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1.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809929

RESUMEN

The occurrence of distant tumor metastases is a major barrier in non-small cell lung cancer (NSCLC) therapy, and seriously affects clinical treatment and patient prognosis. Recently, long non-coding RNAs (lncRNAs) have been demonstrated to be crucial regulators of metastasis in lung cancer. The aim of this study was to reveal the underlying mechanisms of a novel lncRNA LNC CRYBG3 in regulating NSCLC metastasis. Experimental results showed that LNC CRYBG3 was upregulated in NSCLC cells compared with normal tissue cells, and its level was involved in these cells' metastatic ability. Exogenously overexpressed LNC CRYBG3 increased the metastatic ability and the protein expression level of the metastasis-associated proteins Snail and Vimentin in low metastatic lung cancer HCC827 cell line. In addition, LNC CRYBG3 contributed to HCC827 cell metastasis in vivo. Mechanistically, LNC CRYBG3 could directly combine with eEF1A1 and promote it to move into the nucleus to enhance the transcription of MDM2. Overexpressed MDM2 combined with MDM2 binding protein (MTBP) to reduce the binding of MTBP with ACTN4 and consequently increased cell migration mediated by ACTN4. In conclusion, the LNC CRYBG3/eEF1A1/MDM2/MTBP axis is a novel signaling pathway regulating tumor metastasis and may be a potential therapeutic target for NSCLC treatment.


Asunto(s)
Proteínas Portadoras/metabolismo , Cristalinas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Factor 1 de Elongación Peptídica/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Unión Proteica , ARN Largo no Codificante/genética , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
2.
World J Surg Oncol ; 19(1): 122, 2021 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-33865422

RESUMEN

BACKGROUND AND OBJECTIVES: Long non-coding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) was previously shown to exert an oncogenic role in several human cancers. However, whether PART1 is associated with the malignant progression of pancreatic cancer remains unclear. In the current study, we aimed to identify the role and potential mechanism of PART1 in pancreatic cancer. METHODS: qRT-PCR was applied to detect PART1 expression in 45 cases of pancreatic cancer patients. The chi-square test was performed to assess the association between PART1 expression and clinicopathologic features, and Kaplan-Meier method was applied to evaluate overall survival. In vitro CCK-8, transwell invasion, and flow cytometry assays were applied to detect the effects of PART1 on cell proliferation, invasion, and apoptosis, respectively. Luciferase reporter and RNA immunoprecipitation assays were used to identify the regulatory mechanism between PART1 and miR-122. RESULTS: PART1 expression was upregulated in pancreatic cancer tissues and cell lines. High PART1 expression was closely correlated with tumor size, T classification, clinical stage, and vascular invasion, and predicted a poor overall survival. PART1 knockdown significantly suppressed cell proliferation and invasion abilities of pancreatic cancer but promoted cell apoptosis. PART1 was found to serve as a molecular sponge of miR-122, and miR-122 inhibition partially reversed the inhibitory phenotypes of PART1 knockdown on pancreatic cancer cells. CONCLUSIONS: PART1 promotes the malignant progression of pancreatic cancer by sponging miR-122. The PART1/miR-122 axis might be a promising target for anticancer therapy in patients with pancreatic cancer.


Asunto(s)
Proliferación Celular/genética , MicroARNs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN no Traducido/genética , Andrógenos , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico
3.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809516

RESUMEN

Single-gene defects have been revealed to be the etiologies of many kidney diseases with the recent advances in molecular genetics. Autosomal dominant polycystic kidney disease (ADPKD), as one of the most common inherited kidney diseases, is caused by mutations of PKD1 or PKD2 gene. Due to the complexity of pathophysiology of cyst formation and progression, limited therapeutic options are available. The roles of noncoding RNAs in development and disease have gained widespread attention in recent years. In particular, microRNAs in promoting PKD progression have been highlighted. The dysregulated microRNAs modulate cyst growth through suppressing the expression of PKD genes and regulating cystic renal epithelial cell proliferation, mitochondrial metabolism, apoptosis and autophagy. The antagonists of microRNAs have emerged as potential therapeutic drugs for the treatment of ADPKD. In addition, studies have also focused on microRNAs as potential biomarkers for ADPKD and other common hereditary kidney diseases, including HNF1ß-associated kidney disease, Alport syndrome, congenital abnormalities of the kidney and urinary tract (CAKUT), von Hippel-Lindau (VHL) disease, and Fabry disease. This review assembles the current understanding of the non-coding RNAs, including microRNAs and long noncoding RNAs, in polycystic kidney disease and these common monogenic kidney diseases.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Enfermedades Renales/genética , ARN Largo no Codificante/metabolismo , Animales , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Modelos Biológicos
4.
Nat Commun ; 12(1): 2076, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824317

RESUMEN

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.


Asunto(s)
Apolipoproteínas E/genética , Genoma Humano , Enfermedades Neurodegenerativas/genética , Filogenia , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Encéfalo/patología , Cromosomas Humanos Par 19/genética , Secuencia Conservada/genética , ADN Intergénico/genética , Ontología de Genes , Humanos , Intrones/genética , Desequilibrio de Ligamiento/genética , Anotación de Secuencia Molecular , Fenotipo , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Regresión
5.
Toxicol Appl Pharmacol ; 419: 115517, 2021 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-33812962

RESUMEN

Cleft palate (CP) is a common birth defect with a high incidence of occurrence in humans. The 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic halogenated aromatic hydrocarbon, with a strong CP effect on mice. Increasing recent evidences have shown that long-noncoding RNAs (lncRNAs) play an important role in several diseases, including CP. However, there is a paucity of studies on the role of lncRNA MEG3 in the occurrence and development of TCDD-induced CP. In this study, the relationship between MEG3 and the proliferation of palatal mesenchymal cells and the underlying molecular mechanism were studied by establishing fetal CP with TCDD (64 µg/kg) in C57BL/6N mice. The results revealed that MEG3 was highly expressed during the critical period of CP formation and that the fetal mesenchymal proliferation was significantly inhibited at certain critical periods in the mice receiving TCDD. In addition, we noted a possibility of a crosstalk between MEG3 and the TGF-ß/Smad pathway, such that the inhibition of the TGF-ß/Smad pathway was induced by TCDD. Cumulatively, our study suggests that TCDD-induced CP may be caused by MEG3 inhibition of the proliferation of palatal mesenchymal cells involving the TGFß/Smad pathway, which may provide a novel perspective to understand the pathogenesis of CP.


Asunto(s)
Proliferación Celular , Fisura del Paladar/metabolismo , Células Madre Mesenquimatosas/metabolismo , Paladar Duro/metabolismo , ARN Largo no Codificante/metabolismo , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Fisura del Paladar/inducido químicamente , Fisura del Paladar/genética , Fisura del Paladar/patología , Modelos Animales de Enfermedad , Femenino , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Células Madre Mesenquimatosas/patología , Ratones Endogámicos C57BL , Paladar Duro/anomalías , Fosforilación , Dibenzodioxinas Policloradas , Embarazo , ARN Largo no Codificante/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/genética
6.
Medicine (Baltimore) ; 100(16): e25244, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879657

RESUMEN

ABSTRACT: A newly discovered long non-coding RNA (lncRNA) is associated with the progression of a variety of tumors. The purpose of this meta-analysis is to explore further the relationship between clinicopathological features and the prognostic value of LINC00675 in caners.We searched the various database, including PubMed, Web of Science, Cochrane Library, Embase together with Wanfang, and China National Knowledge Infrastructure for articles on LINC00675 and clinicopathological characteristics and prognosis of patients with cancers before February 20, 2020. According to the inclusion and exclusion criteria, the studies that meet the criteria were systematically collected through search keywords. The Newcastle Ottawa document quality assessment system was used to evaluate the quality of documents. The required data from literature were extracted, and the hazard ratio (HR), odds ratio (OR), and 95confidence interval (CI) were calculated using stata12.0 software and RevMan5.3 software.A total of 5 studies covering 462 patients were included in this meta-analysis to evaluate the prognostic value of LINC00675 in cancers. Our results showed that high LINC00675 expression was significantly correlated with poor overall survival (OS) (HR = 1.60, 95% CI: 1.23-2.08, P = .0005). Additionally, upregulated expression of LINC00675 was significantly associated with tumor node metastasis stage (OR = 1.74, 95% CI: 1.18-2.58, P = .006) and distant metastasis (OR = 2.22, 95% CI: 1.21-4.08, P = .01).Our study suggests that LINC00675 could be used as a biomarker to evaluate the prognosis of cancer patients. More studies to further confirm that the clinical value of LINC00675 in cancers will be required.


Asunto(s)
Neoplasias/genética , Neoplasias/mortalidad , ARN Largo no Codificante/metabolismo , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Metástasis de la Neoplasia/genética , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Sensibilidad y Especificidad , Análisis de Supervivencia , Regulación hacia Arriba/genética
7.
Medicine (Baltimore) ; 100(16): e25452, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879677

RESUMEN

BACKGROUND: Currently, an increasing number of long noncoding RNAs (LncRNAs) have been reported to be abnormally expressed in human carcinomas and play a vital role in tumourigenesis. Some studies have been carried out to investigate the influence of the expression of LncRNA human urothelial carcinoma associated 1 (UCA1) on prognosis and clinical significance in patients with esophageal cancer, but the results are contradictory and uncertain. A meta-analysis and was conducted with controversial data to accurately assess the issue. We collected relevant TCGA data to further testify the result. In addition, bioinformatics analysis was conducted to investigate the mechanism and related pathways of LncRNA UCA1 in esophageal carcinoma. METHODS: Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science were thoroughly searched for relevant information. Two reviewers independently performed data extraction and literature quality evaluation. Odd ratio and its 95% confidence intervals were applied to evaluate the relationship between LncRNA UCA1 and clinicopathological characteristics of esophageal carcinoma patients. Hazard ratios and its 95% confidence intervals were adopted to assess the prognostic effects of LncRNA UCA1 on overall survival and disease-free survival. Meta-analysis was performed with Stata 14.0 software. To further assess the function of LncRNA UCA1 in esophageal carcinoma, relevant data from The Cancer Genome Atlas (TCGA) database was collected. Three databases, miRWalk, TargetScan, and miRDB, were used for prediction of target genes. Genes present in these 3 databases were considered as predicted target genes of LncRNA UCA1. Venny 2.1 were used for intersection analysis. Subsequently, GO, KEGG, and PPI network analysis were conducted based on the overlapping target genes of LncRNA UCA1 to explore the possible molecular mechanism in esophageal carcinoma. RESULTS: This study provides a high-quality medical evidence for the correlation between LncRNA UCA1 expression and overall survival, and between disease-free survival and clinicopathological features. Based on bioinformatics analysis, this study enhanced the understanding of the mechanism and related pathways of LncRNA UCA1 in esophageal carcinoma. CONCLUSION: The study provides updated evidence to evaluate whether the expression of LncRNA UCA1 is in association with poor prognosis in patients with esophageal carcinoma. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/8MCHW.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma/mortalidad , Neoplasias Esofágicas/mortalidad , ARN Largo no Codificante/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma/genética , Carcinoma/patología , Biología Computacional , Supervivencia sin Enfermedad , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Esófago/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Metaanálisis como Asunto , Pronóstico , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas/genética , ARN Largo no Codificante/análisis , Revisiones Sistemáticas como Asunto
8.
Medicine (Baltimore) ; 100(16): e25507, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879685

RESUMEN

BACKGROUND: Long noncoding RNA (lncRNA) is reported to be upregulated in many tumors. Although the expression of lncRNA in oral squamous cell carcinoma has been assessed, the association between lncRNA expression and prognosis or clinicopathological feature still remains controversial. Therefore, we conducted a meta-analysis to verify whether lncRNA expression was related to prognosis or clinicopathological features in patients with oral squamous cell carcinoma. METHODS: We searched Embase, PubMed, Web of Science, Cochrane library, Chinese National Knowledge Infrastructure, and Wanfang databases from inception to February 2021. The language included Chinese and English. The published literature on lncRNA expression and prognosis or clinicopathological characteristics of patients with oral squamous cell carcinoma was statistically analyzed. The combination of hazard ratios (HRs), odds ratios (OR), and 95% confidence intervals (95% CIs) were applied to evaluate the effects of lncRNA on the prognosis and clinicopathological features of oral squamous cell carcinoma. RESULTS: This study could provide a comprehensive review of the available evidence of lncRNA on the prognosis and clinicopathological features of oral squamous cell carcinoma. CONCLUSION: The conclusion of our study will provide the updated evidence to judge the lncRNA on the prognosis and clinicopathological features of oral squamous cell carcinoma.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Boca/mortalidad , ARN Largo no Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Biomarcadores de Tumor/análisis , Regulación Neoplásica de la Expresión Génica , Humanos , Metaanálisis como Asunto , Mucosa Bucal/patología , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/genética , Neoplasias de la Boca/terapia , Estadificación de Neoplasias , Pronóstico , ARN Largo no Codificante/análisis , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Revisiones Sistemáticas como Asunto
9.
Nat Genet ; 53(4): 551-563, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33821005

RESUMEN

Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing the formation of mono-ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains until the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.


Asunto(s)
Blastocisto/metabolismo , Epigénesis Genética , Regulación del Desarrollo de la Expresión Génica , Histonas/genética , Herencia Materna , ARN Largo no Codificante/genética , Animales , Blastocisto/citología , Femenino , Fertilización/genética , Histonas/metabolismo , Lisina/metabolismo , Masculino , Ratones , Oocitos/citología , Oocitos/crecimiento & desarrollo , Oocitos/metabolismo , Herencia Paterna , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Embarazo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Largo no Codificante/metabolismo , Espermatozoides/citología , Espermatozoides/metabolismo , Ubiquitinación , Cigoto/citología , Cigoto/crecimiento & desarrollo , Cigoto/metabolismo
10.
DNA Cell Biol ; 40(3): 523-531, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33687273

RESUMEN

Antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as or ciRS-7) is an important member of the circular RNA family and is involved in the regulation of numerous biological functions. Keratinocytes and fibroblasts (FBs) affect melanogenesis through paracrine effects. However, whether ciRS-7 is involved in melanogenesis by regulating paracrine effects remains unclear. This study demonstrates for the first time that ciRS-7 is highly expressed in keratinocytes, FBs, and melanocytes (MCs). Ultraviolet B (UVB) irradiation promotes ciRS-7 expression in keratinocytes and FBs. Following inhibition of ciRS-7 expression in keratinocytes and FBs, the culture supernatant from these cells inhibited melanogenesis of MCs. Further analyses revealed that the expression and secretion of fibroblast growth factor 2 (FGF2) and phosphorylation of STAT3 and AKT in keratinocytes and FBs were significantly downregulated following inhibition of ciRS-7 expression, whereas the level of miR-7 was increased. Overexpression of miR-7 in keratinocytes and FBs significantly inhibited the expression of FGF2. In conclusion, our findings demonstrate that UVB-induced ciRS-7 triggers melanogenesis in MCs through regulation of the miR-7/STAT3 and AKT/FGF2 paracrine axis in both keratinocytes and FBs. ciRS-7 may serve as a regulator in the development of pigmented skin diseases.


Asunto(s)
Regulación de la Expresión Génica/efectos de la radiación , Queratinocitos/metabolismo , Melaninas/biosíntesis , Comunicación Paracrina/efectos de la radiación , ARN Largo no Codificante/metabolismo , Transducción de Señal/efectos de la radiación , Rayos Ultravioleta , Línea Celular Transformada , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo
11.
Life Sci ; 275: 119288, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667514

RESUMEN

AIMS: Hepatocellular carcinoma (HCC) is a malignant cancer that threatened human life seriously. Long non-coding RNA (lncRNA) BACE1-AS has been reported as a key regulator in tumorigenesis. Yet the specific correlation between BACE1-AS and HCC still needs further investigation. The primary purpose of our study is to reveal the exact correlation between BACE1-AS and HCC. MAIN METHODS: Bioinformatics via TCGA database revealed BACE1-AS closely related with HCC. qRT-PCR confirmed the abnormal BACE1-AS level in HCC tissues and cells. Databases prediction suggested that miR-377-3p might be a modulatory target of BACE1-AS and luciferase assay confirmed this hypothesis. Further study discovered that CELF1 also partook in the regulatory axis of BACE1-AS/miR-377-3p. Wound healing assays and transwell assays were utilized to investigate the impact of BACE1-AS, miR-377-3p and CELF1 in vitro. In vivo metastasis was examined by pulmonary metastasis model. KEY FINDINGS: This study found that BACE1-AS was overexpressed in HCC tissues and cell lines. Knockdown of BACE1-AS could restrain HCC progression in vitro, and inhibit pulmonary metastasis in vivo. MiR-377-3p was negatively modulated by BACE1-AS in HCC tumor tissues and cells. MiR-377-3p up-regulation inhibited HCC cells migration and invasion via inactivating EMT process. Moreover, CELF1 was identified as a downstream regulator of miR-377-3p and served as an oncogene in HCC cells. SIGNIFICANCE: Our findings supported that lncRNA BACE1-AS was up-regulated in HCC, promoting invasion and metastasis of hepatocellular carcinoma cells by modulating miR-377-3p/CELF1 axis via contributing to EMT pathway. BACE1-AS could be a potential biomarker in HCC for future treatment.


Asunto(s)
Proteínas CELF1/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Western Blotting , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Humanos , Neoplasias Hepáticas/patología , Ratones , Invasividad Neoplásica , Trasplante de Neoplasias , ARN Largo no Codificante/fisiología , Reacción en Cadena en Tiempo Real de la Polimerasa
12.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33670895

RESUMEN

Long non-coding RNAs (lncRNAs) are functional transcripts with more than 200 nucleotides. These molecules exhibit great regulatory capacity and may act at different levels of gene expression regulation. Despite this regulatory versatility, the biology of these molecules is still poorly understood. Computational approaches are being increasingly used to elucidate biological mechanisms in which these lncRNAs may be involved. Co-expression networks can serve as great allies in elucidating the possible regulatory contexts in which these molecules are involved. Herein, we propose the use of the pipeline deposited in the RTN package to build lncRNAs co-expression networks using TCGA breast cancer (BC) cohort data. Worldwide, BC is the most common cancer in women and has great molecular heterogeneity. We identified an enriched co-expression network for the validation of relevant cell processes in the context of BC, including LINC00504. This lncRNA has increased expression in luminal subtype A samples, and is associated with prognosis in basal-like subtype. Silencing this lncRNA in luminal A cell lines resulted in decreased cell viability and colony formation. These results highlight the relevance of the proposed method for the identification of lncRNAs in specific biological contexts.


Asunto(s)
Neoplasias de la Mama/genética , Redes Reguladoras de Genes , ARN Largo no Codificante/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Biología Computacional , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Pronóstico
13.
Medicine (Baltimore) ; 100(11): e20722, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725920

RESUMEN

ABSTRACT: Bladder cancer-associated transcript 1 (BLACAT1) is one of the most common cancer-associated long non-coding RNAs (lncRNAs), which has been reported as a tumor promotor in several malignancies. Previously, BLACAT1 was found to be overexpressed in glioma tissues and cell lines. Functional assays determined that BLACAT1 promoted glioma cell proliferation, migration, invasion and epithelial-mesenchymal transition, suggesting that BLACAT1 might serve as an oncogene in glioma. In the present study, we aimed to investigate its clinical significance and prognostic value in glioma patients.A total of 137 paired glioma tissue samples and adjacent normal brain tissue samples were collected from 137 glioma patients who underwent surgery from May 2014 to February 2019. The Student t test was applied to determine the statistical significance of the observed differences between 2 groups. Survival curves were constructed and differences among groups were calculated using the Kaplan-Meier method.The relative expression of BLACAT1 in glioma samples was significantly higher than that of matched normal tissues (P < .001). The expression level of tissue BLACAT1 was statistically correlated with tumor size (P = .04), Karnofsky Performance Status (KPS) (P = .006), and WHO grade (P = .017). Kaplan-Meier analysis with the log-rank test revealed that BLACAT1 up-regulation was correlated with shorter overall survival time of patients with glioma (Log Rank test, P = .012). In multivariate Cox analysis, BLACAT1 expression was found to be an independent prognostic factor for overall survival in patients with glioma (HR = 2.739; 95% CI: 1.785-8.229; P = .035). Our study demonstrates that up-regulation of BLACAT1 is able to predict aggressive clinicopathologic characteristics and poor prognosis of glioma patients. These findings may have significant implications for potential treatment options and prognosis for patients with glioma.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Glioma/genética , ARN Largo no Codificante/metabolismo , Regulación hacia Arriba/genética , Encéfalo/metabolismo , Estudios de Casos y Controles , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Glioma/mortalidad , Humanos , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Pronóstico , Modelos de Riesgos Proporcionales
14.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671464

RESUMEN

Obesity is a major risk factor for a large number of secondary diseases, including cancer. Specific insights into the role of gender differences and secondary comorbidities, such as type 2 diabetes (T2D) and cancer risk, are yet to be fully identified. The aim of this study is thus to find a correlation between the transcriptional deregulation present in the subcutaneous adipose tissue of obese patients and the oncogenic signature present in multiple cancers, in the presence of T2D, and considering gender differences. The subcutaneous adipose tissue (SAT) of five healthy, normal-weight women, five obese women, five obese women with T2D and five obese men were subjected to RNA-sequencing, leading to the identification of deregulated coding and non-coding RNAs, classified for their oncogenic score. A panel of DE RNAs was validated via Real-Time PCR and oncogene expression levels correlated the oncogenes with anthropometrical parameters, highlighting significant trends. For each analyzed condition, we identified the deregulated pathways associated with cancer, the prediction of possible prognosis for different cancer types and the lncRNAs involved in oncogenic networks and tissues. Our results provided a comprehensive characterization of oncogenesis correlation in SAT, providing specific insights into the possible molecular targets implicated in this process. Indeed, the identification of deregulated oncogenes also in SAT highlights hypothetical targets implicated in the increased oncogenic risk in highly obese subjects. These results could shed light on new molecular targets to be specifically modulated in obesity and highlight which cancers should receive the most attention in terms of better prevention in obesity-affected patients.


Asunto(s)
Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Obesidad/genética , Oncogenes , Sistemas de Lectura Abierta/genética , ARN Largo no Codificante/genética , Grasa Subcutánea/metabolismo , Grasa Subcutánea/patología , Adulto , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Femenino , Humanos , Masculino , Neoplasias/genética , Obesidad/complicaciones , Pronóstico , ARN Largo no Codificante/metabolismo , Caracteres Sexuales , Transducción de Señal/genética , Transcripción Genética
15.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668685

RESUMEN

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2-specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.


Asunto(s)
Carcinogénesis/metabolismo , Resistencia a Antineoplásicos , Neoplasias Ováricas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/metabolismo , ARN Neoplásico/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Femenino , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Largo no Codificante/genética , ARN Neoplásico/genética , Serina-Treonina Quinasas TOR/genética
16.
Cancer Sci ; 112(5): 1811-1821, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33675124

RESUMEN

Ribosomal proteins (RPs) are important components of ribosomes and related to the occurrence and development of tumors. However, little is known about the effects of the RP network on cervical cancer (CC). In this study, we screened differentially expressed RPL34 in CC by high-throughput quantitative proteome assay. We found that RPL34 acted as a tumor suppressor and was downregulated in CC and inhibited the proliferation, migration, and invasion abilities of CC cells. Next, we verified that RPL34 regulated the CC through the MDM2-P53 pathway by using Act D medicine, MDM2 inhibitor, and a series of western blotting(WB)assays. Moreover, an antisense lncRNA, RPL34-AS1, regulated the expression of RPL34 and participated in the tumorigenesis of CC. RPL34 can reverse the effect of RPL34-AS1 in CC cells. Finally, by RNA-binding protein immunoprecipitation (RIP) assay we found that eukaryotic initiation factor 4A3 (EIF4A3), which binds to RPL34-AS1, regulated RPL34-AS1 expression in CC. Therefore, our findings indicate that RPL34-AS1-induced RPL34 inhibits CC cell proliferation, invasion, and metastasis through modulation of the MDM2-P53 signaling pathway, which provides a meaningful target for the early diagnosis and treatment of CC.


Asunto(s)
Carcinoma in Situ/etiología , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Ribosómicas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias del Cuello Uterino/etiología , Adulto , Animales , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patología , Carcinoma in Situ/prevención & control , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , ARN Helicasas DEAD-box/metabolismo , Regulación hacia Abajo , Factor 4A Eucariótico de Iniciación/metabolismo , Femenino , Células HeLa , Humanos , Inmunoprecipitación/métodos , Ratones , Ratones Desnudos , Invasividad Neoplásica , Proteínas de Neoplasias/análisis , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , ARN Largo no Codificante/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/prevención & control
17.
Mol Med Rep ; 23(6)2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33786624

RESUMEN

The therapeutic effect of sacubitril/valsartan (S/V) on heart failure has been confirmed, while its role in atherosclerosis remains largely unexplored. The present study aimed to investigate the effects of S/V on the expression of metastasis­associated lung adenocarcinoma transcript 1 (MALAT1), inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) induced by oxidized low­density lipoprotein (ox­LDL) and to elucidate its possible mechanism. Cell Counting Kit­8 assay was used to detect cell viability. Reverse transcription­quantitative PCR was performed to detect the MALAT1 expression. ELISA was performed to detect the levels of IL­1ß, IL­6 and TNF­α. Flow cytometry was conducted to detect the apoptotic rate of cells. A nitric oxide (NO) detection kit was used to determine the concentration of NO. Western blotting analysis was performed to determine the levels of intercellular cell adhesion molecule (ICAM)­1, vascular cell adhesion molecule (VCAM)­1, endothelin­1, caspase­3, Bax, Bcl­2, Toll­like receptor 4 (TLR4), p65 and p­p65. Compared with the ox­LDL group, S/V treatment significantly increased the cell viability, NO concentration and Bcl­2 expression, decreased the levels of IL­1ß, IL­6 and TNF­α and reduced the expressions of MALAT1, ICAM­1, VCAM­1, cleaved­caspase­3, Bax, TLR4 and p­p65. Overall, the findings suggested that S/V could downregulate the expression of MALAT1, inhibit inflammation and apoptosis and improve endothelial function in ox­LDL­induced HUVECs via inactivating the TLR4/NF­κB signaling pathway. Therefore, S/V might be utilized as a promising therapeutic strategy for the prevention and treatment of atherosclerosis.


Asunto(s)
Aminobutiratos/farmacología , Antiinflamatorios/farmacología , Apoptosis , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , ARN Largo no Codificante/genética , Tetrazoles/farmacología , Valsartán/farmacología , Combinación de Medicamentos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Lipoproteínas LDL/farmacología , FN-kappa B/metabolismo , ARN Largo no Codificante/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo
18.
BMC Cancer ; 21(1): 290, 2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33736615

RESUMEN

BACKGROUND: Abnormal expression of long non-coding RNA (lncRNA) FTX (five prime to Xist), which is involved in X chromosome inactivation, has been reported in various tumors. However, the effect of FTX on the development of pancreatic cancer (PC) has not been elucidated. The purpose of this study was to explore the possible molecular mechanism of FTX in PC. METHODS: Quantitative real-time PCR (qRT-PCR) was used to measure the expression levels of FTX and miR-513b-5p in PC cell lines. Proliferation and apoptosis of PC cells were determined by CCK-8, Edu assay, and flow cytometry. Invasion and migration ability of PC cells were detected by Transwell assay and scratch test. Bioinformatics analysis, luciferase reporter gene assay, and RNA immunoprecipitation (RIP) assay were used to verify the direct binding between FTX and miR-513b-5p. The xenotransplantation mouse model was established to explore the effect of FTX and miR-513b-5p on the PC tumor growth in vivo. RESULTS: The expression levels of FTX were increased in PC cell lines, and silencing of FTX remarkably suppressed the invasion ability and cell viability. Besides, FTX could bind to miR-513b-5p as a competitive endogenous RNA, thus promoting the invasion and proliferation ability of PC cells. Moreover, knockdown of FTX inhibited the tumor growth and increased the expression levels of miR-513b-5p and apoptosis-related proteins in vivo. CONCLUSIONS: FTX could directly combine with miR-513b-5p as a competitive endogenous RNA, thus promoting the occurrence and development of PC in vitro and in vivo.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Neoplasias Pancreáticas/genética , ARN Largo no Codificante/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Invasividad Neoplásica/patología , Neoplasias Pancreáticas/patología , ARN Largo no Codificante/genética , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Nat Commun ; 12(1): 1956, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33782403

RESUMEN

Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c+). NPM1c+ maintains a unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c+ controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC, a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c+-associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c+-driven leukemogenesis by rectifying the signature of NPM1c+ leukemic transcription programs. Furthermore, overexpression of HoxBlinc (HoxBlincTg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in (Npm1c/+) mice. HoxBlincTg and Npm1c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c+ signature genes to control their activation in HoxBlincTg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c+ leukemia. HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c+ AML.


Asunto(s)
Carcinogénesis/genética , Regulación Leucémica de la Expresión Génica , Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , ARN Largo no Codificante/genética , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular , Perfilación de la Expresión Génica , Xenoinjertos , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Transgénicos , Familia de Multigenes , Mutación , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/genética , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Mielopoyesis/genética , Proteínas Nucleares/deficiencia , Regiones Promotoras Genéticas , ARN Largo no Codificante/agonistas , ARN Largo no Codificante/metabolismo , Transducción de Señal , Transcripción Genética
20.
Sci Total Environ ; 776: 145950, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33647641

RESUMEN

Environmental BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) inhibit proliferation of human villous trophoblast cells, which might further induce recurrent miscarriage (RM). However, the underlying mechanisms remain largely unknown. In this work, we identified a novel lncRNA HZ01 (lnc-HZ01) that is up-regulated in both RM tissues and BPDE-exposed trophoblast cells. Lnc-HZ01 inhibits trophoblast cell proliferation and induces miscarriage. Mechanistically, lnc-HZ01 promotes MXD1 mRNA transcription by up-regulating its transcription factor c-JUN and also enhances MXD1 protein stability by up-regulating its deubiquitin enzyme USP36. Reversely, MXD1 up-regulates lnc-HZ01 level by enhancing its RNA stability due to the increased level of m6A RNA methylation on lnc-HZ01, the first example that m6A modification regulates trophoblast cell functions. Thus, lnc-HZ01 and MXD1 comprise a positive self-feedback loop, which is up-regulated in both RM tissues and BPDE-exposed trophoblast cells. Once this loop is activated by BaP or BPDE exposure, both pathways in this loop would be up-regulated, promote EIF4E transcription, inhibit trophoblast cell proliferation, and further induce miscarriage. This work provides new clinical and scientific understanding in unexplained miscarriage.


Asunto(s)
Aborto Espontáneo , ARN Largo no Codificante , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proliferación Celular , Retroalimentación , Femenino , Humanos , Metilación , Embarazo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas Represoras/metabolismo , Trofoblastos/metabolismo
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