 translocations. Before ICI therapy, patients had received a median of 3 treatment lines (including tyrosine-kinase inhibitor). The median PFS was 2.1 (95% confidence interval [CI], 1.5-3.2) months for the entire cohort, 2.2 (95% CI, 1.4-3.2) for EGFR-mutated patients, and 2.4 (95% CI, 2.1-not reached) months for ALK-translocated patients. The median OS was 14.7 (95% CI, 12.1-19.2) months for the entire population and 13.9 (95% CI, 8.8-20.0) and 19.2 (95% CI, 13.1-not reached) months for EGFR-mutated and ALK-translocated patients, respectively. Seven (13.7%) patients were treated with ICI for >9 months. Toxicities were reported in 22% (11/51), including 8% (4/51) grade ≥3.In this real-world setting, analysis of ICI PFS against EGFR-mutated or ALK-translocated NSCLC patients appeared close to that observed in pretreated unselected NSCLC patients. The more promising OS probably linked to post-ICI treatments. Large prospective studies on these patient subsets are needed.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Quinase do Linfoma Anaplásico/genética , Receptores ErbB/genética , Feminino , França , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Receptores Proteína Tirosina Quinases/genética , Estudos Retrospectivos , Translocação Genética
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