Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 40
Filtrar
1.
Oncogene ; 40(43): 6223-6234, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34552192

RESUMO

Immune-checkpoint blockade (ICB) has been routinely implemented to treat bladder cancer; however, most patients have little or no clinical benefit. In this study, 348 pretreated metastatic urothelial cancer samples from the IMvigor210 cohort were used to identify important genes significantly associated with CD8+ T effector and immune checkpoint signatures. The immune checkpoint inhibitor score (IMS) scoring system was constructed to predict the immunotherapy responsiveness. Transcriptome analysis confirmed that the high IMS score group had significant immune activation with better prognosis and higher immunotherapy responsiveness, which was a powerful biomarker for predicting the prognosis and responsiveness of ICB. Tumor immune dysfunction and exclusion (TIDE) scores were calculated using 2031 external bladder cancer samples for further validation. We selected the important Hub genes as potential therapeutic targets, and validated the genes using genomic, transcriptomic, immunomic, and other multi-omics methods. In addition, we construct a risk prediction model which could stratify patients with bladder cancer and predict patient prognosis and ICB treatment responsiveness. In conclusion, this study identified effective biomarkers for the prediction of immune checkpoint inhibitor treatment responsiveness in bladder cancer patients and provided new immunotherapeutic targets.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células de Transição/tratamento farmacológico , Redes Reguladoras de Genes/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica/métodos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Nomogramas , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia
2.
Front Cell Dev Biol ; 9: 685120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34386492

RESUMO

Uveal melanoma (UVM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic disease and have a poor prognosis. The need for immunotherapies has rapidly emerged, and recent research has yielded impressive results. Emerging evidence has implicated ferroptosis as a novel type of cell death that may mediate tumor-infiltrating immune cells to influence anticancer immunity. In this study, we first selected 11 ferroptosis regulators in UVM samples from the training set (TCGA and GSE84976 databases) by Cox analysis. We then divided these molecules into modules A and B based on the STRING database and used consensus clustering analysis to classify genes in both modules. According to the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), the results revealed that the clusters in module A were remarkably related to immune-related pathways. Next, we applied the ESTIMATE and CIBERSORT algorithms and found that these ferroptosis-related patterns may affect a proportion of TME infiltrating cells, thereby mediating the tumor immune environment. Additionally, to further develop the prognostic signatures based on the immune landscape, we established a six-gene-regulator prognostic model in the training set and successfully verified it in the validation set (GSE44295 and GSE27831). Subsequently, we identified the key molecules, including ABCC1, CHAC1, and GSS, which were associated with poor overall survival, progression-free survival, disease-specific survival, and progression-free interval. We constructed a competing endogenous RNA network to further elucidate the mechanisms, which consisted of 29 lncRNAs, 12 miRNAs, and 25 ferroptosis-related mRNAs. Our findings indicate that the ferroptosis-related genes may be suitable potential biomarkers to provide novel insights into UVM prognosis and decipher the underlying mechanisms in tumor microenvironment characterization.

3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(6): 565-574, 2021 Jun 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34275924

RESUMO

OBJECTIVES: To screen the expression profiles of lncRNA and mRNA related to the radiosensitivity of melanoma cells by inhibiting glycolysis through microarray technology. METHODS: WM35 melanoma cells were treated with different concentrations (1.25, 2.50, 5.00, 10.00 mmol/L) of 2-deoxy-D-glucose (2-DG) and different doses (0, 2, 4, 6, 8 Gy) of X-ray irradiation. MTT assay was used to detect the proliferation ability of NC-0 Gy group (negative control group), NC-4 Gy group (only 4 Gy X-ray irradiation), 2-DG group (only 2.50 mmol/L DG treatment), and 2-DG-4 Gy group (2.50 mmol/L 2-DG treatment, 4 Gy X-ray irradiation). Microarray chip was used to detect the changes in the expression profiles of lncRNA and mRNA in the NC-4 Gy group and the 2-DG-4 Gy group. Real-time RT-PCR was used to quantitatively detect the top 5 upregulated and the top 5 downregulated expression lncRNA. CNC analysis was used to predict potential target genes for the 10 most significantly expressed lncRNAs, after which the co-expression network of lncRNA and co-regulated mRNA were constructed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to predict the functional distribution of differentially expressed lncRNA. Real-time RT-PCR was used to quantitatively detect the top 5 upregulated and the top 5 downregulated expression lncRNAs. RESULTS: After 48 and 96 h, the cell proliferation of WM35 treated with 2-DG was significantly inhibited in a dose-dependent manner (all P<0.05). The cell proliferation of WM35 was inhibited by a high dose of X-ray irradiation, resulting in the death of mass cells. The cell proliferation activity of WM35 after 4 Gy X-ray irradiation descended 61% compared to the negative control group. Microarray analysis showed that there were 1 206 lncRNAs and 543 differentially expressed mRNAs between the NC-4 Gy group and the 2-DG-4 Gy group, while real-time RT-PCR showed basically consistent changes in lncRNA and mRNA microarray. Further CNC analysis showed that these 10 lncRNAs had a positive or negative correlation with 333 target genes. GO analysis was mainly concentrated in DNA binding, DNA damage repair, cell cycle arrest, and oxidative stress, while KEGG pathway analysis showed the 10 lncRNAs were related to radiosensitivity. CONCLUSIONS: Microarray chip screens the expression profiles of differentially expressed lncRNA related to the radiosensitivity of melanoma cells via inhibiting glycolysis, and lncRNA RPL34-AS1 might be a potential biological target for melanoma radiotherapy.


Assuntos
Melanoma , RNA Longo não Codificante , Perfilação da Expressão Gênica , Glicólise , Humanos , Melanoma/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tolerância a Radiação/genética
4.
Front Oncol ; 11: 652206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34123804

RESUMO

PURPOSE: Long non-coding RNAs (lncRNAs) play an important role in the occurrence and development of bladder cancer, but the underlying molecular mechanisms remain largely unknown. In this study, we found that LINC00467 was significantly highly expressed in bladder cancer through bioinformatic analysis. The present study aimed to explore the role of LINC00467 in bladder cancer and its possible underlying molecular mechanisms. METHODS: The expression of LINC00467 was obtained from GEO (GSE31189), the TCGA database, and qRT-PCR. The role of LINC00467 in bladder cancer was assessed both in vitro and in vivo. RIP, RNA pulldown, and CO-IP were used to demonstrate the potential mechanism by which LINC00467 regulates the progression of bladder cancer. RESULTS: Through the analysis of GEO (GSE133624) and the TCGA database, it was found that LINC00467 was highly expressed in bladder cancer tissues and that the expression of LINC00467 was significantly negatively correlated with patient prognosis. Cell and animal experiments suggest that LINC00467 promotes the proliferation and invasion of bladder cancer cells. On the one hand, LINC00467 can directly bind to NF-kb-p65 mRNA to stabilize its expression. On the other hand, LINC00467 can directly bind to NF-kb-p65 to promote its translocation into the nucleus to activate the NF-κB signaling pathway, which promotes the progression of bladder cancer. CONCLUSIONS: LINC00467 is highly expressed in bladder cancer and can promote the progression of bladder cancer by regulating the NF-κB signaling pathway. Therefore, targeting LINC00467 is very likely to provide a new strategy for the treatment of bladder cancer and for improving patient prognosis.

5.
Nanoscale ; 13(25): 11250-11261, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34152347

RESUMO

Chemotherapy-associated intestinal mucositis is still one of the major challenges in the first-line clinical cancer treatment. Selenium element has shown health benefits on enteritis upon uptake in trace amounts; however, it was limited because of its narrow safety margin. In this work, a new form of Se@Albumin complex nanoparticles (Se@Albumin NPs) was developed by self-assembly of denatured human serum albumin and selenite salts. Se@Albumin NPs significantly improve intestinal mucositis induced with cisplatin (CDDP) in a mouse model via attenuating the level of intestinal oxidative stress, reducing intestinal permeability, and relieving gastric dysmotility. It is very interesting that the restoration of anti-inflammatory bacteria (Bacteroidetes and Firmicutes) and reduced abundance of proinflammatory bacteria (Escherichia) contributed to the reduction of intestinal mucositis by Se@Albumin NPs in mice. In addition, the fecal microbiota transplantation (FMT) with materials from Se@Albumin NP-treated mice significantly protected pseudo-aseptic mice from CDDP-induced intestinal mucositis. In conclusion, our findings showed that Se@Albumin NPs can significantly improve CDDP-induced intestinal mucositis, and its function may be directly mediated by gut microbiota regulation, which will provide new helpful information for clinical treatment.


Assuntos
Microbioma Gastrointestinal , Mucosite , Nanopartículas , Albuminas , Animais , Cisplatino , Fluoruracila , Camundongos
6.
Biomed Res Int ; 2021: 9951405, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997050

RESUMO

Although colorectal cancer (CRC) is common, there is a paucity of information regarding its molecular pathogenesis. Studies have shown that miRNAs play pivotal roles in the development and progression of CRC. There is a need to further investigate the biological functions of miRNAs in CRC. In particular, it has been reported that miR-942-5p exhibits tumor-suppressive properties. Thus, we analyzed the functional significance of miR-942-5p in CRC and the underlying molecular mechanisms. We found that miR-942-5p was downregulated in CRC tissues and cells. Cell Counting Kit-8, EdU, and colony formation assays revealed that the overexpression of miR-942-5p by mimics inhibited the proliferation of CRC cells. Use of the miR-942-5p inhibitor effectively enhanced the proliferative potential of CRC cells. Further, in vivo xenograft experiments confirmed these results. Increased expression of miR-942-5p suppressed the invasion, migration, and epithelial-mesenchymal transition of CRC cell lines, while decreased miR-942-5p expression had the opposite effect. CCBE1, a secretory molecule for lymphangiogenesis, was established as a downstream target of miR-942-5p, and its expression was inversely correlated with the expression of miR-942-5p in CRC cells. Additionally, cotransfection of the miR-942-5p inhibitor with si-CCBE1 into CRC cells reversed the effects induced by miR-942-5p overexpression. In conclusion, we confirmed that miR-942-5p exerts oncogenic actions in CRC by targeting CCBE1 and identified miR-942-5p as a potential clinical biomarker for CRC diagnosis and therapy.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias Colorretais , Transição Epitelial-Mesenquimal/genética , MicroRNAs , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Xenoenxertos , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Proteínas Supressoras de Tumor/genética
7.
Front Oncol ; 11: 616133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34041016

RESUMO

Ovarian cancer (OC) is one of the most lethal gynecologic malignant tumors. The interaction between autophagy and the tumor immune microenvironment has clinical importance. Hence, it is necessary to explore reliable biomarkers associated with autophagy-related genes (ARGs) for risk stratification in OC. Here, we obtained ARGs from the MSigDB database and downloaded the expression profile of OC from TCGA database. The k-means unsupervised clustering method was used for clustering, and two subclasses of OC (cluster A and cluster B) were identified. SsGSEA method was used to quantify the levels of infiltration of 24 subtypes of immune cells. Metascape and GSEA were performed to reveal the differential gene enrichment in signaling pathways and cellular processes of the subtypes. We found that patients in cluster A were significantly associated with higher immune infiltration and immune-associated signaling pathways. Then, we established a risk model by LASSO Cox regression. ROC analysis and Kaplan-Meier analysis were applied for evaluating the efficiency of the risk signature, patients with low-risk got better outcomes than those with high-risk in overall survival. Finally, ULK2 and GABARAPL1 expression was further validated in clinical samples. In conclusion, Our study constructed an autophagy-related prognostic indicator, and identified two promising targets in OC.

8.
Front Pharmacol ; 12: 619103, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935710

RESUMO

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1ß, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.

9.
Front Oncol ; 11: 643163, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816295

RESUMO

Background: Increasing evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in cancer tumorigenesis and progression. TMPO antisense RNA 1 (TMPO-AS1) has been found to be involved in several cancers by acting as a competing endogenous RNA. However, the potential roles of TMPO-AS1 in bladder cancer (BC) and the potential interactions with proteins remain poorly understood. Methods: The expression of the lncRNA TMPO-AS1 was evaluated via bioinformatic analysis and further validated by quantitative real-time PCR (qRT-PCR). Loss- and gain-of-function assays were performed to determine the biological functions of TMPO-AS1 in BC cell proliferation, migration, and invasion. Moreover, chromatin immunoprecipitation, Western blotting, and fluorescence in situ hybridization, as well as RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays, were conducted to explore the upstream and downstream molecules interacting with TMPO-AS1. Results: TMPO-AS1 is upregulated in BC. Functional experiments demonstrated that TMPO-AS1 promotes cell proliferation, migration, and invasion in BC and inhibits cell apoptosis in vivo and in vitro. Mechanically, E2F1 is responsible for TMPO-AS1 upregulation. Additionally, TMPO-AS1 facilitates the interaction of E2F1 with OTU domain-containing ubiquitin aldehyde binding 1 (OTUB1), leading to E2F1 deubiquitination and stabilization; therefore, TMPO-AS1 promotes BC malignant phenotypes. Furthermore, rescue experiments showed that TMPO-AS1 promotes BC growth in an E2F1-dependent manner. Conclusions: Our study is the first to uncover the novel TMPO-AS1/E2F1 positive regulatory loop important for the promotion of BC malignant behaviors. The TMPO-AS1/E2F1 loop should be considered in the quest for new BC therapeutic options.

10.
Front Immunol ; 12: 637933, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746977

RESUMO

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high rate of mortality and recurrence. N6-methyladenosine methylation (m6A) is the most common modification to affect cancer development, but to date, the potential role of m6A regulators in ACC prognosis is not well understood. In this study, we systematically analyzed 21 m6A regulators in ACC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. We identified three m6A modification patterns with different clinical outcomes and discovered a significant relationship between diverse m6A clusters and the tumor immune microenvironment (immune cell types and ESTIMATE algorithm). Additionally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that the m6A clusters were strongly associated with immune infiltration in the ACC. Next, to further explore the m6A prognostic signatures in ACC, we implemented Lasso (Least Absolute Shrinkage and Selection Operator) Cox regression to establish an eight-m6A-regulator prognostic model in the TCGA dataset, and the results showed that the model-based high-risk group was closely correlated with poor overall survival (OS) compared with the low-risk group. Subsequently, we validated the key modifications in the GEO datasets and found that high HNRNPA2B1 expression resulted in poor OS and event-free survival (EFS) in ACC. Moreover, to further decipher the molecular mechanisms, we constructed a competing endogenous RNA (ceRNA) network based on HNRNPA2B1, which consists of 12 long noncoding RNAs (lncRNAs) and 1 microRNA (miRNA). In conclusion, our findings indicate the potential role of m6A modification in ACC, providing novel insights into ACC prognosis and guiding effective immunotherapy.


Assuntos
Adenosina/análogos & derivados , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Adenosina/análise , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Humanos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , RNA Longo não Codificante/genética , Estudos Retrospectivos , Microambiente Tumoral/imunologia
11.
Clin Transl Med ; 10(8): e241, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33377647

RESUMO

Long noncoding RNAs (lncRNAs) play a crucial role in progression of bladder urothelial carcinoma (BUC). However, the molecular mechanisms behind this role have not been elucidated yet. Here, we found that the lncRNA MAFG-AS1, which is highly expressed in BUC, is correlated with aggressive characteristics and poor prognosis of BUC. We demonstrate that MAFG-AS1 can promote BUC proliferation, invasion, metastasis, and epithelial-mesenchymal transition in vitro and in vivo. Mechanistically, MAFG-AS1 direct binding to Hu antigen R (HuR) could recruit ubiquitin-specific proteinase 5 (USP5) to prevent HuR from degrading by ubiquitination. We further demonstrate that overexpression of MAFG-AS1 can upregulate the expression of polypyrimidine tract-binding protein 1 (PTBP1) through promoting its stability mediated by bound HuR. In conclusion, these findings indicate that MAFG-AS1 promotes the progression of BUC via regulation of the HUR/PTBP1 axis. Targeting MAFG-AS1 may provide a novel strategy for individualized therapy and a potential biomarker for prognosis of BUC.

12.
Am J Cancer Res ; 10(11): 3686-3704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33294261

RESUMO

Long non-coding RNAs (lncRNAs) play a vital role in the progression of several cancers, including nasopharyngeal carcinoma (NPC). However, the mechanism of lncRNA involvement in the progression of NPC remains to be elucidated. Hence, we conducted in vivo and in vitro experiments to determine the molecular mechanism of FOXD1-AS1. We found that FOXD1-AS1 was over-expressed in NPC cells and tissues, and was significantly associated with poor survival rate in patients with NPC. We also found that FOXD1-AS1 promotes cellular proliferation, migration, invasion, and glycolysis, and inhibits apoptosis by upregulating the expression of FOXD1. Furthermore, FOXD1 could transcriptionally up-regulate the expression of key glycolytic genes to promote the glycolysis levels of NPC. The identified FOXD1-AS1 may serve as a potential prognostic biomarker and therapeutic target for patients with NPC.

13.
Aging (Albany NY) ; 12(21): 21904-21922, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33147570

RESUMO

BACKGROUND: Long non-coding RNAs (LncRNAs) have been associated with several types of cancer. However, little is known about their role in lung adenocarcinoma (LUAD). RESULTS: LINC00968 was significantly differentially expressed in LUAD tissues. Downregulated LINC00968 was associated with clinicopathological features of LUAD. LINC00968 inhibited cell growth and metastasis by regulating the Hippo signaling pathway We demonstrated that LINC00968 acts as a ceRNA to consume miR-21-5p, enhancing the accumulation of SMAD7, a miR-21-5p target. CONCLUSIONS: LINC00968 limits LUAD progression via the miR-21-5p/SMAD7 axis and may serve as a prognostic biomarker and therapeutic target for LUAD. METHODS: We conducted comprehensive data mining on LINC00968 based on the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. The expression of LINC00968 in LUAD cells was determined using in situ hybridization. We detected LINC00968 function in LUAD cells using the MTT, clone formation, and transwell assays, and tumor xenografts. Label-free quantitative proteomics, western blotting, a dual-luciferase reporter assay, immunofluorescence, and RNA immunoprecipitation assays were used to determine the correlations among LINC00968, miR-21-5p, and SMAD7. Gain- and loss-function approaches were used to explore the effects of LINC00968, miR-21-5p, and SMAD7 on cell proliferation, migration, and invasion.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Proteína Smad7/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/secundário , Animais , Movimento Celular , Proliferação de Células , Bases de Dados Genéticas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , RNA Longo não Codificante/genética , Transdução de Sinais , Carga Tumoral
14.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1104-1108, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051425

RESUMO

OBJECTIVES: To study the effect of rotation errors on the γ pass rate of volume-modulated arc therapy (VMAT) plan in rectal cancer based on the ArcCheck phantom. METHODS: CT data from 20 rectal cancer patients underwent VMRT were selected randomly for this study. Targeting areas were selected, and clinical radiotherapy and validation plans were formulated. ArcCheck model was selected to validate the radiotherapy plans. The effect of the rotation errors on the dosimetric verification for VMAT in rectal cancer was simulated and analyzed with ArcCheck model software. RESULTS: When there was no rotation errors, the γ pass rate of VMRT plans was more than 95%. When the absolute rotation angle was less than or equal to 1°, the γ pass rate of VMAT plans was more than 90%, meeting the clinical requirements. When the absolute rotation angle was greater than 1°, the γ pass rate was less than 90%, which did not meet clinical requirements. CONCLUSIONS: The rotation errors affect the γ pass rate of VMAT plans. The larger the rotation angle, the lower the γ pass rate. It meets clinical requirements when the rotation error is less than or equal to 1°.


Assuntos
Radioterapia de Intensidade Modulada , Neoplasias Retais , Humanos , Radiometria , Planejamento da Radioterapia Assistida por Computador , Neoplasias Retais/radioterapia , Rotação
15.
Oncogene ; 39(38): 6071-6084, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32796958

RESUMO

The long non-coding RNA (LncRNA) abnormally expresses in several cancers including non-small cell lung cancer (NSCLC). To better understand the role of key lncRNA involving cancer progress, we conduct a comprehensive data mining on LINC00467 and determine its molecular mechanisms. We identified LINC00467 was the up-regulated lncRNA that common significantly differentially expressed in NSCLC and CRC tissues from GEO database. LINC00467 highly expressed in NSCLC tissues and associated with advanced clinical stages and poor outcome. Knockdown of LINC00467 inhibited cell growth and metastasis via regulating the Akt signaling pathway. Finally, we demonstrated that TDG mediated acetylation is the key factor controlling LINC00467 expression. In conclusion, LINC00467 promotes NSCLC progression via Akt signal pathway. The identified LINC00467 may serve as a valuable diagnostic and prognostic biomarker as well as a therapeutic target for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/genética , Acetilação , Adipocinas/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Camundongos , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Ligação Proteica , Proteólise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais
16.
Front Genet ; 11: 607, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655621

RESUMO

Bladder cancer is one of the most common malignant tumors of the urinary system that seriously threatens the health of a population. In recent years, the application of immunotherapy has significantly changed the treatment of bladder cancer, but only some patients can benefit from the treatment with immune-checkpoint inhibitors. Many problems are unsolved in the field of bladder cancer immunotherapy, especially in the search for genes that are critical to the level of immune cell infiltration and new effective therapeutic targets. We attempted to use bioinformatics analysis to identify immune gene markers related to the prognosis of bladder cancer and to establish a prognostic signature for bladder cancer patients based on their immune gene expression profiles. We used univariate Cox proportional hazards regression analysis, the least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox proportional hazards regression analysis from The Cancer Genome Atlas bladder cancer cohort (TCGA-BLCA). Fifteen genes related to prognosis were screened using the survival analysis, correlation analysis, cancer and adjacent cancer differential expression analysis, and mutation analysis. The potential biological role of these genes was determined using survival analysis and principal component analysis (PCA). The receiver operating characteristic (ROC) curve assesses the prognostic value of the predictive signature. The gene ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), Gene set enrichment analysis (GSEA), and other methods were used to reveal the differential gene enrichment in the signaling pathways and cellular processes of high- and low-risk groups. The single-sample GSEA (ssGSEA) method was used to quantify the infiltration levels of 24 immune cells in the tumor immune microenvironment and these immune genes were found to be closely related to the tumor immune microenvironment. In summary, we screened 15 immune genes that were closely related to bladder cancer overall survival (OS) and may be potential prognostic indicators of bladder cancer. They may have research and clinical application value in bladder cancer immunotherapy. We used 15 immune genes to construct a new immune-related gene signature that was verified and could be helpful in improving individualized prognosis of patients with bladder cancer.

17.
Cancer Cell Int ; 20: 194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32508530

RESUMO

BACKGROUND: Lung cancer is the most common malignant tumor in the world. The Whole-proteome microarray showed that ubiquitin ligase chromatin assembly factor 1 subunit B (CHAF1B) expression in A549/DDP cells is higher than in A549 cells. Our study explored the molecular mechanism of CHAF1B affecting cisplatin resistance in lung adenocarcinoma (LUAD). METHODS: Proteome microarray quantify the differentially expressed proteins between LUAD cell line A549 and its cisplatin-resistant strain A549/DDP. Quantitative real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot (WB) confirmed the CHAF1B expression. Public databases analyzed the prognosis of LUAD patients with varied LUAD expression followed by the substrates prediction of CHAF1B. Public databases showed that nuclear receptor corepressor 2 (NCOR2) may be substrates of CHAF1B. WB detected that CHAF1B expression affected the expression of NCOR2. Cell and animal experiments and clinical data detected function and integrating mechanism of CHAF1B compounds. RESULTS: Proteome chips results indicated that CHAF1B, PPP1R13L, and CDC20 was higher than A549 in A549/DDP. Public databases showed that high expression of CHAF1B, PPP1R13L, and CDC20 was negatively correlated with prognosis in LUAD patients. PCR and WB results indicated higher CHAF1B expression in A549/DDP cells than that in A549 cells. NCOR2 and PPP5C were confirmed to be substrates of CHAF1B. CHAF1B knockdown significantly increased the sensitivity of cisplatin in A549/DDP cells and the upregulated NCOR2 expression. CHAF1B and NCOR2 are interacting proteins and the position of interaction between CHAF1B and NCOR2 was mainly in the nucleus. CHAF1B promotes ubiquitination degradation of NCOR2. Cells and animal experiments showed that under the action of cisplatin, after knockdown of CHAF1B and NCOR2 in A549/DDP group compared with CHAF1B knockdown alone, the cell proliferation and migratory ability increased and apoptotic rate decreased, and the growth rate and size of transplanted tumor increased significantly. Immunohistochemistry suggested that Ki-67 increased, while apoptosis-related indicators caspase-3 decreased significantly. Clinical data showed that patients with high expression of CHAF1B are more susceptible to cisplatin resistance. CONCLUSION: Ubiquitin ligase CAHF1B can induce cisplatin resistance in LUAD by promoting the ubiquitination degradation of NCOR2.

18.
Front Oncol ; 10: 461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32426268

RESUMO

Ubiquitin ligases have been shown to regulate drug sensitivity. This study aimed to explore the role of the ubiquitin ligase WD repeat and HMG-box DNA binding protein 1 (WDHD1) in regulating cisplatin sensitivity in lung adenocarcinoma (LUAD). A quantitative analysis of the global proteome identified differential protein expression between LUAD A549 cells and the cisplatin-resistant strain A549/DDP. Public databases revealed the relationship between ubiquitin ligase expression and the prognosis of patients with LUAD. Quantitative real-time polymerase chain reaction and Western blotting were used to estimate the WDHD1 expression levels. Analysis of public databases predicted the substrate of WDHD1. Western blotting detected the effect of WDHD1 on microtubule-associated protein RP/EB family member 2 (MAPRE2) and DSTN. Functional analysis of MAPRE2 verified the interaction between WDHD1 and MAPRE2, as well as the interacting sites by methyl-thiazolyl-tetrazolium assay and flow cytometry, immunoprecipitation, protein stability, and immunofluorescence. Cell and animal experiments confirmed the effect of WDHD1 and MAPRE2 on cisplatin sensitivity in LUAD. Clinical data evaluated the impact of WDHD1 expression level on cisplatin sensitivity. Quantitative analysis of the global proteome revealed ubiquitin-dependent protein catabolism to be more active in A549/DDP cells than in A549 cells. WDHD1 expression was higher in A549/DDP cells than in A549 cells, and knocking out WDHD1 increased the sensitivity of A549/DDP cells to cisplatin. WDHD1 overexpression negatively correlated with the overall survival of LUAD patients. We observed that MAPRE2 was upregulated when WDHD1 was knocked out. A MAPRE2 knockout in A549 cells resulted in increased cell viability while decreasing apoptosis when the A549 cells exposed to cisplatin. WDHD1 and MAPRE2 were found to interact in the nucleus, and WDHD1 promoted the ubiquitination of MAPRE2. Following cisplatin exposure, the WDHD1 and MAPRE2 knockout groups facilitated cell proliferation and migration, inhibited apoptosis in A549/DDP cells, decreased apoptosis, and increased tumor size and growth rate in animal experiments. Immunohistochemistry showed that Ki67 levels increased, and levels of apoptotic indicators significantly decreased in the WDHD1 and MAPRE2 knockout groups. Clinical data confirmed that WDHD1 overexpression negatively correlated with cisplatin sensitivity. Thus, the ubiquitin ligase WDHD1 induces cisplatin resistance in LUAD by promoting MAPRE2 ubiquitination.

19.
Am J Transplant ; 20(9): 2413-2424, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32243709

RESUMO

Approximately 33.6% of nondiabetic solid organ transplant recipients who received tacrolimus developed hyperglycemia. Whether the tacrolimus-induced gut microbiota is involved in the regulation of hyperglycemia has not been reported. Hyperglycemia was observed in a tacrolimus-treated mouse model, with reduction in taxonomic abundance of butyrate-producing bacteria and decreased butyric acid concentration in the cecum. This tacrolimus-induced glucose metabolic disorder was caused by the gut microbiota, as confirmed by a broad-spectrum antibiotic model. Furthermore, oral supplementation with butyrate, whether for remedy or prevention, significantly increased the butyric acid content in the cecum and arrested hyperglycemia through the regulation of glucose-regulating hormones, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin, in serum. The butyrate-G-protein-coupled receptor 43-GLP-1 pathway in the intestinal crypts may be involved in the pathogenesis of normalization of hyperglycemia caused by the tacrolimus. Therefore, tacrolimus affects glucose metabolism through the butyrate-associated GLP-1 pathway in the gut, and oral supplementation with butyrate provides new insights for the prevention and treatment of tacrolimus-induced hyperglycemia in transplant recipients.


Assuntos
Microbioma Gastrointestinal , Hiperglicemia , Animais , Ácido Butírico , Peptídeo 1 Semelhante ao Glucagon , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Camundongos , Tacrolimo/efeitos adversos
20.
Front Pharmacol ; 11: 284, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256358

RESUMO

Clinical studies and basic science experiments have widely demonstrated the antidepressant and anxiolytic effects of the herbal formula Xiao-Yao-San (XYS). However, the system mechanism of these effects has not been fully characterized. The present study conducted a comprehensive network pharmacological analysis of XYS and sorted all pharmacologically active components (149) through the TCMSP webserver. Then, all potential molecular targets (449) were predicted, of which there were 99 genes clearly related to depression. To further investigate the mechanism of antidepressant effects of XYS, a compound-depression targets (C-DTs) network was constructed, and Gene Ontology (GO) functional and KEGG pathway enrichment analyses were performed for the 99 targets. Enrichment results revealed that XYS could regulate multiple aspects of depression through these targets, related to metabolism, neuroendocrine function, and neuroimmunity. Prediction and analysis of protein-protein interactions resulted in selection of three hub genes (AKT1, TP53, and VEGFA). In addition, a total of seven ingredients from XYS could act on these hub genes and they were identified through ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS), including paeoniflorin, quercetin, luteolin, acacetin, aloe-emodin, Glyasperin C, kaempferol. Hereafter, we investigated the effects of paeoniflorin and its predicted target, the results suggest that it can reverse the neurotoxicity produced by CORT and could be a neuroprotective effect by promoting the phosphorylation of Akt. Overall, our research revealed the complicated antidepressant mechanism of XYS, and also provided a rational strategy for revealing the complex composition and function of Chinese herbal formula.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...