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1.
Adv Exp Med Biol ; 1164: 199-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576550

RESUMO

Cancer cell heterogeneity is a universal feature of human tumors and represents a significant barrier to the efficacy and duration of anticancer therapies, especially targeted therapeutics. Among the heterogeneous cancer cell populations is a subpopulation of relatively quiescent cancer cells, which are in the G0/G1 cell-cycle phase and refractory to anti-mitotic drugs that target proliferative cells. These slow-cycling cells (SCCs) preexist in untreated tumors and frequently become enriched in treatment-failed tumors, raising the possibility that these cells may mediate therapy resistance and tumor relapse. Here we review several general concepts on tumor cell heterogeneity, quiescence, and tumor dormancy. We discuss the potential relationship between SCCs and cancer stem cells (CSCs). We also present our current understanding of how SCCs and cancer dormancy might be regulated. Increasing knowledge of SCCs and tumor dormancy should lead to identification of novel molecular regulators and therapeutic targets of tumor relapse, residual diseases, and metastasis.


Assuntos
Ciclo Celular , Neoplasias , Ciclo Celular/fisiologia , Humanos , Neoplasias/fisiopatologia , Células-Tronco Neoplásicas/citologia
2.
Anticancer Res ; 39(10): 5297-5310, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570424

RESUMO

BACKGROUND/AIM: Low-molecular weight heparins (LMWHs) may possess putative antitumoral properties; however, the underlying mechanism(s) remains elusive. We evaluated the antiproliferative and antimigratory effects of enoxaparin (a LMWH) in lung adenocarcinoma A549 cells, and assessed the possible mechanism involved, and the effect on doxorubicin's efficacy. MATERIALS AND METHODS: Proliferation and migration were evaluated using BrdU and transwell assays, respectively. Immunoblotting was used to measure PAR-1, PAR-2, MMP-2, ERK1/2 and Akt proteins. Apoptosis and cell cycle studies examined the combined effect of enoxaparin and doxorubicin. RESULTS: Enoxaparin inhibited A549 cell proliferation and migration. Following PAR-1 gene knock down, enoxaparin's effect on A549 cell proliferation was diminished compared to scrambled siRNA. Our experiments verified that enoxaparin-mediated down-regulation of MAPK and PI3K, reduced MMP-2 expression and inhibited A549 cell migration. Additionally, enoxaparin increased doxorubicin's efficacy by enhancing apoptosis, while no effect on cell-cycle progression was observed. CONCLUSION: Results suggest that the anticancer activity of enoxaparin in A549 cells was mediated by the interference of two major PAR-1 downstream signaling pathways, MAPK/ERK and PI3K/Akt, which in turn inhibit proliferation and migration. Therefore, enoxaparin may be promising as an adjunct to traditional chemotherapy for lung cancer and warrants further investigation.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Enoxaparina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Receptor PAR-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo
3.
Anticancer Res ; 39(10): 5311-5327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570425

RESUMO

BACKGROUND/AIM: MiR-221, often described both as an oncogenic microRNA and as a tumour suppressor, targets mRNAs involved in carcinogenesis. While other oncogenic microRNAs showed correlations with prostate cancer cell lines' aggressiveness, miR-221 showed an unusual overexpression in PC3. MATERIALS AND METHODS: CRISPR was used to delete miR-221 from PC3 cells. Analysing the characteristics of PC3miR-221del cells, a reduced growth rate and expression of cell-cycle genes was observed. In global gene expression/ontology analysis of PC3miR-221del cells, cell-cell and cell-substrate adhesion pathways were found to be greatly affected. In addition, reduced levels of adhesion, invasion and motility for PC3miR-221del cells, a change in F-actin localisation and a reduction of EMT markers were observed. RESULTS: The tumour suppressor gene, DIRAS3, was a predicted target of miR-221. In PC3miR-221del cells DIRAS3 was up-regulated at the gene and protein level. Ectopic expression of DIRAS3 in PC3wt cells recapitulated the cellular morphology changes seen in PC3miR-221del cells. DIRAS3 3'UTR was more stable in PC3miR-221del cells, as measured by semi-quantitative PCR and luciferase fusion reporter assays. CONCLUSION: MiR-221 promotes aggressiveness of PC3 cells by down-regulating DIRAS3, and promoting epithelial-to-mesenchymal transition.


Assuntos
Adesão Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , MicroRNAs/genética , Deleção de Sequência/genética , Regiões 3' não Traduzidas/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Oncogenes/genética , Células PC-3 , Neoplasias da Próstata/genética , Regulação para Cima/genética , Proteínas rho de Ligação ao GTP/genética
4.
Anticancer Res ; 39(9): 4637-4642, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519561

RESUMO

AIM: The aim of this study was to characterize the role of Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1 (AMMECR1) in human lung cancer cell lines. MATERIALS AND METHODS: AMMECR1 gene expression was evaluated in four lung cell lines, with A549 then selected for further in-depth examination. To characterize the role of AMMECR1, silencing was achieved utilizing lentivirus-mediated RNA interference, and confirmed by quantitative real-time polymerase chain reaction and western blotting. The impact of AMMECR1 silencing on cellular proliferation was assessed using Celigo-based and MTT assays. Apoptosis was determined using the annexin V-allophycocyanin single staining method. Cell-cycle arrest was assessed by flow cytometry. Finally, colony formation was assessed using Giemsa staining. RESULTS: In A549 cells, AMMECR1 silencing was found to significantly suppress cell proliferation, reduce colony formation, promote apoptosis, and arrest cells in the S and G2/M phases. CONCLUSION: AMMECR1 plays a critical role in cell proliferation, cell-cycle progression, and apoptosis of human lung cancer cells, and may serve as a potential therapeutic target for non-small-cell lung cancer.


Assuntos
Apoptose/genética , Ciclo Celular/genética , Neoplasias Pulmonares/genética , Proteínas/genética , Células A549 , Linhagem Celular Tumoral , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas/metabolismo , RNA Mensageiro/genética
5.
Anticancer Res ; 39(9): 4757-4766, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519576

RESUMO

BACKGROUND/AIM: Azacitidine (AZA) is a hypomethylating agent used in myeloid neoplasms, however, approximately half of patients show treatment failure or relapse. This in vitro study investigated the effect of the combination of AZA with the natural compound curcumin (CUR) in increasing its efficacy. MATERIALS AND METHODS: We analyzed the effects of AZA plus CUR on proliferation, apoptosis, cell cycle and differentiation in myeloid leukemic cell lines (U-937, HL-60, K-562, and OCI-AML3) and bone marrow samples of patients. RESULTS: The results showed a synergy between AZA and CUR in all leukemic lines and in most leukemic samples, with a decrease in proliferation and an increase in apoptosis compared to the activity of each drug separately. In addition, AZA plus CUR showed low cytotoxicity in healthy samples. CONCLUSION: A remarkable antioncogenic effect of the combination of AZA plus CUR was shown, providing a basis for future studies analyzing the clinical efficacy of these drugs.


Assuntos
Antineoplásicos/farmacologia , Azacitidina/farmacologia , Curcumina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Mieloide/genética , Masculino , Síndromes Mielodisplásicas/genética
6.
Anticancer Res ; 39(9): 4795-4803, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519581

RESUMO

BACKGROUND/AIM: To determine the mechanism of vitamin D3-induced modulation of antioxidant-related factors in endometrial cancer, we investigated their role in apoptosis of human endometrial cancer cells exposed to vitamin D3 Materials and Methods: The survival rate of human endometrial cancer cells was estimated after treatment with activated vitamin D3 Reactive oxygen species (ROS) levels were measured using flow cytometry. The levels of VDR, Trx, TXNIP and apoptosis-related proteins were investigated using western blotting and immunocytochemistry in human tissues. RESULTS: Treatment with D3 induced apoptotic cell death and cell-cycle arrest by increasing ROS concentration. Vitamin D3 inhibited proliferation of human endometrial cancer cells. It regulated intracellular ROS concentration in endometrial cancer cells via increased TXNIP expression. CONCLUSION: Antioxidant regulation via TXNIP is an important cell death mechanism in human endometrial cancer, and occurs via induction by vitamin D3.


Assuntos
Antioxidantes/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias do Endométrio/metabolismo , Tiorredoxinas/metabolismo , Vitamina D/análogos & derivados , Apoptose/efeitos dos fármacos , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Vitamina D/farmacologia
7.
Anticancer Res ; 39(9): 4805-4810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519582

RESUMO

BACKGROUND/AIM: Ro 90-7501 has been reported as an inhibitor of the amyloid ß42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. MATERIALS AND METHODS: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. RESULTS: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. CONCLUSION: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.


Assuntos
Aminas/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzimidazóis/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo
8.
Anticancer Res ; 39(9): 4829-4835, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519585

RESUMO

BACKGROUND/AIM: Chronic lymphocytic leukemia (CLL) still remains an incurable disease as the cells evade apoptosis, which is an obstacle for current therapeutic approaches. Therefore, our aim was to identify an ideal target of leukemic cell growth for developing inhibitors. MATERIALS AND METHODS: Mouse lymphocytic leukemia cell line L1210, human Toledo cells and a DBA/2 mouse graft model were used to analyze the activity of dual mTORC1/2 inhibitor AZD2014s. Western blotting and flow cytometry were performed to determine the mechanism. RESULTS: AZD2014 inhibited L1210 and human Toledo cell proliferation. Treatment with AZD2014 reduced the phosphorylation levels of S6K1 and 4EBP1 and the protein levels of Rictor, a component of the mTORC2 pathway. AZD2014 induced cell cycle arrest at the G0-G1 phase by reducing the expression of cyclin D1 and CDK4. Oral administration of AZD2014 significantly inhibited the growth of L1210 cell grafts in DBA/2 mice. CONCLUSION: The mTORC1/2 inhibitor may be a better therapeutic agent compared to PI3K/mTORC1 inhibitors for treating patients with CLL.


Assuntos
Antineoplásicos/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucemia Linfoide/tratamento farmacológico , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patologia , Masculino , Camundongos , Morfolinas/farmacologia
9.
Anticancer Res ; 39(9): 4837-4843, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519586

RESUMO

BACKGROUND/AIM: The antiparasitic drug, ivermectin (IVM), exerts anticancer activities in diverse cancer types. However, its anticancer activity against cholangiocarcinoma (CCA), especially the drug-resistant phenotype, has not yet been explored. MATERIALS AND METHODS: IVM was tested for its anticancer activity against gemcitabine-sensitive (KKU214) and gemcitabine-resistant (KKU214GemR) CCA cell lines in vitro using the sulforhodamine B and clonogenic assays as well as cell-cycle analysis. RESULTS: IVM treatment inhibited cell proliferation and colony formation of both KKU214 and KKU214GemR in a dose- and time-dependent manner. KKU214GemR cells were more sensitive than KKU214 to IVM treatment. IVM treatment caused S-phase cell-cycle arrest and also cell death as indicated by an increase of sub-G0/G1 population in KKU214GemR cells treated with IVM for 48 h. CONCLUSION: IVM exerts anti-CCA activities and gemcitabine-resistant KKU214GemR cells are more sensitive to IVM treatment. Thus, IVM might be useful as an alternative treatment for CCA, especially in patients who do not respond to gemcitabine.


Assuntos
Antiparasitários/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Ivermectina/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo
10.
Adv Exp Med Biol ; 1159: 109-138, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31502202

RESUMO

Despite the advancements in modern medicine, there are still difficulties in diagnosing common illnesses. The invasiveness and price of the tests used to follow up certain diseases can be a barrier to proper patient follow-up. Sphingolipids are a diverse category of lipids. They are structural molecules in cell membranes and signaling molecules involved in the regulation of crucial cell functions, including cell growth, differentiation, proliferation and apoptosis. Recent research has shown that abnormal sphingolipid metabolism is associated with genetic and metabolic disease processes. Given their crucial role to maintain homeostasis within the body, sphingolipids have been investigated as potential biomarkers to predict disease in the population. Here we discuss how sphingolipids levels are altered in different diseases, thus illustrating their possible use as diagnostic and prognostic biomarkers for disease.


Assuntos
Biomarcadores , Transdução de Sinais , Esfingolipídeos , Ciclo Celular , Membrana Celular , Homeostase , Humanos
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1259-1264, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418390

RESUMO

OBJECTIVE: To explore the role of bone marrow microenvironment(niche) in the development of acute myeloid leukemia (AML) and the effect of AML patients-derived MSC on the proliferation, cell cycle and immuno-phenotypes of HL-60 cells. METHODS: The MSC derived from bone marrow of patients with newly diagnosed AML were isolated and co-cultured with HL-60 cells. The effect of MSC on proliferation of HL-60 cells was detected by using 3H-TdR incorporation method, the cell cycle and immunophenotypes of HL-60 cells were detected by flow cytometry. RESULTS: The results of 3H-TdR incorporation assay showed that both AML-MSCs and normal MSCs remarkably suppressed the HL-60 cell proliferation in a time- and dose-dependent manner. The results of cell cycle analysis demonstrated that AML MSCs and normal MSCs induced arrest of the HL-60 cells in G0/G1 phase. The results of immunophenotyping revealed that MSCs suppressed the expression of CD11a and CD154 on the surface of HL-60 cells. Moreover, AML MSCs exhibited increased inhibitory effects than that of normal MSCs. However, no remarkable effect of MSCs on CD54 expressions of HL-60 cells was observed in the current study. CONCLUSION: AML-MSCs possess effects on HL-60 cell proliferation, cell cycle and immunophenotypes similiar to normal MSCs, but exhibited increased suppressive capacity on the expression of CD11a and CD154.


Assuntos
Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Células da Medula Óssea , Ciclo Celular , Proliferação de Células , Células HL-60 , Humanos , Imunofenotipagem , Microambiente Tumoral
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1265-1271, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418391

RESUMO

OBJECTIVE: To explore the effect of bone morphogenetic protein 4(BMP4) on the cell cycle and apoptosis of hemaropoictic stem and progenitor cells (HSPC) in conditions of 5-fluorouracil (5-FU)-inducing bone marrow suppression and stress hemogenesis, and its possible mechanism. METHODS: The C57BL transgenic mice with BMP4 overexpression were established and were enrolled in transgenic group (BMP4 group), at the same time the wild type mice matching in age, sex and body weight were selected and were enrolled in control group (WT group). The bone marrow suppression was induced by injection with 5-FU in dose of 150 mg/kg, then the nucleated cells were isolated from bone marrow. After the HSPCs were markered with C-kit/sca-1 fluorescent antibodies, the changes of cell cycle and apoptosis of HSPC were detected by Aunexin V/PI and Ki67/DAPI double staining; the cell cycle-essociated hemotopoietic regulatory factors were detected by RT-qPCR. RESULTS: Under physiologic status, there were no significant differences in cell cycle and apoptotic rate of HSPC between WT group and BMP-4 group. After the bone marrow was suppressed, the ratio of HSPC at G0 phase in BMP4 group significantly decreased(P<0.05); the apoptosis rate of HSPC significantly increased(P<0.05); the mRNA expression levels of hypoxia-inducing factor Hif-1α and chemotactic factor CXCL12 in stroma of BMP4 group were down-regulated significanfly(P<0.05). CONCLUSION: Under non-physiologic conditions such as stress hemogenesis or bone marrow suppression, the up-regulation of BMP4 can promote HSPC into cell cycle and apoptosis of HSPC, moreover, the BMP4 may play a regulatory role for cell cycle of HSPC through direct or indirect down-regulation of Hif-1α and CXCL-12 expressions.


Assuntos
Células-Tronco Hematopoéticas , Animais , Antineoplásicos , Apoptose , Proteína Morfogenética Óssea 4 , Ciclo Celular , Camundongos , Camundongos Endogâmicos C57BL
13.
Anticancer Res ; 39(8): 4031-4041, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366485

RESUMO

BACKGROUND/AIM: Eribulin is currently used to treat advanced and metastatic breast cancer in the clinical setting; however, its efficacy is inhibited by resistance acquisition in many cases. Thus, the present study established two eribulin-resistant breast-cancer cell lines, and used these to investigate the mechanisms that underly eribulin-resistance acquisition. MATERIALS AND METHODS: Eribulin-resistant breast-cancer cell lines were generated by culturing MDA-MB-231 and MCF-7 cells with increasing concentrations of eribulin. RESULTS: The eribulin-resistant cells acquired resistance to eribulin, as well as several other anticancer drugs. After eribulin treatment, the eribulin-resistant cell lines showed no morphological change, no increased expression of epithelial-cadherin, nor any significant alteration in cell-cycle distribution. In contrast, the expression levels of programmed death-ligand 1 were increased in the MCF-7/eribulin-resistant compared to MCF-7 cells. CONCLUSION: The herein developed eribulin-resistant cell lines acquired cross-resistance to various anticancer agents, and displayed resistance to eribulin-induced effects on microtubule function and epithelial-mesenchymal transition (EMT).


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Furanos/administração & dosagem , Cetonas/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Células MCF-7 , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Anticancer Res ; 39(8): 4165-4170, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366501

RESUMO

AIM: To examine the influence of hypoxia on the in vitro growth of leukaemia cells and the activity of signalling proteins to better understand the pathophysiology of leukaemia cells in human bone marrow. MATERIALS AND METHODS: Six human leukaemia cell lines were cultured under normoxic or hypoxic conditions. Cell growth, recovery of clonogenic cells, and the expression and activation of various signalling proteins were examined. RESULTS: Hypoxia suppressed cell growth and the recovery of clonogenic cells. Moreover, hypoxia up-regulated hypoxia-inducible factor (HIF) 1α and HIF2α expression while suppressing the expression and activation of NOTCH1, mechanistic target of rapamycin kinase (mTOR) activation, and nuclear factor-kappa B (NF-κB) phosphorylation. CONCLUSION: We found that hypoxia up-regulated HIF expression while it suppressed the self-renewal capacity of leukaemia cells, NOTCH activity, and expression of its down-stream signalling molecules, which differs from previous reports mentioning that HIF activates NOTCH signalling. Our findings serve to further elucidate the in vivo pathophysiology of leukaemia cells.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leucemia/genética , Receptor Notch1/genética , Ciclo Celular/genética , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Leucêmica da Expressão Gênica/genética , Humanos , Leucemia/patologia , NF-kappa B/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
15.
Gene ; 716: 144031, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377314

RESUMO

Circular RNAs (circRNAs), a novel class of widespread and diverse endogenous RNAs, have been identified as critical regulators of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of circRNAs in HCC are largely unknown. In this study, we identified a novel circRNA, circ-IGF1R, in HCC tumour tissues and cell lines. Circ-IGF1R levels were found to be significantly upregulated in HCC tissues compared with levels in paired peritumoural tissues. The high expression levels of circ-IGF1R in HCC were associated with tumour size. Moreover, knocking down circ-IGF1R with siRNA significantly attenuated cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. Further investigation revealed that PI3K/AKT signalling pathway activation was involved in the oncogenic functions of circ-IGF1R in HCC. Our study suggests that circ-IGF1R may be a potential target for the prevention and treatment of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA/metabolismo , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
16.
Zhonghua Bing Li Xue Za Zhi ; 48(8): 626-632, 2019 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-31422594

RESUMO

Objective: To investigate the expression and significance of MNAT1 in non-small cell lung cancer (NSCLC) and to explore the biological impact of MNAT1 expression in lung cancer cells at the cellular level and related signaling pathway. Methods: Forty-eight cases of NSCLC tissues and paired normal tissues was collected at Nanfang Hospital, Southern Medical University from 2015 to 2017. The expression level of MNAT1 was detected by immunohistochemistry, and the relationship between MNAT1 and clinicopathological features was analyzed. The expression of MNAT1 was detected in lung cancer cells, MNAT1 level was analyzed after knocking down in A549 and H322 cells by siRNA; Plasmid vector of overexpressing MNAT1 was constructed, followed by transfecting H1299 cells and observing proliferation and migration at the cellular level. Flow cytometry was used to analyze the effect of the expression of MNAT1 on cell cycle, and Western blot was used to explore the possible molecular mechanism of MNAT1 on cell proliferation and cell cycle. Results: Immunohistochemistry showed that the expression score of MNAT1 was (4.07±3.55) in normal lung tissue and (7.33±4.09) in NSCLC tissue (P<0.01), and correlated with lymph node metastasis. At the cellular level, MNAT1 promoted cell proliferation(P<0.05), migration(P<0.05) and cell cycle progression(P<0.01). Conclusions: MNAT1 may be involved in the development of non-small cell lung cancer.MNAT1 affects cell cycle and proliferation through the Akt/p21 pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas de Transporte , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos
17.
J Cancer Res Clin Oncol ; 145(10): 2457-2468, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31463718

RESUMO

BACKGROUND: Our previous study identified a Wilms tumor-suppressing peptide (WTSP) that was upregulated in healthy children, but downregulated in children with Wilms tumor (WT). This study aimed to investigate the effect of WTSP on WT growth in vivo and in vitro. METHODS: WTSP was synthesized by solid-phase synthesis of FOMC-protected amino acids. Cell growth curve, cytotoxicity, and apoptosis of WTSP-treated human WT cell line (SK-NEP-1) were determined by cell count, Cell Counting Kit-8 assay, and flow cytometry. The expression of key proteins of four WT-associated signaling pathways was determined by real-time PCR and western blotting. The WT xenograft mouse model was established by the armpit injection of SK-NEP-1 cells. The TUNEL assay was used to detect apoptosis in mouse tumor cells. RESULTS: WTSP inhibited the proliferation of SK-NEP-1 cells in a dose- and time-dependent manner, and it arrested SK-NEP-1 cells in G2/M phase. WTSP-treated cells exhibited a low expression of PCNA and Bcl-2 and high expression of Bax. The expression of ß-catenin was markedly changed after WTSP treatment. WTSP-treated mice had significantly smaller tumors than untreated mice. CONCLUSION: Our findings indicated an anti-tumor effect of WTSP, which is correlated with Wnt/ß-catenin pathway. This newly identified peptide may exert a therapeutic effect of WT in the future.


Assuntos
Apoptose/efeitos dos fármacos , Peptídeos/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Camundongos , Peptídeos/síntese química , Peptídeos/química , Transdução de Sinais , Tumor de Wilms/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Results Probl Cell Differ ; 67: 441-485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31435807

RESUMO

The Golgi apparatus is a central intracellular membrane-bound organelle with key functions in trafficking, processing, and sorting of newly synthesized membrane and secretory proteins and lipids. To best perform these functions, Golgi membranes form a unique stacked structure. The Golgi structure is dynamic but tightly regulated; it undergoes rapid disassembly and reassembly during the cell cycle of mammalian cells and is disrupted under certain stress and pathological conditions. In the past decade, significant amount of effort has been made to reveal the molecular mechanisms that regulate the Golgi membrane architecture and function. Here we review the major discoveries in the mechanisms of Golgi structure formation, regulation, and alteration in relation to its functions in physiological and pathological conditions to further our understanding of Golgi structure and function in health and diseases.


Assuntos
Doença , Complexo de Golgi/química , Complexo de Golgi/fisiologia , Saúde , Estresse Fisiológico , Animais , Transporte Biológico , Ciclo Celular , Humanos , Membranas Intracelulares/metabolismo
19.
DNA Cell Biol ; 38(9): 996-1004, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31393166

RESUMO

Osteosarcoma (OS), a highly aggressive bone tumor, mainly occurs in young patients and always presents abnormalities in molecular biology, such as microRNAs (miRNAs). However, the characteristic and underlying mechanism of miR-671-5p in OS are still unclear. In this study, we certify that miR-671-5p is remarkably downregulated in OS tissues and cells. Overexpressed miR-671-5p can suppress OS cell proliferation in vivo and in vitro, by the way of arresting cell-cycle progression. The overexpression of cyclin D1 (CCND1) and CDC34 promotes cell proliferation and cell-cycle promotion, whose functions are contrary to miR-671-5p. miR-671-5p directly binds to CCND1 and CDC34, which are thought as the key factors in regulating cell cycle. Taken together, our results suggest that by targeting CCND1 and CDC34, miR-671-5p plays a tumor suppressor in OS to inhibit the development of OS, implicating it as a novel target for therapeutic intervention in OS.


Assuntos
Ciclo Celular , Proliferação de Células , MicroRNAs/genética , Osteossarcoma/genética , Animais , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação para Baixo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Osteossarcoma/patologia , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
20.
Anticancer Res ; 39(7): 3353-3363, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262856

RESUMO

Vitamin D, or more precisely its active metabolite calcitriol (1,25-(OH)2D3), plays a fundamental role in bone metabolism and differentiation as well as in intestinal absorption of calcium and regulation of calcium-phosphate metabolism. Recent decades have brought about the discovery of the role of calcitriol in processes regulating cell differentiation, proliferation, angiogenesis and apoptosis. This creates the potential for numerous therapeutic applications of vitamin D in diseases associated with autoaggressive immune responses or in cancer. This study presents selected issues regarding current knowledge of the anti-cancer mechanisms of vitamin D.


Assuntos
Neoplasias , Vitamina D/fisiologia , Vitaminas/fisiologia , Animais , Apoptose , Ciclo Celular , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica , Receptores de Calcitriol/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta/efeitos adversos
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