Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 81
Filtrar
1.
Genes Genomics ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847971

RESUMO

BACKGROUND: RNA-binding proteins (RBPs) perform various biological functions in humans and are associated with several diseases, including cancer. Therefore, RBPs have emerged as novel therapeutic targets. Although recent investigations have shown that RBPs have crucial functions in breast cancer (BC), detailed research is underway to determine the RBPs that are closely related to cancers. OBJECTIVE: To provide an insight into estrogen receptor (ER) regulation by cold-inducible RNA binding protein (CIRBP) as a novel therapeutic target. RESULTS: By analyzing the genomic data, we identified a potential RBP in BC. We found that CIRBP is highly correlated with ER function and influences clinical outcomes, such as patient survival and endocrine therapy responsiveness. In addition, CIRBP influences the proliferation of BC cells by directly binding to ER-RNA. CONCLUSION: Our results suggest that CIRBP is a novel upstream regulator of ER and that the interplay between CIRBP and ER may be associated with the clinical relevance of BC.

2.
Exp Mol Med ; 56(6): 1373-1387, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38825643

RESUMO

N6-adenosine methylation (m6A) is critical for controlling cancer cell growth and tumorigenesis. However, the function and detailed mechanism of how m6A methyltransferases modulate m6A levels on specific targets remain unknown. In the current study, we identified significantly elevated levels of RBM15, an m6A writer, in basal-like breast cancer (BC) patients compared to nonbasal-like BC patients and linked this increase to worse clinical outcomes. Gene expression profiling revealed correlations between RBM15 and serine and glycine metabolic genes, including PHGDH, PSAT1, PSPH, and SHMT2. RBM15 influences m6A levels and, specifically, the m6A levels of serine and glycine metabolic genes via direct binding to target RNA. The effects of RBM15 on cell growth were largely dependent on serine and glycine metabolism. Thus, RBM15 coordinates cancer cell growth through altered serine and glycine metabolism, suggesting that RBM15 is a new therapeutic target in BC.


Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glicina , Proteínas de Ligação a RNA , Serina , Neoplasias de Mama Triplo Negativas , Humanos , Serina/metabolismo , Glicina/metabolismo , Feminino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Metilação , Adenosina/metabolismo , Adenosina/análogos & derivados
3.
Int J Mol Sci ; 25(11)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38892310

RESUMO

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.


Assuntos
Movimento Celular , Metaloproteinase 9 da Matriz , Neoplasias de Mama Triplo Negativas , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Movimento Celular/efeitos dos fármacos , Feminino , Linhagem Celular Tumoral , Animais , Camundongos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Invasividade Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos Nus
4.
Plast Reconstr Surg Glob Open ; 12(4): e5718, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38596579

RESUMO

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoimmune disease that typically develops during adolescence and primarily affects women. CRMO primarily targets the bone in arms and legs, with sporadic occurrences in the mandible. CRMO is typically managed with medical treatment, and the efficacy of surgery remains controversial. Complications of surgery include massive bleeding and potential flare-up of CRMO symptoms. Herein, we report a patient with CRMO who had lesions in the bilateral rami of the mandible treated with aesthetic mandibular angloplasty. This is the first case of aesthetic mandibular angloplasty in a patient with CRMO who had bilateral rami involvement of the mandible. The patient began experiencing jaw pain accompanied by swelling and throbbing discomfort beneath the jawline at the age of 10. A pediatrician diagnosed CRMO, and the symptoms were controlled with nonsteroidal antiinflammatory drugs and immunosuppressants (infliximab, adalimumab). Aesthetic mandibular angloplasty was performed at our center because of mandibular hypertrophy. This procedure necessitated considerable removal of the spongy bone, raising concerns about potential massive intraoperative bleeding. Approximately 1.5 cm of the mandibular body was excised to reveal the cortical bone. Bleeding during surgery was not severe, rendering blood transfusions unnecessary. The patient was satisfied with the surgical results. This case indicates the feasibility of angloplasty for such cases.

5.
J Exp Clin Cancer Res ; 42(1): 340, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38098117

RESUMO

BACKGROUND: Cancer cells undergo cellular adaptation through metabolic reprogramming to sustain survival and rapid growth under various stress conditions. However, how brain tumors modulate their metabolic flexibility in the naturally serine/glycine (S/G)-deficient brain microenvironment remain unknown. METHODS: We used a range of primary/stem-like and established glioblastoma (GBM) cell models in vitro and in vivo. To identify the regulatory mechanisms of S/G deprivation-induced metabolic flexibility, we employed high-throughput RNA-sequencing, transcriptomic analysis, metabolic flux analysis, metabolites analysis, chromatin immunoprecipitation (ChIP), luciferase reporter, nuclear fractionation, cycloheximide-chase, and glucose consumption. The clinical significances were analyzed in the genomic database (GSE4290) and in human GBM specimens. RESULTS: The high-throughput RNA-sequencing and transcriptomic analysis demonstrate that the de novo serine synthesis pathway (SSP) and glycolysis are highly activated in GBM cells under S/G deprivation conditions. Mechanistically, S/G deprivation rapidly induces reactive oxygen species (ROS)-mediated AMP-activated protein kinase (AMPK) activation and AMPK-dependent hypoxia-inducible factor (HIF)-1α stabilization and transactivation. Activated HIF-1α in turn promotes the expression of SSP enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). In addition, the HIF-1α-induced expression of glycolytic genes (GLUT1, GLUT3, HK2, and PFKFB2) promotes glucose uptake, glycolysis, and glycolytic flux to fuel SSP, leading to elevated de novo serine and glycine biosynthesis, NADPH/NADP+ ratio, and the proliferation and survival of GBM cells. Analyses of human GBM specimens reveal that the levels of overexpressed PHGDH, PSAT1, and PSPH are positively correlated with levels of AMPK T172 phosphorylation and HIF-1α expression and the poor prognosis of GBM patients. CONCLUSION: Our findings reveal that metabolic stress-enhanced glucose-derived de novo serine biosynthesis is a critical metabolic feature of GBM cells, and highlight the potential to target SSP for treating human GBM.


Assuntos
Proteínas Quinases Ativadas por AMP , Glioblastoma , Humanos , Glioblastoma/patologia , Serina , Glucose/metabolismo , Glicina , RNA , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linhagem Celular Tumoral , Microambiente Tumoral , Fosfofrutoquinase-2
6.
Cancer Sci ; 114(9): 3583-3594, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37650703

RESUMO

Radiotherapy (RT) plays an important role in localized lung cancer treatments. Although RT locally targets and controls malignant lesions, RT resistance prevents RT from being an effective treatment for lung cancer. In this study, we identified phosphomevalonate kinase (PMVK) as a novel radiosensitizing target and explored its underlying mechanism. We found that cell viability and survival fraction after RT were significantly decreased by PMVK knockdown in lung cancer cell lines. RT increased apoptosis, DNA damage, and G2/M phase arrest after PMVK knockdown. Also, after PMVK knockdown, radiosensitivity was increased by inhibiting the DNA repair pathway, homologous recombination, via downregulation of replication protein A1 (RPA1). RPA1 downregulation was induced through the ubiquitin-proteasome system. Moreover, a stable shRNA PMVK mouse xenograft model verified the radiosensitizing effects of PMVK in vivo. Furthermore, PMVK expression was increased in lung cancer tissues and significantly correlated with patient survival and recurrence. Our results demonstrate that PMVK knockdown enhances radiosensitivity through an impaired HR repair pathway by RPA1 ubiquitination in lung cancer, suggesting that PMVK knockdown may offer an effective therapeutic strategy to improve the therapeutic efficacy of RT.


Assuntos
Neoplasias Pulmonares , Humanos , Animais , Camundongos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Fosfotransferases (Aceptor do Grupo Fosfato) , Tolerância a Radiação/genética , Ubiquitinação , Modelos Animais de Doenças
7.
Cancer Cell Int ; 23(1): 172, 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37596639

RESUMO

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

8.
Cancers (Basel) ; 15(13)2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37444482

RESUMO

[BACKGROUND] Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that contributes to the progression of various cancers, including pancreatic cancer. The higher expression of CTHRC1 in tumor tissues is associated with poorer survival outcomes. However, its specific roles in tumor extracellular matrix (ECM) remodeling remain unclear. Our study aims to investigate the influences of CTHRC1 on pancreatic stellate cells (PSCs), a main source of ECM production in pancreatic cancer. [METHODS AND RESULTS] The analyses of the publicly available pancreatic cancer patient data revealed that CTHRC1 is mainly expressed in cancer stroma and highly correlated with ECM-related genes. An in vitro study showed that more than 40% of these genes can be upregulated by CTHRC1. CTHRC1 specifically activated PSC into myofibroblast-like cancer-associated fibroblasts (myCAFs), which are characterized by a significantly upregulated POSTN gene expression. Periostin (coded by the POSTN gene) has a central role in the CTHRC1-PSCs-cancer metastasis axis. Furthermore, CTHRC1 promoted pancreatic cancer cell proliferation through PSC activation to a greater extent than via direct stimulation. Proof-of-concept experiments showed that the long-term (4-week) inhibition of CTHRC1 led to significant tumor suppression and ECM reduction, and also resulted in an unexpected shift in the CAF subtype from myCAFs to inflammatory CAFs (iCAFs). [CONCLUSION] PSC activation was demonstrated to be the key molecular mechanism responsible for the tumor-promoting effects of CTHRC1, and CTHRC1 has a critical role in CAF subtype differentiation and tumor microenvironment (TME) remodeling. The inhibition of CTHRC1 as a therapeutic strategy for the treatment of pancreatic cancer warrants further investigation.

9.
Cell Death Dis ; 13(11): 1002, 2022 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-36435833

RESUMO

Glioblastoma (GBM) is a highly vascular malignant brain tumor that overexpresses vascular endothelial growth factor (VEGF) and phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis. However, whether PFKP and VEGF are reciprocally regulated during GBM tumor growth remains unknown. Here, we show that PFKP can promote EGFR activation-induced VEGF expression in HIF-1α-dependent and -independent manners in GBM cells. Importantly, we demonstrate that EGFR-phosphorylated PFKP Y64 has critical roles in both AKT/SP1-mediated transcriptional expression of HIF-1α and in the AKT-mediated ß-catenin S552 phosphorylation, to fully enhance VEGF transcription, subsequently promoting blood vessel formation and brain tumor growth. Levels of PFKP Y64 phosphorylation in human GBM specimens are positively correlated with HIF-1α expression, ß-catenin S552 phosphorylation, and VEGF expression. Conversely, VEGF upregulates PFKP expression in a PFKP S386 phosphorylation-dependent manner, leading to increased PFK enzyme activity, aerobic glycolysis, and proliferation in GBM cells. These findings highlight a novel mechanism underlying the mutual regulation that occurs between PFKP and VEGF for promoting GBM tumor growth and also suggest that targeting the PFKP/VEGF regulatory loop might show therapeutic potential for treating GBM patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fosforilação , beta Catenina/genética , beta Catenina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfofrutoquinase-1/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Encefálicas/genética , Isoformas de Proteínas/metabolismo , Receptores ErbB/metabolismo
10.
Int J Mol Sci ; 23(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36232715

RESUMO

PAUF, a tumor-promoting protein secreted by cancer cells, exerts paracrine effects on immune cells through TLR4 receptors expressed on immune cell surfaces. This study aimed to investigate if PAUF elicits autocrine effects on pancreatic cancer (PC) cells through TLR4, a receptor that is overexpressed on PC cells. In this study, TLR4 expression was detected in PC cells only, but not normal pancreatic cells. The migration of TLR4 high-expressing PC cells (i.e., BxPC-3) was reduced by a selective TLR4 inhibitor, in a dose-dependent manner. Using TLR4 overexpressed and knockout PC cell lines, we observed direct PAUF-TLR4 binding on the PC cell surfaces, and that PAUF-induced cancer migration may be mediated exclusively through the TLR4 receptor. Further experiments showed that PAUF signaling was passed down through the TLR4/MyD88 pathway without the involvement of the TLR4/TRIF pathway. TLR4 knockout also downregulated PC membrane PD-L1 expression, which was not influenced by PAUF. To the best of our knowledge, TLR4 is the first receptor identified on cancer cells that mediates PAUF's migration-promoting effect. The results of this study enhanced our understanding of the mechanism of PAUF-induced tumor-promoting effects and suggests that TLR4 expression on cancer cells may be an important biomarker for anti-PAUF treatment.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Fator 88 de Diferenciação Mieloide , Subunidade p50 de NF-kappa B , Neoplasias Pancreáticas , Receptor 4 Toll-Like , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Movimento Celular/genética , Movimento Celular/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lectinas/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Neoplasias Pancreáticas
11.
Genes Genomics ; 44(12): 1509-1517, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35917090

RESUMO

BACKGROUND: Overexpression of PD-L1 is observed in many types of human cancer, including glioblastoma (GBM) and contributes to tumor immune evasion. In addition, GBM shows highly-activated aerobic glycolysis due to overexpression of phosphofructokinase 1 platelet isoform (PFKP), which the key enzyme in the glycolysis. However, it remains unclear whether the metabolic enzyme PFKP plays a role in the regulation of PD-L1 expression and GBM immune evasion. OBJECTIVE: We aimed to investigate the non-metabolic role of PFKP in PD-L1 expression-induced GBM immune evasion. METHODS: The mechanisms of PFKP-induced PD-L1 expression were studied by several experiments, including real-time PCR, immunoblot analysis, and ATP production. The coculture experiments using GBM cell and T cells were performed to evaluate the effect of PFKP on T cell activation. The clinical relationship between PFKP and PD-L1 was analyzed in The Cancer Genome Atlas (TCGA) database and in human GBM specimens. RESULTS: We showed that PFKP promotes EGFR activation-induced PD-L1 expression in human GBM cells. Importantly, we demonstrated that EGFR-phosphorylated PFKP Y64 plays an important role in AKT-mediated ß-catenin transactivation and subsequent PD-L1 transcriptional expression, thereby enhancing the GBM immune evasion. In addition, based on our findings, the levels of PFKP Y64 phosphorylation are positively correlated with PD-L1 expression in human GBM specimens, highlighting the clinical significance of PFKP Y64 phosphorylation in the GBM immune evasion. CONCLUSION: These findings provide new mechanistic insight into the regulation of PD-L1 expression by a non-metabolic function of PFKP on tumor cells.


Assuntos
Glioblastoma , Fosfofrutoquinase-1 Tipo C , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Evasão da Resposta Imune , Fosforilação , Isoformas de Proteínas/metabolismo , Fosfofrutoquinase-1 Tipo C/genética , Fosfofrutoquinase-1 Tipo C/metabolismo
12.
Sci Rep ; 12(1): 3537, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241735

RESUMO

A multiple receptor tyrosine kinase inhibitor, sunitinib, is a first-line therapy for clear cell renal cell carcinoma (CCRCC). Unfortunately, it has the major challenges of low initial response rate and resistance after about one year of treatment. Here we evaluated a microRNA (miRNA) and its target responsible for sunitinib resistance. Using miRNA profiling, we identified miR-96-5p upregulation in tumors from sunitinib-resistant CCRCC patients. By bioinformatic analysis, PTEN was selected as a potential target of miR-96-5p, which showed low levels in tumors from sunitinib-resistant CCRCC patients. Furthermore, PTEN and miR-96-5p levels were negatively correlated in a large The Cancer Genome Atlas kidney renal clear cell carcinoma cohort and high miR-96 and low PTEN represented poor prognosis in this cohort. Additionally, four-week sunitinib treatment increased miR-96-5p and decreased PTEN only in tumors from a sunitinib-resistant patient-derived xenograft model. We found a novel miR-96-5p binding site in the PTEN 3' UTR and confirmed direct repression by luciferase reporter assay. Furthermore, we demonstrated that repression of PTEN by miR-96-5p increased cell proliferation and migration in sunitinib-treated cell lines. These results highlight the direct suppression of PTEN by miR-96-5p and that high miR-96-5p and low PTEN are partially responsible for sunitinib resistance and poor prognosis in CCRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , MicroRNAs , PTEN Fosfo-Hidrolase , Sunitinibe , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Extracell Vesicles ; 11(2): e12195, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35188341

RESUMO

Cancer cell-derived extracellular vesicles (EVs) are promising biomarkers for cancer diagnosis and prognosis. However, the lack of rapid and sensitive isolation techniques to obtain EVs from clinical samples at a sufficiently high yield limits their practicability. Chimeric nanocomposites of lactoferrin conjugated 2,2-bis(methylol)propionic acid dendrimer-modified magnetic nanoparticles (LF-bis-MPA-MNPs) are fabricated and used for simple and sensitive EV isolation from various biological samples via a combination of electrostatic interaction, physically absorption, and biorecognition between the surfaces of the EVs and the LF-bis-MPA-MNPs. The speed, efficiency, recovery rate, and purity of EV isolation by the LF-bis-MPA-MNPs are superior to those obtained by using established methods. The relative expressions of exosomal microRNAs (miRNAs) from isolated EVs in cancerous cell-derived exosomes are verified as significantly higher than those from noncancerous ones. Finally, the chimeric nanocomposites are used to assess urinary exosomal miRNAs from urine specimens from 20 prostate cancer (PCa), 10 benign prostatic hyperplasia (BPH), patients and 10 healthy controls. Significant up-regulation of miR-21 and miR-346 and down-regulation of miR-23a and miR-122-5p occurs in both groups compared to healthy controls. LF-bis-MPA-MNPs provide a rapid, simple, and high yield method for human excreta analysis in clinical applications.


Assuntos
Exossomos , Vesículas Extracelulares , MicroRNAs , Nanocompostos , Neoplasias da Próstata , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Masculino , MicroRNAs/metabolismo , Neoplasias da Próstata/diagnóstico
14.
Mol Cancer ; 20(1): 133, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649584

RESUMO

BACKGROUND: AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined. METHODS: AMPKα1fl/flFoxp3YFP-Cre, Foxp3YFP-Cre, Rag1-/-, and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation. RESULTS: The deletion of the AMPKα1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3ß (GSK-3ß), inhibiting the expression of PD-1 in Tregs. CONCLUSION: Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3ß signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hidroximetilglutaril-CoA Redutases/metabolismo , Imunomodulação , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Metabolismo Energético , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Imunofenotipagem , Camundongos , Receptor de Morte Celular Programada 1/metabolismo
16.
Biochem Biophys Res Commun ; 563: 15-22, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34058470

RESUMO

Helicobacter pylori infection is a crucial factor in the development of gastric cancer (GC). Molecular therapeutic targets and mechanisms contributing to H. pylori infection-associated GC induction are poorly understood and this study aimed to fill that research gap. We found that the nuclear receptor estrogen-related receptor gamma (ESRRG) is a candidate factor influencing H. pylori infection-driven GC. ESRRG suppressed H. pylori infection and cell growth induced by H. pylori infection in GC cells and organoid models In addition, H. pylori infection downregulates ESRRG expression. Gene expression profiling revealed that trefoil factor 1 (TFF1), a well-known tumor suppressor in GC, is a downstream target of ESRRG. Mechanistically, ESRRG directly binds to the TFF1 promoter and induces TFF1 gene expression. Furthermore, TFF1 activation by ESRRG was inhibited by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/p65, which is induced by inflammation, such as by H. pylori infection. Our current study provides new molecular insights into how ESRRG regulates H. pylori infection, contributing to GC development. We suggest that modulation of ESRRG-suppressing H. pylori infection could be a therapeutic target for the treatment of GC patients.


Assuntos
Infecções por Helicobacter/metabolismo , Receptores de Estrogênio/metabolismo , Neoplasias Gástricas/metabolismo , Fator Trefoil-1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Gástricas/patologia
17.
Genes Genomics ; 43(8): 913-920, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34021858

RESUMO

BACKGROUND: Nuclear receptors (NRs) are crucial transcription factors involved in cell proliferation, metabolism and homeostasis. Through the development of novel genomic approaches, unknown NR functions have recently been uncovered. NR networks derived from gene expression profiles revealed that NRs are tightly linked to human disease and that targeting these links could provide new therapeutic options. MicroRNAs (miRNAs) have known functions as transcriptional regulators of NR function. OBJECTIVE: I attempted to construct an NR-miRNA transcriptional network based on genomic data from human cancer. METHODS: I performed comprehensive analysis with genomic data. Correlation, clustering and survival analysis were done to identify the NR and miRNA correlation in cancer. RESULTS: Correlation analysis of genomic data revealed relationships between the expression levels of several NRs and miRNAs in human cancer. Based on my NR-miRNA correlation data, I found that NR3C1 expression was highly correlated with that of miR-200 in colon cancer. In most cases, miRNAs suppress expression of their target genes. Thus, miRNAs function as negative regulators during transcription. My analysis revealed that the miR-200 expression level is negatively correlated with that of NR3C1, demonstrating that miR-200 is a negative regulator of NR3C1 in colon cancer. It is known that miR-200 is a master regulator of EMT and that NR3C1 has a link with an EMT marker. CONCLUSIONS: Overall, my genomic analysis revealed that the NR3C1 expression level is correlated with that of miR-200 and that this functional relationship might contribute to colon cancer cell survival. Modulating this axis could be a promising target for treating colon cancer patients.


Assuntos
Neoplasias do Colo/genética , Redes Reguladoras de Genes/genética , MicroRNAs/genética , Receptores de Glucocorticoides/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/genética , Genômica , Homeostase , Humanos , Transcriptoma/genética
18.
Sci Rep ; 10(1): 14932, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913285

RESUMO

Cell-free nucleic acids (cfNAs) in liquid biopsy samples are emerging as important biomarkers for cancer diagnosis and monitoring, and for predicting treatment outcomes. Many cfNA isolation methods have been developed recently. However, most of these techniques are time-consuming, complex, require large equipment, and yield low-purity cfNAs because the genetic background of normal cells is amplified during cell lysis, which limits their clinical application. Here, we report a rapid and simple cfNA sampling platform that can overcome the limitations of conventional methods. We synthesised a biocomposite by combining amine-modified diatomaceous earth (DE) and cucurbituril (CB). The biocomposite platform showed high capture efficiency (86.78-90.26%) with genomic DNA and amplified DNA products (777, 525 and 150 bp). The biocomposite platform allowed the isolation of high purity and quantity cfDNAs from the plasma of 13 cancer patients (three colorectal cancer and ten pancreatic cancer samples) without requiring a lysis step or special equipment. The biocomposite platform may be useful to isolate cfNAs for the diagnosis and treatment of cancers in clinical applications.


Assuntos
Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/patologia , Manejo de Espécimes/métodos , Humanos , Biópsia Líquida , Neoplasias/sangue , Neoplasias/genética
19.
Redox Biol ; 37: 101716, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32961441

RESUMO

The use of human mesenchymal stem cells (hMSCs) in clinical applications requires large-scale cell expansion prior to administration. However, the prolonged culture of hMSCs results in cellular senescence, impairing their proliferation and therapeutic potentials. To understand the role of microRNAs (miRNAs) in regulating cellular senescence in hMSCs, we globally depleted miRNAs by silencing the DiGeorge syndrome critical region 8 (DGCR8) gene, an essential component of miRNA biogenesis. DGCR8 knockdown hMSCs exhibited severe proliferation defects and senescence-associated alterations, including increased levels of reactive oxygen species (ROS). Transcriptomic analysis revealed that the antioxidant gene superoxide dismutase 2 (SOD2) was significantly downregulated in DGCR8 knockdown hMSCs. Moreover, we found that DGCR8 silencing in hMSCs resulted in hypermethylation in CpG islands upstream of SOD2. 5-aza-2'-deoxycytidine treatment restored SOD2 expression and ROS levels. We also found that these effects were dependent on the epigenetic regulator DNA methyltransferase 3 alpha (DNMT3A). Using computational and experimental approaches, we demonstrated that DNMT3A expression was regulated by miR-29a-3p and miR-30c-5p. Overexpression of miR-29a-3p and/or miR-30c-5p reduced ROS levels in DGCR8 knockdown hMSCs and rescued proliferation defects, mitochondrial dysfunction, and premature senescence. Our findings provide novel insights into hMSCs senescence regulation by the miR-29a-3p/miR-30c-5p/DNMT3A/SOD2 axis.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Células-Tronco Mesenquimais , MicroRNAs/genética , Mitocôndrias , Estresse Oxidativo , Superóxido Dismutase/metabolismo , DNA Metiltransferase 3A , Epigênese Genética , Técnicas de Silenciamento de Genes , Humanos , Células-Tronco Mesenquimais/metabolismo , Proteínas de Ligação a RNA
20.
Theranostics ; 10(18): 7974-7992, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724453

RESUMO

Breast cancer (BC) is one of the most common cancers in women. TNBC (Triple-negative breast cancer) has limited treatment options and still lacks viable molecular targets, leading to poor outcomes. Recently, RNA-binding proteins (RBPs) have been shown to play crucial roles in human cancers, including BC, by modulating a number of oncogenic phenotypes. This suggests that RBPs represent potential molecular targets for BC therapy. Methods: We employed genomic data to identify RBPs specifically expressed in TNBC. NONO was silenced in TNBC cell lines to examine cell growth, colony formation, invasion, and migration. Gene expression profiles in NONO-silenced cells were generated and analyzed. A high-throughput screening for NONO-targeted drugs was performed using an FDA-approved library. Results: We found that the NONO RBP is highly expressed in TNBC and is associated with poor patient outcomes. NONO binds to STAT3 mRNA, increasing STAT3 mRNA levels in TNBC. Surprisingly, NONO directly interacts with STAT3 protein increasing its stability and transcriptional activity, thus contributing to its oncogenic function. Importantly, high-throughput drug screening revealed that auranofin is a potential NONO inhibitor and inhibits cell growth in TNBC. Conclusions: NONO is an RBP upstream regulator of both STAT3 RNA and protein levels and function. It represents an important and clinically relevant promoter of growth and resistance of TNBCs. NONO is also therefore a potential therapeutic target in TNBC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica , Humanos , Nanopartículas/química , Medicina de Precisão/métodos , Proteínas de Ligação a RNA/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Nanomedicina Teranóstica/métodos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA