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1.
Life Sci ; 354: 122976, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39142507

RESUMO

AIMS: Endoplasmic reticulum protein 29 (ERP29) is crucial for endoplasmic reticulum stress (ERS). M6A plays an important role in the progression of endometrial cancer (EC). The study investigated the role of ERS-related gene (ERP29) and m6A in EC. MATERIALS AND METHODS: We screened ERS-related genes based on the GEO dataset, GSEA dataset and TCGA-UCEC database using WGCNA and two machine learning algorithms. The m6A-related GEO dataset was employed to identify the ERS-related hub genes with m6A. Expression of hub genes in different cell types were visualize through scRNA-seq data analyzing. Using qPCR, Western blot, and Immunohistochemical assays to detect the expression of ERP29, the effect of ERP29 on cancer cell proliferation was investigated through CCK8, EdU and clone formation experiments. M6A modifications were studied using m6A Dot blot and MeRIP-qPCR. Finally, we conducted rescue experiments. KEY FINDINGS: Ten ERS-related hub genes with m6A were identified. ERP29 is highly expressed in EC. ERP29 knockdown inhibits EC cell proliferation. METTL3 overexpression increases the ERP29 mRNA m6A and decreases the expression of ERP29. Cycloleucine (Cyc), a nucleic acid methylation inhibitor, treatment reduces ERP29 mRNA m6A and increases the expression of ERP29. Cyc rescue the low expression of ERP29 caused by overexpression of METTL3 through m6A. ERP29 knockdown rescued the increased proliferation of EC cells caused by low m6A. SIGNIFICANCE: ERP29 is highly expressed in EC. m6A regulates ERP29 expression and affects the proliferation of endometrial cancer cells. This represents the premise for applying ERP29 and m6A modifications in diagnosing and treating EC.


Assuntos
Proliferação de Células , Neoplasias do Endométrio , Regulação Neoplásica da Expressão Gênica , Humanos , Feminino , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/metabolismo , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/genética , Metiltransferases/metabolismo , Metiltransferases/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética
2.
J Cell Mol Med ; 28(9): e18361, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38722283

RESUMO

Hypoxia and Ferroptosis are associated with the malignant behaviour of cervical cancer. Endothelial PAS domain-containing protein 1 (EPAS1) contributes to the progression of cervical cancer. EPAS1 plays important roles in hypoxia and ferroptosis. Using the GEO dataset, machine-learning algorithms were used to screen for hypoxia- and ferroptosis-related genes (HFRGs) in cervical cancer. EPAS1 was identified as the hub gene. qPCR and WB were used to investigate the expression of EPAS1 in normal and cervical cancer tissues. The proliferation, invasion and migration of EPAS1 cells in HeLa and SiHa cell lines were detected using CCK8, transwell and wound healing assays, respectively. Apoptosis was detected by flow cytometry. A dual-luciferase assay was used to analyse the MALAT1-miR-182-5P-EPAS1 mRNA axis and core promoter elements of the super-enhancer. EPAS1 was significantly overexpressed in cervical cancer tissues. EPAS1 could increase the proliferation, invasion, migration of HeLa and SiHa cells and reduce the apoptosis of HeLa and SiHa cell. According to the double-luciferase assay, EPAS1 expression was regulated by the MALAT1-Mir-182-5p-EPAS1 mRNA axis. EPAS1 is associated with super-enhancers. Double-luciferase assay showed that the core elements of the super-enhancer were E1 and E3. EPAS1, an HFRG, is significantly overexpressed in cervical cancer. EPAS1 promotes malignant behaviour of cervical cancer cells. EPAS1 expression is regulated by super-enhancers and the MALAT1-miR-182-5P- EPAS1 mRNA axis. EPAS1 may be a target for the diagnosis and treatment of cervical cancer.


Assuntos
Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Movimento Celular , Proliferação de Células , Ferroptose , Regulação Neoplásica da Expressão Gênica , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Ferroptose/genética , Proliferação de Células/genética , Movimento Celular/genética , Apoptose/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Células HeLa , RNA Longo não Codificante/genética , RNA Endógeno Competitivo
3.
Artif Cells Nanomed Biotechnol ; 51(1): 57-73, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36748358

RESUMO

Endometrial cancer is one of the most common malignant tumours in women, and cancer stem cells are known to play an important role in its growth, invasion, metastasis, and drug resistance. Immunotherapy for endometrial cancer is still under research. In this study, a total of 547 endometrial cancer cases were randomly divided into training set (351 cases) set and test set (196 cases). The stemness index of patients was calculated using the One-Class Logistic Regression (OCLR) machine learning algorithm to explore the clinicopathological differences between index levels. Stemness subtypes were determined according to the characteristics of cancer stemness and their clinicopathological characteristics, immune features, and therapeutic effects were described. Our study suggests that endometrial cancer is classified into two stemness subtypes. Stemness subtypes, which are associated with its clinical features, may be independent prognostic factors for endometrial cancer. The stemness subtypes differed significantly in immune activity, immune cell infiltration, and the immune microenvironment, including sensitivity to chemotherapeutic drugs and potential therapeutic compounds. Algorithms were utilised to construct a stemness subtype prediction model and predictor. These findings will provide guidance for the clinical diagnosis, treatment, and prognosis of endometrial cancer.


Assuntos
Neoplasias do Endométrio , Humanos , Feminino , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/terapia , Imunoterapia , Aprendizado de Máquina , Células-Tronco Neoplásicas , Microambiente Tumoral
4.
Life Sci ; 315: 121360, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36608869

RESUMO

AIMS: Cervical cancer with different mutations is associated with specific genomic differences. We developed a new mutation prediction model of the ARHGAP4 gene for cervical cancer. MAIN METHODS: We conducted a panoramic analysis of CESC mutations based on The Cancer Genome Atlas-Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) database. We made copy number variation analysis and correlation analysis of somatic mutations and tumor mutation load fraction. Then we established a prediction model of ARHGAP4 mutation, screened related genes based on the risk scores, calculated the correlation between the risk score and immune microenvironment, and analyzed drug sensitivity. KEY FINDINGS: The prediction model of ARHGAP4 mutation based on mRNA expression is closely related to the survival rate of cervical cancer patients and to the effect of immunotherapy. The prediction model is also related to the infiltration of immune cells and human leukocyte antigen family expression in the immune microenvironment. After computational analysis, three drugs (cytarabine, docetaxel, imatinib) were identified as potential agents for the ARHGAP4 mutation high-risk group, and two drugs (erlotinib, methotrexate) were shown to have therapeutic significance for patients in the low-risk group. The expression of ARHGAP4 was higher in cervical cancer tissues. The proliferation ability of HeLa and SiHa cells decreased after ARHGAP4 knockdown. SIGNIFICANCE: This study provides not only a new approach for the prediction of the response of the cervical cancer patients to targeted drug therapy but also a new strategy for combining risk stratification with precision treatment.


Assuntos
Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Variações do Número de Cópias de DNA , Medicina de Precisão , Computadores , Microambiente Tumoral/genética
5.
Cell Biol Int ; 47(1): 201-215, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36208091

RESUMO

Several studies have shown that MutS homolog 2 (MSH2) is highly expressed in many cancer tissues. Transcriptome expression data were collected from the Cancer Genome Atlas (TCGA) database. We analyzed the expression of MSH2 in normal and tumor tissues, the relationship between MSH2 expression and various prognostic factors, and the relationship between MSH2 expression and overall survival, disease specific survival, and progression free interval. We also examined MSH2 promoter methylation between endometrial cancer and normal endometrial tissues, and identified the prognostic value of MSH2 methylation in endometrial cancer. MSH2 was highly expressed in endometrial cancer tumor tissues compared with normal tissues. High MSH2 expression might be an independent prognostic factor for OS, DSS, and PFI. Further, high MSH2 expression was correlated with age and histological type, but not with BMI, clinical stage, tumor invasion, or other clinical features. MSH2 promoter methylation in endometrial cancer was significantly lower than in normal tissues. Additionally, MSH2 levels, OS, DSS, and PFI were associated with BMI, age, tumor invasion, and histological type. ssGSEA showed that MSH2 expression was positively correlated with the infiltration of Th2 cells, Tcm cells, T helper cells, and Tgd cells, whereas it was negatively correlated with NK CD56 bright cells, pDC cells, iDC cells, cytotoxic cells, and neutrophils. Increased MSH2 expression and reduced MSH2 methylation in endometrial cancer predicts poor prognosis. MSH2 may be used as a biomarker for the diagnosis and prognosis of endometrial cancer and as an immunotherapy target.


Assuntos
Biomarcadores Tumorais , Neoplasias do Endométrio , Proteína 2 Homóloga a MutS , Feminino , Humanos , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Regiões Promotoras Genéticas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo
6.
J Transl Med ; 20(1): 385, 2022 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-36058934

RESUMO

BACKGROUND: Cervical cancer is the fourth most common cancer in women. N6-dimethyladenosine (m6A) mRNA methylation is closely associated with cervical cancer. METHODS: Using TCGA database, we studied the expression and mutation of m6A-related genes in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and obtained genetic characteristics based on an m6A risk model and prognostic value of m6A. We studied the effects of the m6A risk score on immune features and genomic changes of patients with CESC, evaluated the sensitivity of patients with CESC to different small-molecule drugs based on the m6A risk score, and established a clinical prediction model. RESULTS: Ten m6A-related genes were differentially expressed between CESC and normal tissues. High-risk patients had a low overall survival (OS) and significantly low immune scores but showed no significantly altered stromal scores. The tumor mutation burden (TMB) and tumor neoantigen levels significantly differed between the high- and low-risk groups. In the high-risk group, copy number variation (CNV) changes mainly led to gene amplification, while in the low-risk group, CNV changes primarily manifested as gene copy number deletions. ZC3H13 expression was low in CESC tissues. ZC3H13 knockdown promoted CESC cell proliferation, migration, and invasion, reducing the RNA methylation levels. Rapamycin suppressed the CESC cell proliferation, migration, and invasion abilities, increasing the m6A levels. CONCLUSION: m6A mRNA methylation is closely related to the occurrence, development, immune invasion, drug sensitivity, and prognosis of cervical cancer. The prognostic m6A feature model of m6A signature genes can accurately predict the OS of patients with CESC. Drugs targeting factors regulating m6A mRNA methylation might offer a good prospect for treating cervical cancer.


Assuntos
Neoplasias do Colo do Útero , Variações do Número de Cópias de DNA , Feminino , Humanos , Metilação , Modelos Estatísticos , Prognóstico , RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias do Colo do Útero/patologia
7.
Biomed Res Int ; 2022: 7948898, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35993041

RESUMO

As a family of transcription factors, the correlations between expression pattern of nine interferon regulatory factor (IRF) family members, the immune invasion pattern, and the associated patient survival rate in endometrial carcinoma (EC) remain to be elucidated. Based on The Cancer Genome Atlas (TCGA), the expression profiles of the high and low IRF mRNA expression groups were analyzed using R (3.6.3) statistical software. Gene annotation and pathway analyses were performed using Metascape. GSEA was performed using the R package clusterProfiler (3.6.3). The single-sample gene set enrichment analysis (ssGSEA) was used to quantify the relative tumor infiltration levels of immune cell types. Immunohistochemistry data provided by HPA database was used to study the expression of the IRF proteins. Using the GEPIA dataset, the correlation between the expression of IRFs and the tumor stage of EC was analyzed. The correlations between the different IRFs were analyzed using cBioPortal. The expression of IRF2, IRF3, IRF5, IRF6, IRF7, IRF8, and IRF9 was different when comparing EC and normal endometrial samples. IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. In combination with receiver operating characteristic analysis results, IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. Levels of individual IRFs were associated with alternate outcomes, with the expression of IRF3 being correlated with the stage of EC and high expression of IRF4 being positively correlated with overall survival (OS); conversely, high expression of IRF5 was negatively correlated with OS. Additionally, high expression levels of both IRF2 and IRF4 were positively correlated with the disease-specific survival rate, and high expression of IRF4 was positively correlated with the progression-free interval. These data suggest a role for IRF2, IRF4, and IRF5 in the prognosis of EC. The expression of IRFs is associated with immune infiltration.


Assuntos
Neoplasias do Endométrio , Fatores Reguladores de Interferon , Neoplasias do Endométrio/genética , Feminino , Humanos , Prognóstico
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