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1.
Genomics ; 115(2): 110599, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36889366

RESUMO

Prostate cancer (PCa) is a common malignant cancer in elderly males in Western countries. Whole-genome sequencing confirmed that long non-coding RNAs (lncRNAs) are frequently altered in castration-resistant prostate cancer (CRPC) and promote drug resistance to cancer therapy. Therefore, elucidating the prospective role of lncRNAs in PCa oncogenesis and progression is of remarkable clinical significance. In this study, gene expression in prostate tissues was determined using RNA-sequencing datasets, and the gene diagnostic and prognostic values of CRPC were analyzed using bioinformatics. Further, the expression levels and clinical significance of MAGI2 Antisense RNA 3 (MAGI2-AS3) in PCa clinical specimens were evaluated. The tumor-suppressive activity of MAGI2-AS3 was functionally explored in PCa cell lines and animal xenograft models. MAGI2-AS3 was found to be aberrantly decreased in CRPC and was negatively correlated with Gleason score and lymph node status. Notably, low MAGI2-AS3 expression positively correlated with poorer survival in patients with PCa. The overexpression of MAGI2-AS3 significantly inhibited the proliferation and migration of PCa in vitro and in vivo. Mechanistically, MAGI2-AS3 could play a tumor suppressor function in CRPC through a novel miR-106a-5p/RAB31 regulatory network and could be a target for future cancer therapy.


Assuntos
MicroRNAs , Neoplasias de Próstata Resistentes à Castração , RNA Longo não Codificante , Masculino , Animais , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Prognóstico , Proliferação de Células/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Guanilato Quinases/genética , Guanilato Quinases/metabolismo
2.
PLoS One ; 18(3): e0278690, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36893174

RESUMO

Regarding the fulfillment optimization of online retail orders, many researchers focus more on warehouse optimization and distribution center optimization. However, under the background of new retailing, traditional retailers carry out online services, forming an order fulfillment model with physical stores as front warehouses. Studies that focus on physical stores and consider both order splitting and store delivery are rare, which cannot meet the order optimization needs of traditional retailers. To this end, this study proposes a new problem called the "Multi-Store Collaborative Delivery Optimization (MCDO)", in which not only make the order-split plans for stores but also design the order-delivery routes for them, such that the order fulfillment cost is minimized. To solve the problem, a Top-K breadth-first search and a local search are integrated to construct a hybrid heuristic algorithm, named "Top-K Recommendation & Improved Local Search (TKILS)". This study optimizes the search efficiency of the breadth-first search by controlling the number of sub-orders and improving the initial solution of the local search using a greedy cost function. Then achieve the joint optimization of order-split and order-delivery by improving the local optimization operators. Finally, extensive experiments on synthetic and real datasets validate the effectiveness and applicability of the algorithm this study proposed.


Assuntos
Algoritmos , Heurística
3.
Diabetes Metab Syndr Obes ; 15: 1961-1974, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35783031

RESUMO

Alpha-ketoglutarate (AKG) is a key intermediate of various metabolic pathways including tricarboxylic acid (TCA) cycle, anabolic and catabolic reactions of amino acids, and collagen biosynthesis. Meanwhile, AKG also participates in multiple signaling pathways related to cellular redox regulation, epigenetic processes, and inflammation response. Emerging evidence has shown that kidney diseases like diabetic nephropathy and renal ischemia/reperfusion injury are associated with metabolic disorders. In consistence with metabolic role of AKG, further metabolomics study demonstrated a dysregulated AKG level in kidney diseases. Intriguingly, earlier studies during the years of 1980s and 1990s indicated that AKG may benefit wound healing and surgery recovery. Recently, interests on AKG are arising again due to its protective roles on healthy ageing, which may shed light on developing novel therapeutic strategies against age-related diseases including renal diseases. This review will summarize the physiological and pathological properties of AKG, as well as the underlying molecular mechanisms, with a special emphasis on kidney diseases.

4.
Int J Oncol ; 60(4)2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35191516

RESUMO

Energy metabolism reprogramming is becoming an increasingly important hallmark of cancer. Specifically, cancers tend to undergo metabolic reprogramming to upregulate a cell­dependent glutamine (Gln) metabolism. Notably, hepatocellular cell adhesion molecule (HepaCAM) has been previously reported to serve a key role as a tumour suppressor. However, the possible regulatory role of HepaCAM in Gln metabolism in prostate cancer (PCa) remains poorly understood. In the present study, bioinformatics analysis predicted a significant negative correlation among the expression of HepaCAM, phosphatidylinositol­4,5­bisphosphate 3­kinase catalytic subunit α (PIK3CA), glutaminase (GLS) and solute carrier family 1 member 5 (SLC1A5), components of Gln metabolism, in clinical and genomic datasets. Immunohistochemistry results verified a negative correlation between HepaCAM and PIK3CA expression in PCa tissues. Subsequently, liquid chromatography­tandem mass spectrometry (LC­MS/MS) and gas chromatography­mass spectrometry (GC­MS) assays were performed, and the results revealed markedly reduced levels of Gln and metabolic flux in the blood samples of patients with PCa and in PCa cells. Mechanistically, overexpression of HepaCAM inhibited Gln metabolism and proliferation by regulating PIK3CA in PCa cells. In addition, Gln metabolism was discovered to be stress­resistant in PCa cells, since the expression levels of GLS and SLC1A5 remained high for a period of time after Gln starvation. However, overexpression of HepaCAM reversed this resistance to some extent. Additionally, alpelisib, a specific inhibitor of PIK3CA, effectively potentiated the inhibitory effects of HepaCAM overexpression on Gln metabolism and cell proliferation through mass spectrometry and CCK­8 experiments. In addition, the inhibitory effect of PIK3CA on the growth of tumor tissue in nude mice was also confirmed by immunohistochemistry in vivo. To conclude, the results from the present study revealed an abnormal Gln metabolic profile in the blood samples of patients with PCa, suggesting that it can be applied as a clinical diagnostic tool for PCa. Additionally, a key role of the HepaCAM/PIK3CA axis in regulating Gln metabolism, cell proliferation and tumour growth was identified. The combination of alpelisib treatment with the upregulation of HepaCAM expression may serve as a novel method for treating patients with PCa.


Assuntos
Proliferação de Células/genética , Glutamina/metabolismo , Transdução de Sinais/genética , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral/metabolismo , Proliferação de Células/fisiologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Glutamina/genética , Masculino , Camundongos , Camundongos Nus/genética , Camundongos Nus/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/prevenção & controle
5.
Gene ; 808: 145977, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34592353

RESUMO

Increased expression of histone deacetylases (HDACs) affiliated to the epigenetic regulation is common aberration in prostate cancer (PCa). We have confirmed that hepatocyte cell adhesion molecule (hepaCAM), acting as a tumor suppressor gene, is rarely expressed in PCa previously, However, the mechanisms of which is still unknown. The level of histone acetylation reportedly may involve anti-oncogene transcription and expression. In this study, we investigated the effect of panobinostat, the broad-spectrum histone deacetylases inhibitor, on PCa LNCaP and DU145 cell growth, and observed re-expression of hepaCAM when treated with panobinostat. We demonstrated that intranuclear acetylation of lys9 of histone H3 (Ac-H3K9) were increased, while that of both mRNA and protein of HDAC1, HDAC3, and HDAC4 were decreased when the treating concentration of panobinostat increased. We confirmed the relationship between histone acetylation and the expression of hepaCAM and AR in prostate cancer tissues. We also confirmed that panobinostat could overcome the resistance for androgen deprivation therapy (ADT). Further, we combined panobinostat with Ad-hepaCAM, which resulted in significantly increased antitumor activity and significant attenuation of the proliferation-associated genes CCND1 and PCNA compared to each single treatment. In conclusion, panobinostat may enhance the acetylation of lys9 of histone 3 and reverse the hepaCAM expression through its inhibitory effect on HDACs activity in PCa LNCaP and DU145 cells; Ad-hepaCAM combined with panobinostat may synergistically inhibit the growth of LNCaP and DU145 cells, via a potential mechanism associated with the down-regulation of the expression of CCND1 and PCNA. These findings suggest that this therapeutic strategy should be further developed in clinical trials.


Assuntos
Proteínas de Ciclo Celular/genética , Panobinostat/farmacologia , Neoplasias da Próstata/genética , Antagonistas de Androgênios/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , China , Epigênese Genética/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Masculino , Panobinostat/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos , Transdução de Sinais/efeitos dos fármacos
6.
Front Public Health ; 9: 686282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327187

RESUMO

Background: To mobilize family's positive involvement in improving and sustaining self-management activities of older adults with diabetes, we developed a couple-based collaborative management model (CCMM) for community-dwelling older Chinese. Methods: The model was developed stepwise through applying theoretical models, interviewing older couples and community healthcare workers, as well as incorporating expert reviews. A 3-month pilot study was conducted to test the model's feasibility and its treatment effects by linear regression on 18 pairs of older couples aged 60 years+, who were equally divided into a couple-based intervention arm and a patient-only control arm. Results: The developed CCMM covered four theory-driven intervention modules: dyadic assessment, dyadic education, dyadic behavior-change training, and dyadic monitoring. Each module was delivered by community healthcare workers and targeted at older couples as the management units. Based on interviews with older couples and healthcare workers, 4 weekly education and training group sessions and 2-month weekly behavior change booster calls were designed to address older adults' main management barriers. These modules and session contents were evaluated as essential and relevant by the expert panel. Furthermore, the CCMM showed good feasibility and acceptability in the pilot, with non-significant yet more positive changes in physiological outcomes of diabetic participants and couples' well-being and exercise levels of these in the intervention arm than their controlled counterparts. Conclusion: We systematically developed a couple-based collaborative management model of diabetes, which was well-received by healthcare practitioners and highly feasible among older Chinese couples living in the community. The model's treatment effects need to be verified in fully powered randomized controlled trials. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=42964, identifier: ChiCTR1900027137.


Assuntos
Diabetes Mellitus Tipo 2 , Vida Independente , Idoso , China , Diabetes Mellitus Tipo 2/terapia , Exercício Físico , Humanos , Projetos Piloto
7.
Onco Targets Ther ; 13: 4545-4558, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547085

RESUMO

BACKGROUND: Circular RNAs (circRNAs) play a crucial role in gene expression regulation. CircHIPK3 is a circRNA derived from Exon 2 of HIPK3 gene and its role in prostate cancer (PCa) is still unclear. METHODS: CCK8 assays, flow cytometry and colony formation assays were performed to assess the effects of circHIPK3 in PCa cells. Bioinformatics analysis, RNA pull-down assay, RNA immunoprecipitation assay (RIP), and luciferase activity assay were performed to dissect the mechanism underlying circHIPK3-mediated G2/M transition in PCa cells. RESULTS: CircHIPK3 expression was upregulated in PCa cells and prostate cancer tissues. Overexpression of circHIPK3 or circHIPK3 silencing altered PCa viability, proliferation and apoptosis in vitro. CircHIPK3 could sponge miR-338-3p and inhibit its activity, resulting in increased expression of Cdc25B and Cdc2 in vitro. CONCLUSION: CircHIPK3 promotes G2/M transition and induces PCa cell proliferation by sponging miR-338-3p and increasing the expression of Cdc25B and Cdc2. CircHIPK3 may play an oncogenic role in PCa.

8.
J Cell Physiol ; 235(11): 8546-8557, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32383180

RESUMO

Phospholipase C-ε (PLCε) is frequently overexpressed in tumors and plays an important role in the regulation of tumorigenesis. Although great progress has been made in understanding biological roles of PLCε, the relevant molecular mechanisms underlying its pro-tumor activity remain largely unclear. Here, we demonstrated that PLCε knockdown reduced cell metastasis, glucose consumption and lactate production in a manner that depended on hypoxia inducible factor 1α (HIF-1α) expression in prostate cancer cells. Interestingly, our findings showed that the expression levels of PLCε were positively associated with those of HIF-1α in clinical prostate carcinoma samples. Knockdown of PLCε impaired HIF-1α levels and transcriptional activity by regulating the extracellular-signal-regulated kinase pathway, and blocking HIF-1α nuclear translocation. Furthermore, PLCε could interact with the von Hippel-Lindau E3 ligase complex to modulate the stability of HIF-1α. Collectively, our findings demonstrate that PLCε could be a crucial positive regulator of HIF-1α, which would promote PLCε-enhanced tumorigenesis.


Assuntos
Fosfoinositídeo Fosfolipase C/metabolismo , Neoplasias da Próstata/metabolismo , Transdução de Sinais/fisiologia , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Metástase Neoplásica/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Int J Hyperthermia ; 36(1): 477-484, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915864

RESUMO

OBJECTIVE: The objective of this study was to explore the correlations between the therapeutic effect of high intensity focused ultrasound (HIFU) and histopathological characteristics of excised uterine fibroids with different signal intensities as visualized on T2-weighted magnetic resonance imaging (MRI). METHODS: We collected 47 specimens of uterine fibroids after surgical resection and classified them into four groups according to preoperative T2-weighted MRI hypo-intense, isointense, heterogeneous intense and homogeneous hyper-intense. Then, specimens in each group were irradiated by HIFU with the same parameters and the necrotic tissue volume was calculated. The smooth muscle cell (SMC) count and collagen fiber content were quantitatively measured and compared between different groups. We analyzed the correlation between the necrotic tissue volume and SMC count and the collagen fiber content. RESULTS: Necrotic tissue volume gradually decreased from the hypo-intense group to the homogeneous hyper-intense group (p = .008). The SMC count from the hypo-intense group to the homogeneous hyper-intense group was 215.6 ± 59.3, 237.0(89.5), 232.3 ± 72.5 and 330.5 ± 30.9, respectively; collagen fiber content was 0.65 ± 0.07, 0.64 ± 0.10, 0.53 ± 0.11 and 0.41 ± 0.06, respectively. Comparison among the four groups showed that SMC count progressively increased (p = .001) but collagen fiber content progressively decreased (p = .000) from the hypo-intense group to the homogeneous hyper-intense group. Correlation analysis showed that necrotic tissue volume was negatively correlated with SMC count (R = -0.488, p=.013) but positively correlated with collagen fiber content (R = 0.534, p = .005). CONCLUSIONS: Differences in histopathological characteristics may be one of the reasons for different therapeutic effects of HIFU ablation on uterine fibroids with different signal intensities on T2-weighted MRI.


Assuntos
Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Leiomioma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Criança , Feminino , Humanos , Resultado do Tratamento , Adulto Jovem
10.
Urology ; 127: 61-67, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30528714

RESUMO

OBJECTIVE: To investigate how hepatocyte cell adhesion molecule (hepaCAM) regulates cancer energy metabolism through hypoxia-inducible factor (HIF-1α) in renal cell carcinoma (RCC). MATERIALS AND METHODS: The expression of hepaCAM and HIF-1α in RCC tissue samples was examined by immunohistochemistry. Glucose consumption and lactate production assays were used to detect metabolic activity in RCC cell lines. P65 and IκB kinase (IKKß) mRNA and protein expression were detected using quantitative real-time polymerase chain reaction and western blotting, respectively. Nuclear translocation of P65 was observed by immunofluorescence staining after re-expressing hepaCAM. The luciferase reporter assay was applied to validate the transcriptional activity of HIF-1α. RESULTS: HIF-1α expression was elevated and hepaCAM suppressed in RCC compared with adjacent normal tissues. Furthermore, hepaCAM re-expression significantly decreased glycolytic metabolism in RCC cell lines, and reduced HIF-1α, IKKß, and P65 expression. The expression of HIF-1α, GLUT1, LDHA, and PKM2 were further reduced with combined hepaCAM overexpression and treatment with the NF-κB inhibitor BAY11-7082, compared to hepaCAM overexpression alone. Additionally, hepaCAM decreased the transcriptional activity of HIF-1α and blocked P65 nuclear translocation by the NF-κB pathway. CONCLUSION: Our data suggest that hepaCAM suppresses the Warburg effect via the HIF-1α/NF-κB pathway in RCC, which is a facilitating factor in hepaCAM-reduced tumorigenesis.


Assuntos
Carcinogênese/genética , Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/genética , Proteínas/genética , Análise de Variância , Biópsia por Agulha , Carcinoma de Células Renais/patologia , Proteínas de Ciclo Celular , Divisão Celular/genética , Proliferação de Células/genética , Humanos , Quinase I-kappa B/genética , Imuno-Histoquímica , Neoplasias Renais/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transdução de Sinais/genética , Células Tumorais Cultivadas
11.
Sci Rep ; 7(1): 5382, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28710380

RESUMO

Osteosarcoma (OS) is the most common bone tumor characterized with a high risk of amputation and malignant morbidity among teenagers and adolescents. However, relevant pathogenic/biological mechanisms underlying OS-genesis remains to be ambiguous. The aim of this study was to elucidate functional relationship about microRNAs-mRNAs networks and to identify potential molecular markers via a computational method. Gene expression profile (GSE70415) was recruited from Gene Expression Omnibus. 3856 differentially expressed genes and 250 significantly expressed microRNAs were identified by using GCBI. The results of GO and KEGG pathways associated proteomics analysis indicated that extracellular matrix organization, small molecule metabolic process, cell adhesion (GO IDs: 0030198, 0044281, 0007155) and pathways in cancer, PI3K-Akt signaling pathway, metabolic pathways (pathway IDs: 5200, 4151, 1100) were significantly enriched. In addition, CKMT2, miR-93b-5p, miR-29b-3p were found to be positively/negatively correlated with TP53, EGFR, and MMP members mediated OS development, including angiogenesis, migration and invasion. Further visualization of collective effect of 1181 microRNAs-mRNAs pairs and protein-protein interactions was realized by applying with cytosacpe. In summary, our work provided a better understanding of non-coding regulatory mechanisms of transcriptomics and unraveled essential molecular biomarkers in osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteínas de Neoplasias/genética , Osteossarcoma/genética , Adolescente , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Creatina Quinase/genética , Creatina Quinase/metabolismo , Creatina Quinase Mitocondrial , Bases de Dados Genéticas , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Osteossarcoma/diagnóstico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Mol Med Rep ; 13(1): 720-30, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26648540

RESUMO

Embryonic stem cells (ESCs) are pluripotent stem cells derived from early stage embryos. It remains unclear whether inhibiting the Wnt/ß­catenin signaling pathway using dickkopf Wnt signaling pathway inhibitor 1 (DKK1) impacts on the differentiation potential of mouse ESCs in vitro and in vivo. In the present study, immunohistochemical staining was used to measure the expression of markers of the three germ layers in ESCs and teratomas derived from ESCs. The expression of markers for the Wnt/ß­catenin signaling pathway were detected by reverse transcription­polymerase chain reaction (RT­qPCR). Immunohistochemistry and western blotting indicated that the expression levels of octamer­binding transcription factor 4 in the DKK1­treated ESC group were significantly greater compared with the control ESCs. Reduced expression levels of NeuroD and bone morphogenetic protein 4 were observed in the DKK1­treated ESCs and teratomas derived from DKK1­treated ESCs compared with the control group. Increased expression levels of SOX17 were observed in the DKK1­treated ESCs compared with the control group. RT­qPCR indicated that ß­catenin expression was significantly reduced in DKK1­treated ESCs and teratomas derived from DKK1­treated ESCs compared with the control groups. Western blotting indicated no alterations in the expression of GSK­3ß, however, the levels of phosphorylated­GSK­3ß were significantly greater in the DKK1 treatment groups, while cyclin D1 and c­Myc expression levels were significantly reduced in the DKK1 treatment groups compared with the control groups. These results suggest that inhibiting Wnt signaling in ESCs using DKK1 may promote mouse ESCs to differentiate into endoderm in vitro and in vivo, and suppress the tumorigenicity of ESCs.


Assuntos
Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Via de Sinalização Wnt , Animais , Western Blotting , Proliferação de Células , Ciclina D1/metabolismo , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Imuno-Histoquímica , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Teratoma/patologia , Fatores de Transcrição/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
13.
Cancer Biol Ther ; 16(10): 1502-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26192362

RESUMO

We previously established that hepatocyte cell adhesion molecule (hepaCAM), a typical structure of immunoglobulin (Ig)-like adhesion molecules, inhibited the proliferation and the progression of cultured human bladder cancer cells. As increasing evidence reveals that aberrant activation of canonical Wnt pathway is involved in the pathogenesis of bladder cancer, and ß-catenin serves as a pivotal molecule of Wnt pathway. Then, we explored whether the anti-proliferation effect of hepaCAM was associated with Wnt/ß-catenin pathway in human bladder cancer cells. The negative correlation between hepaCAM and ß-catenin in transitional cell carcinoma of bladder (TCCB) was found. Follow by, studied the effect of hepaCAM on the key elements of Wnt pathway. Here, Our researches showed that hepaCAM played a central role in modulating the Wnt/ß-catenin signaling pathway by interfering nuclear protein levels of ß-catenin, leading to down-regulate transcriptional activity of LEF/TCF and its target genes c-Myc and cyclinD1. Mechanistically, we demonstrated that hepaCAM-activated GSK3ß led to elevate the phosphorylation of ß-catenin, contributing to the aberrant translocation of ß-catenin. In addition, Anti-proliferation and associated molecular mechanisms of hepaCAM were demonstrated by using vivo experiment. In conclusion, our reports uncover that expression of hepaCAM suppresses the proliferation of bladder cancer cells through a Wnt/ß-catenin-dependent signaling pathway in vitro and in vivo.


Assuntos
Proteínas/genética , Proteínas/metabolismo , Neoplasias da Bexiga Urinária/genética , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias da Bexiga Urinária/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
14.
Tumour Biol ; 36(12): 9723-32, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26156799

RESUMO

Phospholipase Cε (PLCε) is a multifunctional enzyme implicated in inflammatory functions. There are limited data, however, on how PLCε can alter inflammatory cytokine by affecting downstream pathways. Recent studies suggest that inflammation is likely to have an important role in transitional cell carcinoma of bladder (TCCB) and cancer disease progression. Here, we showed that PLCε and p-STAT3 expression were both elevated in TCCB tissues compared to adjacent tissues, and the increase of PLCε level was associated with the increase of p-STAT3 level. Then, knockdown of PLCε using adenovirus-shPLCε significantly decreased inflammatory cytokine (IL-6, TNF-α, IL-1ß) expression and inflammation-associated gene (TLR4, MyD88, p-STAT3) expression. Furthermore, we demonstrated that PLCε knockdown blocked LPS-induced inflammatory cytokine and p-STAT3 expression. Additionally, we found that combined treatment of STAT3 inhibitor S3I-201 with adenovirus-shPLCε exhibited synergistic inhibitory effects on expression of p-STAT3. Our results suggested that STAT3 phosphorylation is involved in PLCε-mediated inflammatory cytokine release. Our research is of potential importance in drug development programs using PLCε as a therapeutic target for TCCB.


Assuntos
Carcinoma de Células de Transição/genética , Inflamação/genética , Fosfoinositídeo Fosfolipase C/genética , Fator de Transcrição STAT3/biossíntese , Neoplasias da Bexiga Urinária/genética , Carcinoma de Células de Transição/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Inflamação/patologia , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Fosfoinositídeo Fosfolipase C/antagonistas & inibidores , Fosfoinositídeo Fosfolipase C/biossíntese , Fosforilação/genética , Fator de Transcrição STAT3/genética , Fator de Necrose Tumoral alfa/biossíntese , Neoplasias da Bexiga Urinária/patologia
15.
Cancer Lett ; 362(1): 61-9, 2015 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-25796442

RESUMO

Phospholipase Cε (PLCε), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCε functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCε expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCε depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCε was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCε-mediated oncogenic effects in PCa. Our findings suggest that PLCε is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa.


Assuntos
Fosfoinositídeo Fosfolipase C/deficiência , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptor Notch1/metabolismo , Receptores Androgênicos/metabolismo , Transporte Ativo do Núcleo Celular , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fosfoinositídeo Fosfolipase C/biossíntese , Fosfoinositídeo Fosfolipase C/genética , Fosfoinositídeo Fosfolipase C/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/enzimologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/biossíntese , Receptores Androgênicos/biossíntese , Fase S/fisiologia , Transdução de Sinais , Fatores de Transcrição HES-1
16.
Mol Cell Biochem ; 389(1-2): 265-75, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24510280

RESUMO

Phospholipase Cε (PLCε), a downstream effector of small GTPase superfamily, has been identified to play a crucial role in tumorigenesis. Previously, our studies have showed that PLCε promotes proliferation of renal cell carcinoma (RCC) cells. However, the molecular mechanisms by which PLCε enhances the survival phenotype of RCC cells are still not fully instructed. In the present study, we first demonstrated that PLCε was highly expressed and had a close correlation with Ki67 protein expression in RCC tissue samples. Further, we found that downregulation of PLCε expression repressed growth and induced apoptosis in RCC cells. In addition, we reported a mechanism by which knockdown of PLCε gene potently suppressed the nuclear factor kappa (NF-κB) signaling pathway through action on inhibitor of κB kinase. Moreover, silencing PLCε gene decreased vascular endothelial growth factor (VEGF) expression, which was a downstream growth factor of NF-κB signaling pathway. Finally, downregulation of VEGF was severely enhanced by treatment cells with NF-κB specific inhibitor BAY11-7028 in PLCε knockdown cells. Taken together, these findings suggest that PLCε promotes RCC cell growth via NF-κB-mediated upregulation of VEGF.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , NF-kappa B/genética , Fosfoinositídeo Fosfolipase C/genética , Transdução de Sinais/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo/genética , Feminino , Humanos , Antígeno Ki-67/genética , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/genética
17.
Cancer Biother Radiopharm ; 28(3): 233-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23484808

RESUMO

Transitional cell carcinoma of bladder (TCCB) is a common malignancy worldwide, and outcomes for patients with advanced bladder cancer remain poor. To study the pathogenesis of TCCB, we investigated roles of Phospholipase C (PLC)ɛ, an effector of Ras and Rap small GTPases. RNA interference was used to knockdown PLCɛ expression in human bladder cancer cell lines (BIU-87 and T24). The expression levels of PLCɛ mRNA and protein were detected by reverse transcriptase-polymerase chain reaction and Western blot, respectively. Flow cytometry (FCM) was used to detect distribution of cell cycle. Cellular apoptosis was reflected by transmission electron microscopy and the expression of bcl-2 and bax. We found that PLCɛ could be efficiently knocked down by shRNA. FCM assay showed that the pGenesil-PLCɛ-transfected cells were arrested at the G0/G1 phase. Silence of PLCɛ might induce apoptosis via modulation of bcl-2 and bax. In conclusion, our results suggest that PLCɛ plays an important role in the pathogenesis of human bladder cancer cells. PLCɛ may be used as a potential target of gene therapy for bladder cancer in future.


Assuntos
Apoptose/genética , Carcinoma de Células de Transição/genética , Fosfoinositídeo Fosfolipase C/genética , RNA Interferente Pequeno/genética , Neoplasias da Bexiga Urinária/genética , Proteína X Associada a bcl-2/metabolismo , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/terapia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Microscopia Eletrônica de Transmissão , Fosfoinositídeo Fosfolipase C/deficiência , RNA Interferente Pequeno/administração & dosagem , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Proteína X Associada a bcl-2/genética
18.
Cancer Genet Cytogenet ; 200(2): 110-9, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20620593

RESUMO

Mutational activation of the ras proto-oncogenes is frequently found in cancers. The phospholipase C epsilon gene (PLCE1) encodes a novel ras-related protein (R-Ras) effector mediating the effects of R-Ras on the actin cytoskeleton and membrane protrusion, because R-Ras is coprecipitated with the PLCE1 protein and can increase its activity. The nature of downstream signaling pathways from Ras involved in bladder cancer remains poorly understood. We aimed to construct a small hairpin RNA (shRNA) expression plasmid against the PLCE1 gene and to observe the inhibition of human bladder carcinoma cell T24 migration by RNA interference suppressing the expression of PLCE1. Two PLCE1 plasmids (P1 and P2) were constructed and inserted into T24 cells. Reverse transcriptase-polymerase chain reaction and Western blot analyses were performed to investigate inhibition of PLCE1 expression after plasmid transfection. Invasive power of the T24 cell line was measured before and after transfection by a membrane invasion culture system (transwell chamber), gelatin enzymography, and immunocytochemistry of cells. The RT-PCR analysis of BCL2 mRNA levels among different groups of T24 cell line indicated that expression of BCL2 mRNA was lower in the two positive plasmid-transfected cell groups than in the blank control or HK-A groups. Silencing of PLCE1 might downregulate the level of MMP and BCL2 gene expression, decreasing the invasive power of bladder cancer T24 cells and thus inhibiting tumor development.


Assuntos
Fosfoinositídeo Fosfolipase C/genética , Interferência de RNA , Neoplasias da Bexiga Urinária/patologia , Western Blotting , Linhagem Celular Tumoral , Movimento Celular , Genes ras , Humanos , Imuno-Histoquímica , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Invasividade Neoplásica , Fosfoinositídeo Fosfolipase C/análise , Fosfoinositídeo Fosfolipase C/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/análise , RNA Interferente Pequeno/genética
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