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1.
Cell Death Dis ; 14(6): 346, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37264022

RESUMO

Esophageal squamous carcinoma (ESCC) is a common malignant cancer. Although the non-coding roles of circRNAs in the pathogenesis of human tumors have been well studied, whether circRNAs participate in the progression of ESCC by encoding novel proteins remains unclear. In this study, we identified an overexpression circRNA with protein-coding ability in ESCC tissues, called circUBE4B, whose expression level is correlated with tumor size and tumor differentiation level of ESCC patients. Moreover, a higher level of circUBE4B in ESCC patients is correlated with a worse prognosis. Functionally, we found that circUBE4B promoted the proliferation of ESCC cells by encoding a novel cancer-promoting protein, circUBE4B-173aa. Mechanistically, the circUBE4B-173aa protein interacts with MAPK1 and promotes the phosphorylation level of MAPK1 to eventually activate MAPK/ERK signaling pathway. The xenograft model revealed that overexpression of circUBE4B-173aa in ESCC cells significantly promoted the growth of grafts. Our study provides new insights into the mechanism of circRNA in the development of ESCC and circUBE4B-173aa has the potential to serve as a biomarker and a novel therapeutic target for ESCC therapy.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/genética , RNA Circular/genética , Transdução de Sinais/genética
2.
Oxid Med Cell Longev ; 2023: 6811625, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36703911

RESUMO

Background: Lipid metabolism reprogramming played an important role in cancer occurrence, development, and immune regulation. The aim of this study was to identify and validate lipid metabolism-related genes (LMRGs) associated with the phenotype, prognosis, and immunological characteristics of lung squamous cell carcinoma (LUSC). Methods: In the TCGA cohort, bioinformatics and survival analysis were used to identify lipid metabolism-related differentially expressed genes (DEGs) associated with the prognosis of LUSC. PTGIS/HRASLS knockdown and overexpression effects on the LUSC phenotype were analyzed in vitro experiments. Based on the expression distribution of PTGIS/HRASLS, LUSC patients were divided into two clusters by consensus clustering. Clinical information, prognosis, immune infiltration, expression of immune checkpoints, and tumor mutation burden (TMB) level were compared between the TCGA and GSE4573 cohorts. The genes related to clustering and tumor immunity were screened by weighted gene coexpression network analysis (WGCNA), and the target module genes were analyzed by functional enrichment analysis, protein-protein interaction (PPI) analysis, and immune correlation analysis. Results: 191 lipid metabolism-related DEGs were identified, of which 5 genes were independent prognostic genes of LUSC. PTGIS/HRASLS were most closely related to LUSC prognosis and immunity. RT-qPCR, western blot (WB) analysis, and immunohistochemistry (IHC) showed that the expression of PTGIS was low in LUSC, while HRASLS was high. Functionally, PTGIS promoted LUSC proliferation, migration, and invasion, while HRASLS inhibited LUSC proliferation, migration, and invasion. The two clusters' expression and distribution of PTGIS/HRASLS had the opposite trend. Cluster 1 was associated with lower pathological staging (pT, pN, and pTNM stages), better prognosis, stronger immune infiltration, higher expression of immune checkpoints, and higher TMB level than cluster 2. WGCNA found that 28 genes including CD4 and IL10RA were related to the expression of PTGIS/HRASLS and tumor immune infiltration. PTGIS/HRASLS in the GSE4573 cohort had the same effect on LUSC prognosis and tumor immunity as the TCGA cohort. Conclusions: PTGIS and HRASLS can be used as new therapeutic targets for LUSC as well as biomarkers for prognosis and tumor immunity, which has positive significance for guiding the immunotherapy of LUSC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Sistema Enzimático do Citocromo P-450 , Neoplasias Pulmonares , Fosfolipases A , Humanos , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Sistema Enzimático do Citocromo P-450/genética , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos/genética , Pulmão , Neoplasias Pulmonares/genética , Fenótipo , Fosfolipases A/genética
3.
Am J Cancer Res ; 12(11): 5160-5182, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36504901

RESUMO

Necroptosis is a new programmed formation of necrotizing cell death, which plays important role in tumor biological regulation, including tumorigenesis and immunity. In this study, we aimed to establish and validate a prediction model based on necroptosis-related genes (NRGs) for lung adenocarcinoma (LUAD) prognosis and tumor immunity. The training set consisted of samples from The Cancer Genome Atlas (TCGA) dataset (n = 334), and the validation sets consisted of samples from the Gene Expression Omnibus (GEO) (n = 439) and clinical (n = 20) datasets. Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that 28 necroptosis-related differentially expressed genes (DEGs) were enriched in cell death and immune regulation. RT-qPCR and western blot results showed the low expression of necroptosis markers in LUAD cells. A prognostic gene signature based on 6 NRGs (PYGB, IL1A, IFNAR2, BIRC3, H2AFY2, and H2AFX) was constructed and the risk score was calculated. Multivariate Cox regression analysis showed that the risk score was an independent risk factor [hazard ratio (HR) = 1.220, 95% confidence interval (CI): 1.154-1.290, P<0.001]. In the TCGA cohort, a high-risk score was associated with poor prognosis, weak immune infiltration, and low expression at immune checkpoints, which was validated in the GEO and clinical cohorts. Our findings showed that the patients in the low-risk group had a better progression-free survival (PFS) [not reached vs. 8.5 months, HR = 0.18, 95% CI: 0.04-0.72, P<0.001] than those in the high-risk score group. Immunotherapy tolerance was found to be correlated with the high-risk score, and the risk score combined with PD-L1 (AUC = 0.808, 95% CI: 0.613-1.000) could better predict the immunotherapy response of LUAD. A nomogram was shown to have a strong ability to predict the individual survival rate of patients with LUAD in the TCGA and GSE68465 cohorts. We constructed and validated a potential prognostic signature consisting of 6 NRGs to predict the prognosis and tumor immunity of LUAD, which may be helpful to guide the individualized immunotherapy of LUAD.

4.
Am J Cancer Res ; 12(5): 2012-2031, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693080

RESUMO

Circular RNAs (circRNAs) have been reported to play crucial roles in the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). However, the function of circRNAs in ESCC stemness has not been reported. This study aimed to identify novel circRNAs that regulate ESCC stemness and explore their internal mechanisms in ESCC. We found that hsa_circ_0001741 was upregulated in ESCC tissues and was positively related to lymphatic metastasis, higher TNM stage, and poor prognosis. Functionally, hsa_circ_0001741 promoted ESCC cell stemness, invasion, and migration in vitro. Mechanistically, analysis of the relationship between hsa_circ_0001741 and tumor suppressor miR-491-5p revealed that hsa_circ_0001741 functioned as a miR-491-5p sponge. Specifically, hsa_circ_0001741 bound to miR-491-5p to prevent the microRNA from binding to the 3'-UTR of NOTCH3 mRNA and suppressing NOTCH3 expression. Moreover, the ablation of hsa_circ_0001741 significantly inhibited the tumorigenicity in vivo. In conclusion, hsa_circ_0001741 promotes ESCC stemness, invasion, and migration by sponging tumor suppressor miR-491-5p to upregulate NOTCH3 expression. Our findings identify a novel therapeutic target for ESCC patients and the expression level of hsa_circ_0001741 has the potential to serve as a prognostic biomarker for ESCC.

5.
Drug Des Devel Ther ; 14: 5109-5118, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262572

RESUMO

BACKGROUND: Gastric cancer was still one of the commonly diagnosed cancer types and the third-most common cause of cancer-related death in the world. Gentiopicroside, which is extracted from the Gentianella acuta, is commonly used in both traditional treatment and modern clinical care; therefore, its anticancer effects have been attracted more attention. However, the systematic analysis of action mechanism of Gentiopicroside on gastric cancer (GC) has not yet been carried out. AIM: A network pharmacology-based strategy combined with molecular docking studies and in vitro validation was employed to investigate potential targets and molecular mechanism of Gentiopicroside against GC. MATERIALS AND METHODS: Potential targets of Gentiopicroside, as well as related genes of GC, were acquired from public databases. Potential targets, and signaling pathways were determined through bioinformatic analysis, including protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, molecular docking and cell experiments were performed to further verify the above findings. RESULTS: Our findings revealed that the anticancer activity of Gentiopicroside potentially involves 53 putative identified target genes. In addition, GO, KEGG, and network analyses revealed that these targets were associated with cell proliferation, metabolic process, and other physiological processes. Furthermore, we have proved that critical compound affected the expression of CCND1, CCNE1, p-AKT and p-P38 at protein levels. These findings provide an overview of the anticancer action of Gentiopicroside from a network perspective; meanwhile, it might also set an example for future studies of other materials used in traditional Chinese medicine (TCM). CONCLUSION: This study comprehensively illuminated the potential targets and molecular mechanism of Gentiopicroside against GC. It also provided a promising approach to uncover the scientific basis and therapeutic mechanism of TCM treating for disease.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Biologia Computacional , Medicamentos de Ervas Chinesas/farmacologia , Glucosídeos Iridoides/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Gentianella/química , Humanos , Glucosídeos Iridoides/química , Medicina Tradicional Chinesa , Conformação Molecular , Simulação de Acoplamento Molecular , Mapas de Interação de Proteínas , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas
6.
Lung Cancer ; 147: 64-70, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32673828

RESUMO

OBJECTIVE: Aberrant MET activation, which promotes cell proliferation and tumor metastasis, occurs in many types of cancer and results from multiple mechanisms. A novel MET duplication mutation was found in a non-small cell lung cancer (NSCLC) patient. The clinical response to crizotinib was investigated and the functional relevance was characterized in cellular models. MATERIALS AND METHODS: Next-generation sequencing (NGS) was performed on the tumor tissue and circulating tumor DNA (ctDNA) of a patient with advanced NSCLC. In vitro studies including western blot, proliferation assays and colony formation assays were used to confirm the clinical observations. RESULTS: The patient was identified to harbor a duplication of the MET SEMA domain. After a month of treatment, the patient showed a marked response to crizotinib, a multikinase inhibitor with potent activity against MET. Functional in vitro studies demonstrated that expression of MET SEMA duplication in NIH-3T3 cells stimulated the activation of MET signaling. Crizotinib treatment obviously repressed cell proliferation, colony formation, and MET signaling pathway. CONCLUSION: Crizotinib treatment resulted in a clinical response in a patient with MET SEMA duplication. Results of cellular analyses together with the clinical data suggest that this novel alteration may represent an actionable target in NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética
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