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1.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638823

RESUMO

Despite recent advances in therapies including immunotherapy, patients with acute myeloid leukaemia (AML) still experience relatively poor survival rates. The Inhibition of Apoptosis (IAP) family member, survivin, also known by its gene and protein name, Baculoviral IAP Repeat Containing 5 (BIRC5), remains one of the most frequently expressed antigens across AML subtypes. To better understand its potential to act as a target for immunotherapy and a biomarker for AML survival, we examined the protein and pathways that BIRC5 interacts with using the Kyoto Encyclopedia of Genes and Genomes (KEGG), search tool for recurring instances of neighbouring genes (STRING), WEB-based Gene Set Analysis Toolkit, Bloodspot and performed a comprehensive literature review. We then analysed data from gene expression studies. These included 312 AML samples in the Microarray Innovations In Leukemia (MILE) dataset. We found a trend between above median levels of BIRC5 being associated with improved overall survival (OS) but this did not reach statistical significance (p = 0.077, Log-Rank). There was some evidence of a beneficial effect in adjusted analyses where above median levels of BIRC5 were shown to be associated with improved OS (p = 0.001) including in Core Binding Factor (CBF) patients (p = 0.03). Above median levels of BIRC5 transcript were associated with improved relapse free survival (p < 0.0001). Utilisation of a second large cDNA microarray dataset including 306 AML cases, again showed no correlation between BIRC5 levels and OS, but high expression levels of BIRC5 correlated with worse survival in inv(16) patients (p = 0.077) which was highly significant when datasets A and B were combined (p = 0.001). In addition, decreased BIRC5 expression was associated with better clinical outcome (p = 0.004) in AML patients exhibiting CBF mainly due to patients with inv(16) (p = 0.007). This study has shown that BIRC5 expression plays a role in the survival of AML patients, this association is not apparent when we examine CBF patients as a cohort, but when those with inv(16) independently indicating that those patients with inv(16) would provide interesting candidates for immunotherapies that target BIRC5.


Assuntos
Bases de Dados de Ácidos Nucleicos , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Proteínas de Neoplasias/biossíntese , Survivina/biossíntese , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Proteínas de Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Taxa de Sobrevida , Survivina/genética
2.
Anticancer Res ; 41(9): 4321-4331, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475052

RESUMO

BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. MATERIALS AND METHODS: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. RESULTS: Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. CONCLUSION: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Cloridrato de Lurasidona/administração & dosagem , Survivina/metabolismo , Células A549 , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Cloridrato de Lurasidona/farmacologia , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Pak Med Assoc ; 71(9): 2208-2213, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34580516

RESUMO

OBJECTIVE: To measure and compare micro ribonucleic acid-16, survivin and tumour protein p53-regulated apoptosis-inducing protein 1 expression levels in preeclamptic and normotensive pregnancies, and to check the correlation of micro ribonucleic acid-16 with messenger ribonucleic acid expression of survivin and tumour protein p53. METHODS: The observational cross-sectional comparative study was conducted at the Department of Physiology and Cell Biology, University of Health Sciences, Lahore, Pakistan, from 2016 to 2018, and comprised preeclamptic women in group A and normotensive women in group B. The preeclamptic patients were further categorised into early-onset preeclampsia subgroup A1and late-onset preeclampsia group A2. Expression of micro ribonucleic acid-16, messenger ribonucleic acid expression of survivin and tumour protein p53 in preeclamptic and normotensive pregnancies were analysed using real time polymerase chain reaction. Data was analysed using SPSS 22. RESULTS: Of the 54 patients, 27(50%) were in each of the two groups. Within group A, 14(52%) patients were in group A1 and 13(48%) in group A2. The expression of micro ribonucleic acid 16 showed significant increase in group A compared to group B (p<0.05). The difference was not significant between the subgroups A1 and A2. The levels of messenger ribonucleic acid expression of survivin and tumour protein p53 were deregulated in group A, with a decrease in survivin and an increase in tumour protein p53. The messenger ribonucleic acid expression of survivin and tumour protein p53 showed statistically significant differences across subgroups A1 and A2 (p<0.05). The micro ribonucleic acid-16 expression correlated negatively with messenger ribonucleic acid expression of survivin, but exhibited a positive correlation with tumour protein p53. CONCLUSIONS: Deregulated micro ribonucleic acid-16 along with differentially expressed apoptotic genes, survivin and tumour protein p53 might result in altered apoptosis implicated in the pathogenesis of preeclampsia.


Assuntos
MicroRNAs , Pré-Eclâmpsia , Estudos Transversais , Feminino , Humanos , Pré-Eclâmpsia/genética , Gravidez , Survivina/genética , Proteína Supressora de Tumor p53/genética
4.
Math Biosci Eng ; 18(5): 6941-6960, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34517565

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world, the detection and prognosis of which are still unsatisfactory. Thus, it is essential to explore the factors that may identify ESCC and evaluate the prognosis of ESCC patients. RESULTS: Both protein and mRNA expression levels of BIRC5 are upregulated in ESCC group rather than non-ESCC group (standardized mean difference > 0). BIRC5 mRNA expression is related to the age, tumor location, lymph node stage and clinical stage of ESCC patients (p < 0.05). BIRC5 expression makes it feasible to distinguish ESCC from non-ESCC (area under the curve > 0.9), and its high expression is related to poor prognosis of ESCC patients (restrictive survival time difference = -0.036, p < 0.05). BIRC5 may play an important role in ESCC by influencing the cell cycle pathway, and CDK1, MAD2L and CDC20 may be the hub genes of this pathway. The transcription factors-MAZ and TFPD1 -are likely to regulate the transcription of BIRC5, which may be one of the factors for the high expression of BIRC5 in ESCC. CONCLUSIONS: The current study shows that upregulation of BIRC5 may have essential clinical value in ESCC, and contributes to the understanding of the pathogenesis of ESCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Survivina/genética , Regulação para Cima
5.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576188

RESUMO

PolyPurine Reverse Hoogsteen Hairpins (PPRHs) are gene-silencing DNA-oligonucleotides developed in our laboratory that are formed by two antiparallel polypurine mirror repeat domains bound intramolecularly by Hoogsteen bonds. The aim of this work was to explore the feasibility of using viral vectors to deliver PPRHs as a gene therapy tool. After treatment with synthetic RNA, plasmid transfection, or viral infection targeting the survivin gene, viability was determined by the MTT assay, mRNA was determined by RT-qPCR, and protein levels were determined by Western blot. We showed that the RNA-PPRH induced a decrease in cell viability in a dose-dependent manner and an increase in apoptosis in PC-3 and HeLa cells. Both synthetic RNA-PPRH and RNA-PPRH intracellularly generated upon the transfection of a plasmid vector were able to reduce survivin mRNA and protein levels in PC-3 cells. An adenovirus type-5 vector encoding the PPRH against survivin was also able to decrease survivin mRNA and protein levels, leading to a reduction in HeLa cell viability. In this work, we demonstrated that PPRHs can also work as RNA species, either chemically synthesized, transcribed from a plasmid construct, or transcribed from viral vectors. Therefore, all these results are the proof of principle that viral vectors could be considered as a delivery system for PPRHs.


Assuntos
Inativação Gênica/fisiologia , Adenoviridae/genética , Apoptose/genética , Apoptose/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células HeLa , Humanos , Oligonucleotídeos/genética , Oligonucleotídeos/metabolismo , Células PC-3 , Survivina/genética , Survivina/metabolismo
6.
Invest Ophthalmol Vis Sci ; 62(12): 16, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34533562

RESUMO

Purpose: Over 90% of uveal melanomas harbor pathogenic variants of the GNAQ or GNA11 genes that activate survival pathways. As previous studies found that Ras-mutated cell lines were vulnerable to a combination of survival pathway inhibitors and the histone-deacetylase inhibitor romidepsin, we investigated whether this combination would be effective in models of uveal melanoma. Methods: A small-scale screen of inhibitors of bromodomain-containing protein 4 (BRD4; OTX-015), extracellular signal-related kinase (ERK; ulixertinib), mechanistic target of rapamycin (mTOR; AZD-8055), or phosphoinositide 3-kinase (PI3K; GDC-0941) combined with a clinically relevant administration of romidepsin was performed on a panel of uveal melanoma cell lines (92.1, Mel202, MP38, and MP41) and apoptosis was quantified by flow cytometry after 48 hours. RNA sequencing analysis was performed on Mel202 cells treated with romidepsin alone, AZD-8055 alone, or the combination, and protein changes were validated by immunoblot. Results: AZD-8055 with romidepsin was the most effective combination in inducing apoptosis in the cell lines. Increased caspase-3 and PARP cleavage were noted in the cell lines when they were treated with romidepsin and mTOR inhibitors. RNA sequencing analysis of Mel202 cells revealed that apoptosis was the most affected pathway in the romidepsin/AZD-8055-treated cells. Increases in pro-apoptotic BCL2L11 and decreases in anti-apoptotic BIRC5 and BCL2L1 transcripts noted in the sequencing analysis were confirmed at the protein level in Mel202 cells. Conclusions: Our data suggest that romidepsin in combination with mTOR inhibition could be an effective treatment strategy against uveal melanoma due in part to changes in apoptotic proteins.


Assuntos
Apoptose/efeitos dos fármacos , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Melanoma/tratamento farmacológico , Morfolinas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias Uveais/tratamento farmacológico , Proteína 11 Semelhante a Bcl-2/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Combinação de Medicamentos , Citometria de Fluxo , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Immunoblotting , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Análise de Sequência de RNA , Survivina/genética , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia , Proteína bcl-X/genética
7.
Biochem Biophys Res Commun ; 574: 48-55, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34438346

RESUMO

Survivin is the key component of the chromosomal passenger complex and plays important roles in the regulation of cell division. Survivin has also been implicated in the regulation of apoptosis and tumorigenesis. Although the survivin protein has been reported to be degraded by a ubiquitin/proteasome-dependent mechanism, whether there is a DUB that is involved in the regulation of its protein stability is largely unknown. Using an expression library containing 68 deubiquitinating enzymes, we found that ubiquitin-specific-processing protease 35 (USP35) regulates survivin protein stability in an enzymatic activity-dependent manner. USP35 interacted with and promoted the deubiquitination of the survivin protein. USP38, an ortholog of USP35 encoded by the human genome, is also able to regulate survivin protein stability. Moreover, we found that the deubiquitinating enzyme DUBAI, the Drosophila homolog of human USP35, is able to regulate the protein stability of Deterin, the Drosophila homolog of survivin. Interestingly, USP35 also regulated the protein stability of Aurora B and Borealin which are also the component of the chromosomal passenger complex. By regulating protein stabilities of chromosomal passenger complex components, USP35 regulated cancer cell proliferation. Taken together, our work uncovered an evolutionarily conserved relationship between USP35 and survivin that might play an important role in cell proliferation.


Assuntos
Endopeptidases/metabolismo , Survivina/metabolismo , Proliferação de Células , Células Cultivadas , Endopeptidases/genética , Humanos , Estabilidade Proteica , Survivina/genética
8.
Anal Chem ; 93(35): 12081-12089, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34436865

RESUMO

Precise detection of cancer-related mRNAs can significantly benefit the early diagnosis and potential therapy of cancers. Herein, we report organic dark quencher-encapsulated surface-cross-linked micelles (qSCMs) as a new sort of nanoquencher for construction of potential multiple-color fluorescence imaging nanosensors. Such nanoquenchers featured simple preparation (one-pot), broad-spectrum quenching (450-800 nm), high quenching efficiency (>94%), good stability, negligible cargo leakage, facile covalent surface modification, and finally excellent modularity. As a proof-of-concept demonstration, a mRNA-detecting qSCM nanosensor was generated, capable of simultaneous live-cell imaging of endogenous actin mRNA (a house-keeping gene) and cancer-related survivin mRNA. This nanosensor was found to be GSH- and DNase I-resistant, and with actin mRNA as an intrinsic reference, it was used to image the precise survivin mRNA expression across different mammalian cells through convenient normalization of the signal readouts. Moreover, the nanosensor was further used to quantitatively image the downregulation of endogenous survivin mRNA in HeLa cells upon treatment of YM155 (an imidazolium bioactive compound known to suppresses endogenous survivin mRNA expression). These results clearly demonstrated the promising application of these qSCMs as new nanoquenchers in potential multicolor imaging of various endogenous biomarkers.


Assuntos
Imagem Óptica , Animais , Linhagem Celular Tumoral , Células HeLa , Humanos , RNA Mensageiro/genética , Survivina/genética
9.
Cancer Sci ; 112(10): 4166-4175, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34288272

RESUMO

Various molecular-targeting drugs have markedly improved the treatment of patients with breast cancer. As yet, therapies for triple-negative breast cancer are mainly cytotoxic agents. To investigate the novel therapy for triple-negative breast cancer, we herein examined the effects of a new combination therapy comprising a RAF/MEK inhibitor CH5126766, also known as VS-6766, which we originally discovered, and eribulin. The combination of CH5126766 and eribulin potently inhibited cell growth in the triple-negative breast cancer cell lines tested. The underlying mechanism in the efficacy of this combination treatment in vitro and in vivo was due to enhanced apoptosis through the suppression of survivin and Bcl-2 family proteins. We also showed the suppressed expression of programmed cell death ligand 1 (PD-L1) in combination therapy in vivo. We found that combination therapy with eribulin and CH5126766 for triple-negative breast cancer inhibited cell growth by apoptosis and raised a possibility that immune responses through suppression of PD-L1 might partially contribute to inhibition of tumor growth, indicating the potential of this combination as a novel strategy for triple-negative breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cumarínicos/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Proteína Oncogênica v-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória , Survivina/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaio Tumoral de Célula-Tronco
10.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198613

RESUMO

Breast cancer is the most common cancer in females. The aim of this study was to determine the effect of paclitaxel (PTX) and doxorubicin (DOX) therapy on the ßIII-tubulin, carbonic anhydrase IX (CA IX), and survivin expression in chemically-induced rat mammary tumors. Animals with induced mammary carcinogenesis were randomly divided into treatment groups and an untreated group. The total proportion of tumors, the proportion of carcinoma in situ (CIS), and invasive carcinoma (IC) were evaluated. Protein expression in tumor tissue was determined using IHC. Statistical analysis of the data, evaluated by Fisher-exact test and unpaired t-test. Significantly increased levels of proteins in the tumor cells were confirmed using the IHC method for all studied proteins. The expression of ßIII-tubulin, CA IX, and survivin increased significantly after treatment with both cytostatics (PTX and DOX). Depending on the type of tumor, a significant increase in all proteins was observed in IC samples after PTX treatment, and CA IX expression after DOX treatment. In CIS samples, a significant increase of ßIII-tubulin and survivin expression was observed after a DOX treatment. The results suggest that ßIII-tubulin, survivin, and CA IX may be significant drug resistance markers and the clinical regulation of their activity may be an effective means of reversing this resistance.


Assuntos
Anidrase Carbônica IX/metabolismo , Doxorrubicina/uso terapêutico , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/metabolismo , Paclitaxel/uso terapêutico , Survivina/metabolismo , Tubulina (Proteína)/metabolismo , Animais , Doxorrubicina/farmacologia , Feminino , Paclitaxel/farmacologia , Ratos Sprague-Dawley
11.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281156

RESUMO

Cardiotoxicity is associated with the long-term clinical application of doxorubicin (DOX) in cancer patients. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) including exosomes have been suggested for the treatment of various diseases, including ischemic diseases. However, the effects and functional mechanism of MSC-sEVs in DOX-induced cardiomyopathy have not been clarified. Here, MSC-sEVs were isolated from murine embryonic mesenchymal progenitor cell (C3H/10T1/2) culture media, using ultrafiltration. H9c2 cardiac myoblast cells were pretreated with MSC-sEVs and then exposed to DOX. For in vivo studies, male C57BL/6 mice were administered MSC-sEVs intravenously, prior to a single dose of DOX (15 mg/kg, intraperitoneal). The mice were sacrificed 14 days after DOX treatment. The results showed that MSC-sEVs protected cardiomyocytes from DOX-induced cell death. H9c2 cells treated with DOX showed downregulation of both phosphorylated Akt and survivin, whereas the treatment of MSC-sEVs recovered expression, indicating their anti-apoptotic effects. Three microRNAs (miRNAs) (miR 199a-3p, miR 424-5p, and miR 21-5p) in MSC-sEVs regulated the Akt-Sp1/p53 signaling pathway in cardiomyocytes. Among them, miR 199a-3p was involved in regulating survivin expression, which correlated with the anti-apoptotic effects of MSC-sEVs. In in vivo studies, the echocardiographic results showed that the group treated with MSC-sEVs recovered from DOX-induced cardiomyopathy, showing improvement of both the left ventricle fraction and ejection fraction. MSC-sEVs treatment also increased both survivin and B-cell lymphoma 2 expression in heart tissue compared to the DOX group. Our results demonstrate that MSC-sEVs have protective effects against DOX-induced cardiomyopathy by upregulating survivin expression, which is mediated by the regulation of Akt activation by miRNAs in MSC-sEVs. Thus, MSC-sEVs may be a novel therapy for the prevention of DOX-induced cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiomiopatias/prevenção & controle , Cardiotoxicidade/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Exossomos/metabolismo , Vesículas Extracelulares/fisiologia , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Survivina/genética , Survivina/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Theranostics ; 11(14): 6873-6890, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093859

RESUMO

Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Descoberta de Drogas/métodos , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Complexo Repressor Polycomb 2/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Complexo Repressor Polycomb 2/química , Complexo Repressor Polycomb 2/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Quinases Associadas a Fase S/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Survivina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
BMC Cancer ; 21(1): 687, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112092

RESUMO

BACKGROUND: The baculoviral IAP repeat containing 5 (BIRC5) related to epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of hepatocellular carcinoma (HCC). However, it remains unclear whether BIRC5-related genes can be used as prognostic markers of HCC. METHODS: Kaplan-Meier (K-M) survival curve was used to assess the Overall Survival (OS) of high- and low-expression group divided by the median of BIRC5 expression. The differentially expressed genes (DEGs) between the two groups were screened using the limma package, and performed the functional enrichment analysis by the clusterProfiler package. WGCNA was used to analyze the relationship of the module and the clinical traits. The risk signature was constructed by univariate and multivariate Cox regression analyses and the enrichment analysis of genes in the risk signature was performed by the Intelligent pathway analysis (IPA). The immunophenoscore (IPS) and the tumor immune dysfunction and exclusion (TIDE) were used to estimate the clinical significance of the risk groups. RESULTS: BIRC5 was high-expressed in HCC samples and associated with a poor prognosis (p-value < 0.0001). WGCNA screened 180 module genes which were overlapped with the 241 DEGs, ultimately getting 33 candidate genes. After the Cox regression analyses, CENPA, CDCA8, EZH2, KIF20A, KPNA2, CCNB1, KIF18B and MCM4 were preserved and used to construct risk signature, followed by calculating the risk score. The patients in high-risk groups stratified by median of the risk score were associated with a poor prognosis. The risk score had high accuracy [the area under the curve (AUC) > 0.72] and was closely associated with clinicopathological characteristics of HCC patients. IPA suggested that the 8 genes were enriched in Cancer and Immunological disease related pathways. IPS and TIDE score indicated that the genes in low-risk group could cause an immune response, and patients in the low-risk group may be more sensitive to the immune checkpoint blockade (ICB) therapy. CONCLUSION: The risk score constructed by the 8 genes could not only predict the clinical outcome but also distinguish the cohort of ICB therapy in HCC, which exerted a vital value in treatment and prognosis of HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Redes Reguladoras de Genes/imunologia , Neoplasias Hepáticas/mortalidade , Survivina/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Estudos de Viabilidade , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Nomogramas , Valor Preditivo dos Testes , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/imunologia , Medição de Risco/métodos , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
14.
Cell Mol Life Sci ; 78(14): 5587-5604, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34100981

RESUMO

To clarify whether differential compartmentalization of Survivin impacts temozolomide (TMZ)-triggered end points, we established a well-defined glioblastoma cell model in vitro (LN229 and A172) and in vivo, distinguishing between its nuclear and cytoplasmic localization. Expression of nuclear export sequence (NES)-mutated Survivin (SurvNESmut-GFP) led to impaired colony formation upon TMZ. This was not due to enhanced cell death but rather due to increased senescence. Nuclear-trapped Survivin reduced homologous recombination (HR)-mediated double-strand break (DSB) repair, as evaluated by γH2AX foci formation and qPCR-based HR assay leading to pronounced induction of chromosome aberrations. Opposite, clones, expressing free-shuttling cytoplasmic but not nuclear-trapped Survivin, could repair TMZ-induced DSBs and evaded senescence. Mass spectrometry-based interactomics revealed, however, no direct interaction of Survivin with any of the repair factors. The improved TMZ-triggered HR activity in Surv-GFP was associated with enhanced mRNA and stabilized RAD51 protein expression, opposite to diminished RAD51 expression in SurvNESmut cells. Notably, cytoplasmic Survivin could significantly compensate for the viability under RAD51 knockdown. Differential Survivin localization also resulted in distinctive TMZ-triggered transcriptional pathways, associated with senescence and chromosome instability as shown by global transcriptome analysis. Orthotopic LN229 xenografts, expressing SurvNESmut exhibited diminished growth and increased DNA damage upon TMZ, as manifested by PCNA and γH2AX foci expression, respectively, in brain tissue sections. Consequently, those mice lived longer. Although tumors of high-grade glioma patients expressed majorly nuclear Survivin, they exhibited rarely NES mutations which did not correlate with survival. Based on our in vitro and xenograft data, Survivin nuclear trapping would facilitate glioma response to TMZ.


Assuntos
Núcleo Celular/metabolismo , Senescência Celular , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Recombinação Homóloga , Survivina/metabolismo , Temozolomida/farmacologia , Animais , Antineoplásicos Alquilantes/farmacologia , Apoptose , Biomarcadores Tumorais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Núcleo Celular/genética , Proliferação de Células , Dano ao DNA , Reparo do DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Survivina/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Medicine (Baltimore) ; 100(22): e26219, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087900

RESUMO

BACKGROUND: Autophagy is closely related to skin cutaneous melanoma (SKCM), but the mechanism involved is unclear. Therefore, exploration of the role of autophagy-related genes (ARGs) in SKCM is necessary. MATERIALS AND METHODS: Differential expression autophagy-related genes (DEARGs) were first analysed. Univariate and multivariate Cox regression analyses were used to evaluate the expression of DEARGs and prognosis of SKCM. Further, the expression levels of prognosis-related DEARGs were verified by immunohistochemical (IHC) staining. Finally, gene set enrichment analysis (GSEA) was used to explore the underlying molecular mechanisms of SKCM. RESULTS: Five ARGs (APOL1, BIRC5, EGFR, TP63, and SPNS1) were positively correlated with the prognosis of SKCM. IHC verified the results of the differential expression of these 5 ARGs in the bioinformatics analysis. According to the receiver operating characteristic curve, the signature had a good performance at predicting overall survival in SKCM. The signature could classify SKCM patients into high-risk or low-risk groups according to distinct overall survival. The nomogram confirmed that the risk score has a particularly large impact on the prognosis of SKCM. Calibration plot displayed excellent agreement between nomogram predictions and actual observations. Principal component analysis indicated that patients in the high-risk group could be distinguished from those in low-risk group. Results of GSEA indicated that the low-risk group is enriched with aggressiveness-related pathways such as phosphatidylinositol-3-kinase/protein kinase B and mitogen-activated protein kinase signalling pathways. CONCLUSION: Our study identified a 5-gene signature. It revealed the mechanisms of autophagy that lead to the progression of SKCM and established a prognostic nomogram that can predict overall survival of patients with SKCM. The findings of this study provide novel insights into the relationship between ARGs and prognosis of SKCM.


Assuntos
Autofagia/genética , Biologia Computacional/métodos , Melanoma/genética , Neoplasias Cutâneas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apolipoproteína L1/genética , Receptores ErbB/genética , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/mortalidade , Proteínas de Membrana/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nomogramas , Fosfatidilinositol 3-Quinase/metabolismo , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Curva ROC , Fatores de Risco , Survivina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
16.
Biosens Bioelectron ; 190: 113445, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34153827

RESUMO

Benefiting from the outstanding signal amplification effect and the admirable construction flexibility, the currently proposed DNA motors (particularly DNA walkers) based biosensing concepts have provided a forceful fluorescence imaging tool for intracellular detection. Even so, this promising sensing means is not only subject to poor controllability and prone to produce false signals but also requires exogenous powering forces owing to the common employment of DNAzyme. In response to these challenges, we are herein motivated to present some meaningful solving strategies. For one thing, the surfaces of gold nanoparticles are conducted with a photo-gated walking behavior by introducing a photocleave mode, under which the light-switchable DNA walkers are capable of being selectively activated via an external ultraviolet source to faultlessly prevent the sensing frame from being pre-initiated during cellular uptake and intracellular delivery. For another, the intracellular biothiols are consumed by MnO2 nanosheets to effectively avoid the competitions to Au-S bonds to eliminate potential false outputs and also self-supply sufficient cofactors (Mn2+) to actualize a self-powered operation pattern as well as facilitate the endocytosis process. Following these breakthroughs, a favorable analysis performance towards a model tumor biomarker (survivin mRNA) is endowed with the newly raised biosensor, whose sensitivity is low to pM level with a sound specificity for identifying single base mismatching. Moreover, the significantly improved autonomous three-dimensional DNA walkers can be used to determine and dynamically trace the targets in live cancer cells with an exceptional precise and efficient manner, commendably impelling the sensing ability of DNA motors in biological specimens.


Assuntos
Técnicas Biossensoriais , DNA Catalítico , Nanopartículas Metálicas , MicroRNAs , DNA/genética , Ouro , Compostos de Manganês , Óxidos , RNA Mensageiro/genética , Survivina/genética
17.
Int J Cardiol ; 338: 176-184, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082009

RESUMO

BACKGROUND: Long non-coding RNA (lncRNA) is crucial for heart development and for adult heart structural maintenance and function. Herein, we performed a study to explore the effect of lncRNA PART1 on myocardial ischemia-reperfusion (I/R) injury by targeting BIRC5 through miR-503-5p pathway. METHODS: I/R model was created in vivo and vitro. The level of gene and protein was detected by RT-PCR and western blot. The apoptosis level was assessed by TUNEL and flow cytometry. Cell viability was determined by MTT. Mitochondrial function was evaluated by ATP content, ROS production, GSH level, and mitochondrial membrane potential. Cardiac function was confirmed by echocardiography, TTC staining, and H&E staining. RESULTS: Here, we found that the expression of lncRNA PART1 was down-regulated in the I/R hearts and H/R cardiomyocytes. Forced expression of PART1 remitted cardiac I/RI and H/R cardiomyocyte injury. Silencing of PART1 aggravated apoptosis and mitochondrial damage in cardiomyocytes. We found that PART1 functioned as a competing endogenous RNA of miR-503-5p, which decreased the expression of miR-503-5p. We further established BIRC5 as a target of miR-503-5p. Furthermore, PART1 prevented apoptosis and improved mitochondrial function in myocardial I/RI by targeting miR-503-5p/BIRC5. CONCLUSIONS: In summary, PART1 protected mitochondrial function via miR-503-5p/BIRC5 pathway in MI/RI, which may provide the new theoretical basis for MI/RI treatment in the clinic.


Assuntos
MicroRNAs , Traumatismo por Reperfusão Miocárdica , RNA Longo não Codificante , Apoptose/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Survivina/metabolismo
18.
Clin Oral Investig ; 25(12): 6643-6652, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33954850

RESUMO

AIM: To investigate the influence of nonsurgical periodontal treatment (NSPT) on clinical periodontal status, rheumatoid arthritis (RA) activity, and plasmatic and salivary levels of biomarkers through a controlled clinical trial on individuals with RA and periodontitis (PE). METHODS: Sixty-six individuals from a convenience sample were considered eligible and consecutively allocated in 3 groups: (1) individuals without PE and RA (-PE-RA, n = 19); (2) individuals without PE and with RA (-PE+RA, n = 23), and (3) individuals with PE and RA (+PE+RA, n = 24). Full-mouth periodontal clinical examinations, Disease Activity Score (DAS-28) evaluations, and analysis in plasma and saliva of RANKL, OPG, RANKL/OPG, and Survivin were performed at baseline (T1) and 45 days after NSPT (T2). RESULTS: NSPT in the +PE+RA group was very effective to improve periodontal condition. At T2, significant reductions in DAS-28 were observed in +PE+RA (p = 0.011). Significantly higher levels of Survivin and RANKL were observed in saliva and plasma from RA individuals (with and without PE) compared to controls. Additionally, Survivin e RANKL demonstrated positive correlations with DAS-28 and an expressively significant reduction in +PE+RA at T2 (p < 0.001). CONCLUSIONS: NSPT was effective on improving both the periodontal and the RA clinical status and reducing the concentration of Survivin and RANKL in saliva and plasma. PRACTICAL IMPLICATIONS: Nonsurgical periodontal treatment was effective on reducing the concentration of Survivin and RANKL and on improving both the periodontal and the RA clinical status of affected individuals. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (ReBEC) protocol #RBR-8g2bc8 ( http://www.ensaiosclinicos.gov.br/rg/RBR-8g2bc8/ ).


Assuntos
Artrite Reumatoide , Doenças Periodontais , Periodontite , Artrite Reumatoide/terapia , Humanos , Periodontite/terapia , Saliva , Survivina
19.
Drug Deliv ; 28(1): 995-1006, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34042551

RESUMO

The effective delivery system plays an important role in the application of siRNA in the antitumor study. However, until now, researches on the delivery systems targeting hepatocarcinoma cells are still being explored. Here we designed and prepared a novel siRNA delivery system, cRGD-PSH-NP, which was based on a modified polyethyleneimine (PSH) and DSPE-PEG2000-cRGD. cRGD-PSH-NP loaded with survivin siRNA (cRGD-PSH-NP/S) was composed of egg phosphatidylcholine, cationic PSH, PEGylated lipids, survivin siRNA, and cRGD peptide as a targeting ligand. The formulations of cRGD-PSH-NP/S were optimized and characterized. In vitro investigations showed excellent gene silencing and antitumor activity compared with the unmodified nanoparticles in HepG2 cells. In vivo antitumor efficacy of cRGD-PSH-NP/S exhibited potent tumor inhibition (74.71%) in HepG2-bearing nude mice without inducing toxicity. These data suggested further research of cRGD-PSH-NP/S in hepatocarcinoma therapy.


Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Peptídeos Cíclicos/química , Polietilenoimina/química , RNA Interferente Pequeno/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Química Farmacêutica , Portadores de Fármacos , Inativação Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , Distribuição Aleatória , Propriedades de Superfície , Survivina/efeitos dos fármacos
20.
Hypertens Pregnancy ; 40(2): 144-151, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34014801

RESUMO

Objective: To evaluate the serum survivin level in preeclampsia.Methods: Eighty-eight pregnancies complicated with preeclampsia and 88 gestational-age (GA)-matched uncomplicated pregnancies were evaluated.Results: Mean serum survivin was detected to be significantly decreased in the early- (EOPE) and late-onset (LOPE) preeclampsia subgroups than the GA-matched control-groups; and were comparable in EOPE- and LOPE-groups after correction for GA. Serum survivin had weak negative correlations with systolic and diastolic arterial blood pressure.Conclusion: The serum survivin level was decreased in preeclamptic patients than the GA-matched controls. More comprehensive studies are needed to clarify the timing and extent of placental apoptosis in preeclampsia.


Assuntos
Pré-Eclâmpsia/diagnóstico , Survivina/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Pré-Eclâmpsia/sangue , Gravidez
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