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1.
Aging (Albany NY) ; 13(17): 21483-21496, 2021 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-34511433

RESUMO

2,5-dimethyl celecoxib (DMC), a close derivative of celecoxib, has also been reported to have anticancer effects. However, the effects and underlying molecular mechanisms of DMC with respect to nasopharyngeal carcinoma are still largely unknown. In this study, we present that DMC has displayed anticancer potency in nasopharyngeal carcinoma in vitro and in vivo. Mechanistically, we found DMC induced apoptosis and autophagy for anticancer therapy against nasopharyngeal carcinoma. Furthermore, DMC-induced autophagy could remarkably attenuate after the treatment of reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (SP). Taken together, these results suggested DMC induced apoptosis and autophagic death via activation of ROS/JNK axis in NPC cells, which providing us new insights into developing potential therapeutic agents for nasopharyngeal carcinoma patients.

2.
Breast Cancer Res ; 23(1): 89, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488828

RESUMO

BACKGROUND: Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the "stemness" of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells. METHODS: siRNA and shRNA was used to generate TAZ-depleted TNBC cell lines. qPCR and Southern analysis of terminal restriction fragments techniques were used to test telomere length. Co-immunoprecipitation, Western blotting, immunofluorescence, Luciferase reporter assay and Chromatin-IP were conducted to investigate the underlying mechanism. RESULTS: By knocking down the expression of TAZ in TNBC cells, we found, for the first time, that TAZ is essential for the maintenance of telomeres in TNBC cells. Moreover, loss of TAZ causes senescence phenotype of TNBC cells. The observed extremely shortened telomeres in late passages of TAZ knocked down cells correlate with an elevated hTERT expression, reductions of shelterin proteins, and an activated DNA damage response pathway. Our data also showed that depletion of TAZ results in overexpression of TERRAs, which are a group of telomeric repeat-containing RNAs and regulate telomere length and integrity. Furthermore, we discovered that TAZ maintains telomere length of TNBC cells likely by facilitating the expression of Rad51C, a crucial element of homologous recombination pathway that promotes telomere replication. CONCLUSIONS: This study supports the notion that TAZ is an oncogenic factor in TNBC, and further reveals a novel telomere-related pathway that is employed by TAZ to regulate TNBC.

3.
Sci Transl Med ; 13(579)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536281

RESUMO

Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)-dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion-induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.


Assuntos
Eosinófilos , Traumatismo por Reperfusão , Transferência Adotiva , Animais , Humanos , Interleucina-13 , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
4.
Front Genet ; 11: 931, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005169

RESUMO

Introduction: The Pals1-associated tight junction (PATJ) is a Crumbs (CRB) complex component that regulates epithelial cell apico-basal polarity and directional migration. This study assessed PATJ expression in clear cell renal cell carcinoma (ccRCC) vs. normal tissues and associated with ccRCC progression and prognosis. Methods: The effects of PATJ knockdown were investigated on regulation of normal kidney epithelial cell viability and protein expression in vitro. The PATJ mRNA data in ccRCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and analyzed with UALCAN, LinkedOmics, Kaplan-Meier Plotter, GEPIA, and SurvExpress tools. Immunohistochemistry was performed for PATJ in tissue microarray sections (n = 150 ccRCC and 30 normal renal specimens). Normal human kidney tubular epithelial cell (HKC) cells were transfected with PATJ and negative control siRNA for cell viability CCK-8 assay, flow cytometry, and western blots. Results: The data showed that PATJ mRNA and protein were downregulated in ccRCC tissues and cell lines. Downregulation of PATJ mRNA was associated with male patients, advanced tumor stages, grades, and ccB subtypes as well as poorer overall and disease-free survival of patients. Furthermore, PATJ protein was also significantly downregulated in ccRCC tissues and associated with advanced tumor pathologic, TNM stages and poorer overall. In vitro, knockdown of PATJ expression promoted HKC proliferation and the activation of mitogen-activated protein kinases (MAPK) pathway proteins. Conclusions: This study revealed that a decrease of PATJ in ccRCC, which was associated with male patients, advanced tumor, and poorer survival, suggesting that PATJ may be a useful prognostic biomarker and therapeutic target for ccRCC.

5.
Cytoskeleton (Hoboken) ; 77(8): 303-312, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32748571

RESUMO

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are a large protein complex that is involved in the membrane fusion in vesicle trafficking, cell growth, cytokinesis, membrane repair, and synaptic transmission. As one of the SNARE proteins, SEC22B functions in membrane fusion of vesicle trafficking between the endoplasmic reticulum and the Golgi apparatus, antigen cross-presentation, secretory autophagy, and other biological processes. However, apart from not being SNARE proteins, there is little knowledge known about its two homologs (SEC22A and SEC22C). SEC22B alterations have been reported in many human diseases, especially, many mutations of SEC22B in human cancers have been detected. In this review, we will introduce the specific functions of SEC22B, and summarize the researches about SEC22B in human cancers and other diseases. These findings have laid the foundation for further studies to clarify the exact mechanism of SEC22B in the pathological process and to seek new therapeutic targets and better treatment strategies.

6.
Am J Cancer Res ; 10(2): 507-522, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195023

RESUMO

Triple-negative breast cancer (TNBC) is one of the most aggressive cancers with a high rate of recurrence and metastasis. Trifluridine (TFT) is a thymidine analog to target thymidylate synthase (TS) and has potent ant-herpes simplex virus activity. However, little is known whether and how TFT treatment can modulate the growth of TNBC. In this study, we found that treatment with TFT selectively inhibited the proliferation of TNBC cells and triggered their apoptosis. TFT treatment significantly up-regulatd the expression of G1 phase inhibitor p21 and p27, and pro-apoptotic factor γ-H2AX, Bax and cleaved caspase-7 in TNBC cells. TFT treatment significantly down-regulated the expression of proliferating cell nuclear antigen (PCNA), minichromosome maintenance component 7 (MCM7) and anti-apoptotic Bcl-2 in TNBC cells. TFT treatment significantly mitigated the growth of implanted mouse TNBC in vivo, associated with increased expression of γ-H2AX and cleaved caspase-7 in mouse TNBC tumors. TS expression was up-regulated in breast cancer, particularly in TNBC tissues, and up-regulated TS expression was significantly associated with a shorter overall survival and disease free survival in TNBC patients. TS silencing selectively decreased the proliferation of TNBC cells, but did not trigger their apoptosis. Treatment with TFT induced DNA double strand break (DSB) and damages in TNBC cells. Collectively, TFT selectively inhibited the growth of TNBC by inducing chromosome instability and inhibiting thymidine synthase. Therefore, TFT may be valuable for the intervention of TNBC.

7.
J Exp Clin Cancer Res ; 38(1): 361, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419991

RESUMO

BACKGROUND: Triple Negative Breast cancer (TNBC) is incurable cancer with higher rates of relapse and shorter overall survival compared with other subtypes of breast cancer. Cellular retinoic acid binding protein 2 (CRABP2) belongs to fatty acid binding protein (FABP) family which binds with all-trans retinoic acid (RA). Previous studies from the database have reported the patients with high expression of CRABP2 showed different prognosis in ER+ and ER- breast cancer. However, its biological role and exact mechanism in breast cancer remain unknown. This aim of this study was to explore how CRABP2 regulated invasion and metastasis based on the estrogen receptor-α (herein called ER) status in breast cancer. METHODS: Immunohistochemical staining method was used to analyze the expression of CRABP2 in human breast cancer tissues. Lentivirus vector-based shRNA technique was used to test the functional relevance of CRABP2 knockdown in breast tumors. Tail vein injection model was used to examine the lung metastasis. Co-immunoprecipitation, Western blotting, immunofluorescence, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were conducted to investigate the underlying mechanism that influenced the ER to the regulation of CRABP2 to Lats1. RESULTS: We observed that knockdown of CRABP2 promotes EMT, invasion and metastasis of ER+ breast cancer cells in vitro and in vivo, whereas overexpression of CRABP2 yields the reverse results. In ER+ mammary cancer cells, the interaction of CRABP2 and Lats1 suppress the ubiquitination of Lats1 to activate Hippo pathway to inhibit the invasion and metastasis of ER+ mammary cancer. However, in ER- mammary cancer cells, the interaction of CRABP2 and Lats1 promote the ubiquitination of Lats1 to inactivate Hippo pathway to promote the invasion and metastasis of ER- mammary cancer. CONCLUSIONS: Our findings indicate that CRABP2 can suppress invasion and metastasis of ER+ breast cancer and promote invasion and metastasis of ER- breast cancer by regulating the stability of Lats1 in vitro and in vivo, and it provides new ideas for breast cancer therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Receptor alfa de Estrogênio/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Receptores do Ácido Retinoico/genética , Células Tumorais Cultivadas , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cell Death Dis ; 10(3): 179, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30792381

RESUMO

Growing evidence indicates that Angiomotin (Amot)-p130 and Amot-p80 have different physiological functions. We hypothesized that Amot-p130 is a tumor suppressor gene in breast cancer, in contrast with the canonical oncogenicity of Amot-p80 or total Amot. To clarify the role of Amot-p130 in breast cancer, we performed real-time quantitative PCR, western blotting, flow cytometry, microarray, immunofluorescence, immunoprecipitation, and tumor sphere-formation assays in vitro, as well as tumorigenesis and limited-dilution analysis in vivo. In this study, we showed that Amot-p130 inhibited the proliferation, migration, and invasion of breast cancer cells. Interestingly, transcriptional profiles indicated that genes differentially expressed in response to Amot-p130 knockdown were mostly related to ß-catenin signaling in MCF7 cells. More importantly, most of the downstream partners of ß-catenin were associated with stemness. In a further validation, Amot-p130 inhibited the cancer stem cell potential of breast cancer cells both in vitro and in vivo. Mechanistically, Amot-p130 decreased ß-catenin stability by competing with Axin for binding to tankyrase, leading to a further inhibition of the WNT pathway. In conclusions, Amot-p130 functions as a tumor suppressor gene in breast cancer, disrupting ß-catenin stability by competing with Axin for binding to tankyrase. Amot-p130 was identified as a potential target for WNT pathway-targeted therapies in breast cancer.


Assuntos
Proteína Axina/metabolismo , Neoplasias da Mama/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas dos Microfilamentos/metabolismo , Tanquirases/metabolismo , beta Catenina/metabolismo , Animais , Proteína Axina/genética , Neoplasias da Mama/genética , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Células MCF-7 , Camundongos , Proteínas dos Microfilamentos/genética , Células-Tronco Neoplásicas/metabolismo , Fosfoproteínas/metabolismo , Tanquirases/genética , Transplante Heterólogo , Via de Sinalização Wnt/genética , beta Catenina/genética
9.
Oncol Rep ; 41(3): 1980-1990, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30569128

RESUMO

Bladder cancer is the most common malignancy of the urinary tract, and ~50% of patients with bladder cancer experience recurrence and metastasis. The results of mass spectrometry revealed that the expression of zinc finger and BTB domain­containing 38 (ZBTB38) was higher in highly aggressive human bladder cancer 253J B­V cells compared with in the less aggressive bladder cancer 253J cells. However, the association between ZBTB38 and bladder cancer is currently not well defined, and the association of ZBTB38 with migration and invasive growth of bladder cancer cells remains unclear. Previous studies have suggested that ZBTB38 may act as an oncogene, similar to Kaiso. Furthermore, analysis of a clinical database suggested that ZBTB38 expression may be associated with poor prognosis of patients with bladder cancer. Using cell proliferation, migration and invasion assays, and western blotting, the present study demonstrated that ZBTB38 promoted the migration and invasive growth of bladder cancer cells, but inhibited their proliferation. Further experiments suggested that ZBTB38 promoted epithelial­mesenchymal transition and the expression levels of genes downstream of the Wnt/ß­catenin signaling pathway. Notably, further experiments using a xenograft tumor metastasis model revealed that ZBTB38 promoted bladder cancer lung metastasis in vivo. These findings suggested that ZBTB38 promoted migration and invasive growth of bladder cancer cells through facilitation of the Wnt/ß­catenin signaling pathway. To the best of our knowledge, this is the first study to reveal that ZBTB38 may promote migration and invasive growth of bladder cancer cells via modulation of the Wnt/ß­catenin signaling pathway.


Assuntos
Movimento Celular , Neoplasias Pulmonares/patologia , Proteínas Repressoras/metabolismo , Neoplasias da Bexiga Urinária/patologia , Via de Sinalização Wnt , Animais , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/patologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos SCID , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/genética , Análise de Sobrevida , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/mortalidade , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cell Death Dis ; 8(3): e2673, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28300827

RESUMO

Loss or dysfunction of tumor suppressor retinoblastoma (RB) is a common feature in various tumors, and contributes to cancer cell stemness and drug resistance to cancer therapy. However, the strategy to suppress or eliminate Rb-deficient tumor cells remains unclear. In the present study, we accidentally found that reduction of DNA replication licensing factor MCM7 induced more apoptosis in RB-deficient tumor cells than in control tumor cells. Moreover, after a drug screening and further studies, we demonstrated that statin drug Simvastatin and Atorvastatin were able to inhibit MCM7 and RB expressions. Further study showed that Simvastatin and Atorvastatin induced more chromosome breaks and gaps of Rb-deficient tumor cells than control tumor cells. In vivo results showed that Simvastatin and Atorvastatin significantly suppressed Rb-deficient tumor growth than control in xenograft mouse models. The present work demonstrates that 'old' lipid-lowering drugs statins are novel weapons against RB-deficient tumors due to their effects on suppressing MCM7 protein levels.


Assuntos
Atorvastatina/farmacologia , Proliferação de Células/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Componente 7 do Complexo de Manutenção de Minicromossomo/metabolismo , Retinoblastoma/tratamento farmacológico , Retinoblastoma/metabolismo , Sinvastatina/farmacologia , Animais , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Camundongos , Proteína do Retinoblastoma/metabolismo
11.
Sci Rep ; 7: 42125, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28169360

RESUMO

Discs Large Homolog 5 (DLG5) plays an important role in the maintenance of epithelial cell polarity. Recent research showed that DLG5 is decreased in Yes-associated protein (YAP)-overexpressing cells. However, the exact relationship between DLG5 and YAP is not clear. In this study, we showed that loss of DLG5 promoted breast cancer cell proliferation by inhibiting the Hippo signaling pathway and increasing nuclear YAP expression. Furthermore, depletion of DLG5 induced epithelial-mesenchymal transition (EMT) and disrupted epithelial cell polarity, which was associated with altered expression of Scribble, ZO1, E-cadherin and N-cadherin and their mislocalization. Interestingly, we first reported that loss of DLG5 inhibited the interaction of Mst1 and Lats1 with Scribble, which was crucial for YAP activation and the transcription of TEA domain (TEAD) family members. In summary, loss of DLG5 expression promoted breast cancer malignancy by inactivating the Hippo signaling pathway and increasing nuclear YAP.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/genética , Caderinas/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Polaridade Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Células MCF-7 , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Camundongos Nus , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transplante Heterólogo , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
12.
Sci Rep ; 7: 41776, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28150753

RESUMO

Acquired tamoxifen resistance (TamR) remains a major challenge in breast cancer endocrine therapy. The mechanism of acquiring tamoxifen resistance remains elusive, and no effective drugs are available. In this investigation, we determined that the expression of the DNA damage marker γH2AX is upregulated under minichromosome maintenance protein 7 (MCM7) knockdown in phospho Ser807/811-retinoblastoma protein (p-Rb) defect cells. In addition, the expression of p-Rb was lower in TamR cells than in parental cells, and the expression of γH2AX was significantly upregulated when MCM7 was knocked down in TamR cells. Simvastatin, an agent for hypercholesterolemia treatment, activated the MCM7/p-RB/γH2AX axis and induced DNA damage in TamR cells, especially when combined with tamoxifen. Finally, in vitro and in vivo experiments demonstrated that simvastatin combined with tamoxifen increased TamR cell apoptosis and inhibited xenograft growth. In conclusion, simvastatin may suppress TamR cell growth by inhibiting MCM7 and Rb and subsequently inducing DNA damage.


Assuntos
Replicação do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Componente 7 do Complexo de Manutenção de Minicromossomo/antagonistas & inibidores , Sinvastatina/farmacologia , Tamoxifeno/farmacologia , Animais , Antineoplásicos Hormonais/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Componente 7 do Complexo de Manutenção de Minicromossomo/genética , Componente 7 do Complexo de Manutenção de Minicromossomo/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cell Death Dis ; 8(1): e2546, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28079891

RESUMO

The loss of contact inhibition is a hallmark of cancer cells. The Hippo pathway has recently been shown to be an important regulator of contact inhibition, and the cell apical polarity determinant protein CRB3 has been suggested to be involved in Hippo signalling. However, whether CRB3 regulates contact inhibition in mammary cells remains unclear, and the underlying mechanisms have not been elucidated. As shown in the present study, CRB3 decreases cell proliferation, promotes apoptosis, and enhances the formation of tight and adherens junctions. Furthermore, we report for the first time that CRB3 acts as an upstream regulator of the Hippo pathway to regulate contact inhibition by recruiting other Hippo molecules, such as Kibra and/or FRMD6, in mammary epithelial cells. In addition, CRB3 inhibits tumour growth in vivo. Collectively, the present study increases our understanding of the Hippo pathway and provides an important theoretical basis for exploring new avenues for breast cancer treatment.


Assuntos
Neoplasias da Mama/genética , Inibição de Contato/genética , Proteínas do Citoesqueleto/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Glândulas Mamárias Humanas/metabolismo , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Fosfoproteínas/genética , Animais , Apoptose/genética , Neoplasias da Mama/patologia , Polaridade Celular/genética , Proliferação de Células/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Camundongos , Proteínas Serina-Treonina Quinases/genética
14.
Eur J Cancer ; 68: 90-105, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27728841

RESUMO

Myeloid-derived suppressor cells (MDSCs) mostly consisting of polymorphonuclear (PMN)-MDSCs and mononuclear MDSCs have been considered to play critical roles in immunosuppression, angiogenesis, invasion and metastases of various tumours. However, it is still unclear the regulated mechanisms underlying the generation and immunosuppression of two major MDSC subsets. Here, we report Notch signalling was inhibited significantly in tumour-bearing mouse MDSCs, in which PMN-MDSCs were the major population. MDSCs without recombination signal binding protein-Jк (RBP-J), the critical transcription factor mediating signalling from all four mammalian Notch receptors, reduced their ability of inhibiting the proliferation and activation of allogenic T cells. RBP-J-deficient MDSCs could not down-regulate the expression of co-stimulation molecules on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J-deficient MDSCs was not impaired in contrast to controls. Moreover, we show the blockage of Notch signalling could improve the generation of PMN-MDSCs but inhibit the production of mononuclear MDSCs both in vitro and in vivo. Stat3 pathway was suppressed in MDSCs blocked Notch signalling and Stat3 activation by IL-6 could reverse the phenotype and immunosuppression of Notch signalling-deficient MDSCs. Therefore, targeting Notch signalling may be an effective therapeutic strategy in tumour therapy.


Assuntos
Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , Receptores Notch/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apresentação do Antígeno , Medula Óssea , Proteínas de Ligação ao Cálcio , Células Dendríticas , Tolerância Imunológica , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteína Jagged-1/imunologia , Proteína Jagged-2/imunologia , Linfonodos/citologia , Proteínas de Membrana/imunologia , Camundongos , Cavidade Peritoneal/citologia , RNA Interferente Pequeno , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Baço/citologia , Linfócitos T
15.
Oncotarget ; 6(42): 44579-92, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26625311

RESUMO

Anti-angiogenesis is currently considered as one of the major antitumor strategies for its protective effects against tumor emergency and later progression. The anti-diabetic drug metformin has been demonstrated to significantly inhibit tumor angiogenesis based on recent studies. However, the mechanism underlying this anti-angiogenic effect still remains an enigma. In this study, we investigated metformin-induced inhibitory effect on tumor angiogenesis in vitro and in vivo. Metformin pretreatment significantly suppressed tumor paracrine signaling-induced angiogenic promotion even in the presence of heregulin (HRG)-ß1 (a co-activator of HER2) pretreatment of HER2+ tumor cells. Similar to that of AG825, a specific inhibitor of HER2 phosphorylation, metformin treatment decreased both total and phosphorylation (Tyr 1221/1222) levels of HER2 protein and significantly reduced microvessel density and the amount of Fitc-conjugated Dextran leaking outside the vessel. Furthermore, our results of VEGF-neutralizing and -rescuing tests showed that metformin markedly abrogated HER2 signaling-induced tumor angiogenesis by inhibiting VEGF secretion. Inhibition of HIF-1α signaling by using RNAi or YC-1, a specific inhibitor of HIF-1α synthesis, both completely diminished mRNA level of VEGF and greatly inhibited endothelial cell proliferation promoted by HER2+ tumor cell-conditioned medium in both the absence and presence of HRG-ß1 pretreatment. Importantly, metformin treatment decreased the number of HIF-1α nucleus positive cells in 4T1 tumors, accompanied by decreased microvessel density. Our data thus provides novel insight into the mechanism underlying the metformin-induced inhibition of tumor angiogenesis and indicates possibilities of HIF-1α-VEGF signaling axis in mediating HER2-induced tumor angiogenesis.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias da Mama/tratamento farmacológico , Capilares/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metformina/farmacologia , Neovascularização Patológica , Receptor ErbB-2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capilares/metabolismo , Capilares/patologia , Técnicas de Cocultura , Feminino , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células MCF-7 , Camundongos Endogâmicos BALB C , Comunicação Parácrina/efeitos dos fármacos , Fosforilação , Interferência de RNA , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Fator A de Crescimento do Endotélio Vascular/genética
16.
Int J Med Sci ; 11(6): 652-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24834012

RESUMO

The objective of this study was to investigate the main risk factors for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), to allow the improvement of transplantation outcomes through preventive measures. Clinical data for 124 patients who received allo-HSCT were analyzed retrospectively. There were 83 males (66.9%) and 41 females (33.1%) with a median age of 28 years (4-60 years). The median follow-up time was 7 months (1-116 months). Factors analyzed included age, gender, disease diagnosis, source of hematopoietic stem cells, donor type, human leukocyte antigen (HLA) matching, conditioning regimen, numbers of infused mononuclear cells and CD34(+) cells, donor-recipient sex and blood-type matching, prophylactic treatment of graft-versus-host disease (GVHD), grades of GVHD, Epstein-Barr virus or cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorders and hepatic veno-occlusive disease. Data were analyzed by univariate and multivariate conditional logistic regression analyses. Among the 124 patients who underwent allo-HSCT, 15 developed PGF (12.1%). Univariate logistic regression analysis identified age, donor-recipient blood type and CMV infection (in 30 days) as potential risk factors for PGF. Multivariate analysis of factors with P<0.1 in univariate analysis showed that age, donor-recipient blood type and CMV infection (in 30 days) were significant risk factors for PGF. Patients were divided into subgroups based on age <20, 20-30, 30-40, and >40 years. The risk of PGF increased 2.747-fold (odds ratio (OR)=2.625, 95% confidence interval: 1.411-5.347) for each increment in age level. Patients with mismatched blood type (OR=4.051) or CMV infection (OR=9.146) had an increased risk of PGF. We conclude that age, donor-recipient blood-type matching and CMV infection are major risk factors for PGF after allo-HSCT.


Assuntos
Função Retardada do Enxerto/patologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo/efeitos adversos , Adolescente , Adulto , Fatores Etários , Tipagem e Reações Cruzadas Sanguíneas , Criança , Pré-Escolar , Citomegalovirus/patogenicidade , Função Retardada do Enxerto/epidemiologia , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 21(6): 1568-71, 2013 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-24370050

RESUMO

This study was aimed to explore the effect of TNF-α on the vascular cell adhesion molecule 1 (VCAM-1) expression of human bone marrow mesenchymal stem cells (BMMSC) and the relationship between this process and ERK signalling pathway. BMMSC were isolated by density gradient centrifugation combined with adherent culture method, and then identified by surface antigen expression and differentiation potential. Flow cytometry was used to detect expression of VCAM-1 on BMMSC exposed to TNF-α at different concentrations, and the effect of ERK inhibitor U0126 on VCAM-1 of BMMSC. ERK signaling pathway activation was analyzed by Western blot. The results showed that BMMSC positively expressed CD29, CD69, CD44, CD105, and negatively expressed CD34, CD45. BMMSC could be induced to differentiate into osteoblasts and adipocytes. Flow cytometry analysis showed that after the TNF-α stimulation, the expression of VCAM-1 on BMMSC increased in a dose-dependent manner. And this increase was inhibited by U0126. TNF-α caused activation of ERK signal pathway, and U0126 suppressed this effect induced by TNF-α. It is concluded that TNF-α can increase expression of VCAM-1 of BMMSC via ERK signaling pathway.


Assuntos
Células da Medula Óssea/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
18.
Zhonghua Xue Ye Xue Za Zhi ; 34(9): 771-6, 2013 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-24103875

RESUMO

OBJECTIVE: To observe the changes of telomere length and telomerase activity in patients with aplastic anemia (AA), and relationship with immunosuppressive therapy (IST) efficacy, to explore the pathogenesis of AA and the role of telomere length in evaluating immunosuppressive therapy efficacy. METHODS: 71 cases of AA patients between September 2010 and March 2013 were enrolled into this study. 3 ml peripheral blood specimens from this cohort of patients were collected to test the telomere length in peripheral blood mononuclear cell (PBMNC) with flow-FISH and detect telomerase activity with TRAP-PCR-ELISA method. RESULTS: Telomere length and age showed negative correlation (b=-0.387, P=0.001) in normal control, NSAA and SAA + VSAA groups, telomere length became shorter with the growth of age, and normal control group telomere length decreased along with the age growth slightly greater than the other two groups (NSAA, SAA+VSAA). Besides the effect of age on telomere length, no significant difference was observed between NSAA and SAA+VSAA groups (P=0.573), and NSAA, SAA+VSAA (30.957 ± 4.502,29.510 ± 5.911)groups were significantly shorter than normal control group (51.086±10.844) (P<0.01). Telomere length in NR group (25.357±4.848)was significantly lower than normal control group (51.086 ± 10.844) (P=0.005), telomere length in CR(32.808 ± 4.685)/PR groups (30.334±4.464) compared with normal control group had no significant difference (P=0.517, P=0.254). Telomere length below 29.21% obviously decreased outcomes of IST. Telomerase activity had significant difference (χ²=20.385, P<0.01). The telomerase activity had no significant difference in terms of age and gender in three groups, multiple comparison found that telomerase activities in SAA + VSAA (0.324±0.178) (P<0.01), and NSAA (0.234±0.175) groups (P=0.002) were significantly higher than normal control group (0.107±0.083). CONCLUSION: Telomere length of PBMNC in AA patients was significantly shortened than normal control group with telomerase activity increased, and telomere shorted more apparently in NR group, these patients should adjust the treatment as early as possible. Telomeres could predict the curative effect of IST.


Assuntos
Anemia Aplástica/enzimologia , Anemia Aplástica/terapia , Imunossupressão , Telomerase/metabolismo , Telômero/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
19.
Stem Cell Res ; 11(2): 721-35, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23735298

RESUMO

Recent evidence has shown that bone marrow stromal cells (BMSCs) may exhibit immuno-suppression activities through soluble mediators and direct cell-cell contact, but how these processes are modulated has been poorly understood. In this study, we show that the Notch signaling pathway participates in the modulation of BMSCs to elicit their immuno-suppressive roles. In a murine lethal acute graft versus host disease (aGvHD) model, BMSCs deficient for RBP-J, the critical transcription factor mediating signaling from all four mammalian Notch receptors, failed to delay the development of the disease. RBP-J deficient BMSCs were not able to inhibit the proliferation and activation of allogenic T-cells. Moreover, RBP-J deficient BMSCs could not down-regulate the expression of MHC II and co-stimulation molecules CD80 and CD86 on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J deficient BMSCs was not impaired in contrast to wild type BMSCs. Furthermore, we showed that the productions of IL-6 and PGE2, two critical molecules mediating the immuno-suppressive activities of BMSCs, were reduced significantly in RBP-J deficient BMSCs. Both of the two molecules were importantly involved in the regulation of BMSCs by Notch signaling. In conclusion, our data suggests that the immuno-suppressive effects of BMSCs in aGvHD are dependent on Notch-RBP-J signaling, which regulates the productions of IL-6 and PGE2.


Assuntos
Transplante de Medula Óssea/métodos , Doença Enxerto-Hospedeiro/terapia , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptores Notch/metabolismo , Doença Aguda , Animais , Células Cultivadas , Feminino , Citometria de Fluxo , Doença Enxerto-Hospedeiro/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais
20.
J Nanosci Nanotechnol ; 13(2): 1256-60, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23646614

RESUMO

The configurations and corresponding adsorption energies of Rh(n) (n = 4-13) nanoclusters on the boron nitride sheet are investigated by density functional theory (DFT). We use the force-matching method (FMM) to modify parameters of Morse and Tersoff potential functions. To elucidate the dynamical behaviors of Rh nanoclusters on the boron nitride sheet, molecular dynamics (MD) is applied with modified Morse potential function parameter. Finally, the square displacement (SD) is utilized the dynamics behavior of different size Rh nanoclusters at different temperatures.

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