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1.
Biol Res ; 53(1): 18, 2020 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-32349783

RESUMEN

BACKGROUND: Cisplatin resistance (DDP-resistance) remains one of the major causes of poor prognosis in females with ovarian cancer. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of cellular processes, including chemoresistance. The aim of this study was to explore the role of HOX transcript antisense RNA (HOTAIR) in DDP-resistant ovarian cancer cells. METHODS: DDP-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. Real-time PCR, western blot, dual-luciferase reporter assay, and flow cytometry were then used to evaluate the effect of HOTAIR/miR-138-5p axis on chemoresistance of DDP-resistant ovarian cancer cells to DDP. RESULTS: We found that HOTAIR was upregulated in DDP-resistant cells, while miR-138-5p was downregulated. Knockdown of HOTAIR increased the expression of miR-138-5p in DDP-resistant cells and miR-138-5p is directly bound to HOTAIR. Upregulation of miR-138-5p induced by HOTAIR siRNA or by its mimics enhanced the chemosensitivity of DDP-resistant cells and decreased the expression of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1). Furthermore, the HOTAIR silencing-induced chemosensitivity of DDP-resistant cells was weakened by miR-138-5p inhibitor. CONCLUSIONS: These data demonstrate that HOTAIR acts as a sponge of miR-138-5p to prevent its binding to EZH2 and SIRT1, thereby promoting DDP-resistance of ovarian cancer cells. Our work will shed light on the development of therapeutic strategies for ovarian cancer treatment.


Asunto(s)
Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Neoplasias Ováricas/genética , ARN Largo no Codificante/genética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes/métodos , Humanos , MicroARNs/antagonistas & inhibidores , Reacción en Cadena en Tiempo Real de la Polimerasa , Sirtuina 1/antagonistas & inhibidores , Regulación hacia Arriba
2.
Anticancer Res ; 40(5): 2645-2655, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366409

RESUMEN

BACKGROUND/AIM: Two-thirds of head and neck squamous cell carcinoma (HNSCC) patients present with locally advanced (LA) stages and have a poor survival rate. The aim of this study was to investigate the roles of the long non-coding RNAs MALAT1 on radiation and cisplatin sensitivity of HNSCC cells. MATERIALS AND METHODS: Clonogenic, cell viability, and apoptosis assays were performed in cells following MALAT1 knockdown using CRISPR/Cas9 system. RESULTS: MALAT1 was overexpressed in HNSCC cell lines as compared to a non-tumorigenic cell line. The number of colonies formed after radiation was significantly reduced in MALAT1 knockdown cells. The IC50 value of cisplatin in MALAT1 knockdown cells was lower than that of the control cells. MALAT1 knockdown resulted in cell cycle arrest at G2/M phase, DNA damage and apoptotic cell death. CONCLUSION: MALAT1 knockdown enhanced the sensitivity of HNSCC cells to radiation and cisplatin partly through the induction of G2/M cell cycle arrest resulting in DNA damage and apoptosis.


Asunto(s)
Cisplatino/uso terapéutico , ARN Largo no Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , ARN Largo no Codificante/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia
3.
Biol Res ; 53(1): 14, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32293550

RESUMEN

BACKGROUND: Previous studies have shown that long noncoding RNA (lncRNA) LINC00483 was aberrantly expressed in human cancers, including gastric cancer. However, the regulatory mechanism of this lncRNA in gastric cancer remains largely unknown. The present study aimed to investigate the effect of LINC00483 on gastric cancer development and explore the potential regulatory network of LINC00483/microRNA (miR)-490-3p/mitogen-activated protein kinase 1 (MAPK1). METHODS: Thirty patients with gastric cancer were recruited for tissues collection. The expression levels of LINC00483, miR-490-3p and MAPK1 were detected by quantitative real-time polymerase chain reaction or western blot. Cell viability, apoptosis, migration and invasion were determined by MTT, flow cytometry, transwell assays and western blot, respectively. The target association between miR-490-3p and LINC00483 or MAPK1 was confirmed by luciferase reporter assay. Xenograft model was established to assess the function of LINC00483 in vivo. RESULTS: LINC00483 and MAPK1 levels were increased in gastric cancer tissues and cells. Knockdown of LINC00483 or MAPK1 inhibited cells viability, migration and invasion but promoted apoptosis in gastric cancer cells. Moreover, MAPK1 overexpression attenuated the effect of LINC00483 knockdown on gastric cancer development. LINC00483 could increase MAPK1 expression by competitively sponging miR-490-3p. miR-490-3p overexpression suppressed gastric cancer development, which was abated by introduction of LINC00483. Besides, inhibition of LINC00483 decreased xenograft tumor growth by regulating miR-490-3p/MAPK1 axis. CONCLUSION: Knockdown of LINC00483 inhibited gastric cancer development in vitro and in vivo by increasing miR-490-3p and decreasing MAPK1, elucidating a novel mechanism for understanding the development of gastric cancer.


Asunto(s)
MicroARNs/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Apoptosis , Carcinogénesis/metabolismo , Línea Celular Tumoral/metabolismo , Movimiento Celular , Supervivencia Celular , Células Epiteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Luciferasas/metabolismo , Masculino , Ratones Endogámicos BALB C , MicroARNs/genética , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Med Sci Monit ; 26: e920504, 2020 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-32277695

RESUMEN

BACKGROUND Evidence indicates that there is an important role for long non-coding RNAs (lncRNA) in numerous cellular processes and that lncRNAs dysregulation contributes to tumor progression. Improved insight into the molecular characteristics of bladder cancer is required to predict outcomes and to develop a new rationale for targeted therapeutic strategies. Bioinformatics methods, including functional enrichment and network analysis combined with survival analysis, are required to process a large volume of data to obtain further information about differentially expressed genes (DEGs) in bladder cancer. This study aimed to explore the role of lncRNAs and their regulation network in bladder cancer. MATERIAL AND METHODS We analyzed bladder cancer data by The Cancer Genome Atlas profiling to identify differentially expressed lncRNAs in bladder cancer. The genes involved in the circlncRNAnet database were evaluated using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), evolutionary relationship analysis, and protein-protein interaction (PPI) networks. RESULTS Two new lncRNAs, ADAMTS9-AS1 and LINC00460, were shown to be differentially expressed in bladder cancer. Patients were divided into 2 groups (high expression and low expression) according to their median expression values. The overall survival and disease-free survival of patients with high ADAMTS9-AS1 bladder cancer were significantly shorter; the expression of LINC00460 had no significant correlation with survival. GO and KEGG analysis of the 2 lncRNA-related genes revealed that these lncRNAs played a vital role in tumorigenesis. Bioinformatics analysis showed that key genes related to LINC00460, including CXCL, CCL, and CSF2, may be related to the development of bladder cancer. The low expression of ADAMTS9-AS1 may influence the survival rate of bladder cancer with the hub gene as a target. CONCLUSIONS LncRNA, including LINC00460 and ADAMTS9-AS1, might play a crucial role in the biosynthesis network of bladder cancer. Differential expression results of ADAMTS9-AS1 suggests it may be correlated with a worse prognosis and a shorter survival time. We outlined the biosynthesis network that regulates lncRNAs in bladder cancer. Further experimental data is needed to validate our results.


Asunto(s)
ARN Largo no Codificante/genética , Neoplasias de la Vejiga Urinaria/genética , Biomarcadores de Tumor/genética , Biología Computacional , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Pronóstico , Mapas de Interacción de Proteínas , Análisis de Supervivencia , Transcriptoma , Neoplasias de la Vejiga Urinaria/diagnóstico
5.
Med Sci Monit ; 26: e922210, 2020 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-32238798

RESUMEN

BACKGROUND The aim of this study was to explore the potential therapeutic targets and pathways of liraglutide against type 2 diabetes mellitus (T2DM) in streptozotocin-induced diabetic rats based on lncRNA sequencing. MATERIAL AND METHODS Male Wistar rats were randomly divided into 3 groups: the control group (n=10), the T2DM model group (high-sugar and high-fat diet, and streptozotocin-induced, n=11), and the liraglutide group (model plus liraglutide, n=10). After 8 weeks of drug treatment, lncRNA sequencing was used to identify the lncRNA therapeutic targets and their related protein-coding genes of liraglutide against T2DM, which were further studied by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to determine the major biological processes and pathways involved in the action of liraglutide treatment. Lastly, several lncRNA targets were randomly detected based on quantitative real-time polymerase chain reaction (QRT-PCR) to verify the accuracy of sequencing results. RESULTS A total of 104 lncRNA targets of liraglutide against T2DM were screened, with 27 upregulated and 77 downregulated, including NONRATT030354.2, MSTRG.1456.6, and NONRATT011758.2. The major biological processes involved were glucose and lipid metabolism and amino acid metabolism. Liraglutide had a therapeutic effect in T2DM, mainly through the Wnt, PPAR, amino acid metabolism signaling, mTOR, and lipid metabolism-related pathways. CONCLUSIONS In this study, we screened 104 lncRNA therapeutic targets and several signaling pathways (Wnt, PPAR, amino acid metabolism signaling pathway, mTOR, and lipid metabolism-related pathways) of liraglutide against T2DM based on lncRNA sequencing.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Regulación de la Expresión Génica/efectos de los fármacos , Hipoglucemiantes/farmacología , Liraglutida/farmacología , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Masculino , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ratas , Ratas Wistar
6.
Medicine (Baltimore) ; 99(15): e19322, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32282694

RESUMEN

BACKGROUND: H19, a well-known long non-coding RNA, is involved in carcinogenesis and progression of multiple cancers. Molecular epidemiological research suggests that polymorphisms in H19 are associated with an increased risk of cancer, but the results are inconsistent. Thus, we performed a meta-analysis to estimate the associations between H19 polymorphisms and cancer susceptibility. METHODS: PubMed, Embase, and Web of Science databases were searched. Odds ratios with 95% confidence interval were applied to assess the association between H19 rs2107425, rs217727, rs2839698, rs2735971, rs3024270, and rs3741219 polymorphisms and cancer susceptibility in all 5 models. We also predicted the H19 secondary structure, as well as the generation and abolishment of miRNA binding sites on H19 through the selected SNPs. RESULTS: Eighteen related studies, involving 17,090 patients and 23,532 control samples, were analyzed. The pooled data showed that rs2839698 polymorphism was significantly associated with an increased cancer susceptibility. As for rs217727 and rs3024270 polymorphisms, similarly increased risks were found in specific genetic models and stratified groups. However, significant decreases in cancer risk were observed for rs2107425 and rs2735971 in the total population, as well as in subgroup analyses. In addition, no significant associations were found in all 5 models for rs3741219 polymorphism. Furthermore, RNAfold prediction revealed that the centroid secondary structure was markedly altered in rs217727 and rs2735971. We also identified that rs217727 G>A and rs2839689 G>A alleles could create and destroy miRNA binding sites on H19. CONCLUSION: The results of our meta-analyses suggest that H19 polymorphisms may be associated with the risk of cancer development.


Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias/genética , ARN Largo no Codificante/genética , Humanos , Polimorfismo de Nucleótido Simple
7.
J Biol Regul Homeost Agents ; 34(1): 49-56, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32138500

RESUMEN

Dysregulation of lncRNA cancer susceptibility candidate 2 (CASC2) is involved in the pathogenesis of multiple malignancies. However, the underlying mechanisms by which lncRNA CASC2 regulates the proliferation of hemangiomas (HAs) remain undocumented. Herein, the expression levels of lncRNA CASC2 and VEGF in proliferating or involuting phase HAs were assessed by qRT-PCR analysis, and the effects of lncRNA CASC2 on HAs cell growth were evaluated by MTT, colony formation assays and Western blot analysis. lncRNA CASC2 specific binding with miR-18a-5p was confirmed by luciferase report assay. Consequently, we found that the expression of lncRNA CASC2 was reduced in proliferating phase HAs as compared with the involuting phase HAs or normal tissues, and possessed a negative correlation with VEGF expression in proliferating phase HAs. Restored expression of lncRNA CASC2 repressed cell viability and colony formation and downregulated VEGF expression, while silencing lncRNA CASC2 showed the opposite effects. Moreover, lncRNA CASC2 was confirmed to bind with miR-18a-5p, which could reverse lncRNA CASC2-induced anti-proliferative effects by targeting FBXL3 in HAs cells. Altogether, our findings demonstrated that lncRNA CASC2 suppressed the growth of HAs cells by regulating miR-18a-5p/FBXL3 axis.


Asunto(s)
Proteínas F-Box/genética , Hemangioma/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Proteínas Supresoras de Tumor/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Hemangioma/patología , Humanos , Factor A de Crecimiento Endotelial Vascular
8.
Cell Prolif ; 53(4): e12750, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32130753

RESUMEN

OBJECTIVES: LOC100133669 is a lncRNA whose function during tumorigenesis remains unclear now. Thus, we aimed to explore its clinical significance and function in oesophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: ISH was used to detect LOC100133669 expression in ESCC tissues. The full-length LOC100133669 was identified by using RACE assay. Subcellular distribution of LOC100133669 was examined by nuclear/cytoplasmic RNA fractionation and qPCR. The role of LOC100133669 in ESCC cell growth was determined by colony formation, MTT and flow cytometry experiments in vitro, as well as xenograft tumour experiment in vivo. RNA pull-down assay was performed to find LOC100133669-interacted protein, which was further examined by RIP, IP, Western blot and rescue experiments. RESULTS: LOC100133669 was upregulated in ESCC tissues compared with adjacent non-tumour tissues. High LOC100133669 expression was associated with poor prognosis of patients with ESCC. We defined LOC100133669 to be 831 nt in length and mainly localized in the cytoplasm of ESCC cells. Knockdown of LOC100133669 inhibited ESCC cell proliferation and cell cycle progression, while overexpression of LOC100133669 showed the opposite effects. Furthermore, LOC100133669 could bind to Tim50 and upregulated its protein level through inhibiting ubiquitination. Overexpression of Tim50 in part abolished the LOC100133669 depletion-caused inhibitory effect on ESCC cell proliferation. CONCLUSIONS: LOC100133669 plays an oncogenic role in ESCC and may serve as a promising diagnostic marker and therapeutic target for ESCC patients.


Asunto(s)
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , ARN Largo no Codificante/genética , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/diagnóstico , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Pronóstico , ARN Largo no Codificante/análisis , Regulación hacia Arriba
9.
Life Sci ; 250: 117559, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32198051

RESUMEN

Cardiovascular diseases (CVD) remain one of the leading causes of mortality worldwide, especially in developing countries. It is widely known that severe inflammation can lead to atherosclerosis, which can cause various downstream pathologies, including myocardial injury and viral myocarditis. To date, several strategies have been proposed to prevent and cure CVD. The use of targeting macrophages has emerged as one of the most effective therapeutic approaches. Macrophages play a crucial role in eliminating senescent and dead cells while maintaining myocardial electrical activity and repairing myocardial injury. They also contribute to tissue repair and remodeling and plaque stabilization. Targeting macrophage pathways can, therefore, be advantageous in CVD care since it can lead to decreased aggregation of mononuclear cells at the injured site in the heart. Furthermore, it inhibits the development of pro-inflammatory factors, facilitates cholesterol outflow, and reduces the lipid concentration. More in-depth studies are still needed to formulate a comprehensive classification of phenotypes for different macrophages and determine their roles in the pathogenesis of CVD. In this review, we summarize the recent advances in the understanding of the role of macrophages in the prevention and cure of CVD.


Asunto(s)
Aterosclerosis/fisiopatología , Enfermedades Cardiovasculares/fisiopatología , Macrófagos/fisiología , Animales , Colesterol/metabolismo , Endocitosis , Corazón , Humanos , Inflamación/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/citología , Espectrometría de Masas , MicroARNs/genética , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Fenotipo , ARN Largo no Codificante/genética , Análisis de Secuencia de ARN
10.
BMC Med Genet ; 21(1): 56, 2020 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-32188434

RESUMEN

BACKGROUND: The prognosis of the glioblastoma (GBM) is dismal. This study aims to select an optimal RNA signature for prognostic prediction of GBM patients. METHODS: For the training set, the long non-coding RNA (lncRNA) and mRNA expression profiles of 151 patients were downloaded from the TCGA. Differentially expressed mRNAs (DEGs) and lncRNAs (DE-lncRNAs) were identified between good prognosis and bad prognosis patients. Optimal prognostic mRNAs and lncRNAs were selected respectively, by using univariate Cox proportional-hazards (PH) regression model and LASSO Cox-PH model. Subsequently, four prognostic scoring models were built based on expression levels or expression status of the selected prognostic lncRNAs or mRNAs, separately. Each prognostic model was applied to the training set and an independent validation set. Function analysis was used to uncover the biological roles of these prognostic DEGs between different risk groups classified by the mRNA-based signature. RESULTS: We obtained 261 DEGs and 33 DE-lncRNAs between good prognosis and bad prognosis patients. A panel of eight mRNAs and a combination of ten lncRNAs were determined as predictive RNAs by LASSO Cox-PH model. Among the four prognostic scoring models using the eight-mRNA signature or the ten-lncRNA signature, the one based on the expression levels of the eight mRNAs showed the greatest predictive power. The DEGs between different risk groups using the eight prognostic mRNAs were functionally involved in calcium signaling pathway, neuroactive ligand-receptor interaction pathway, and Wnt signaling pathway. CONCLUSION: The eight-mRNA signature has greater prognostic value than the ten-lncRNA-based signature for GBM patients based on bioinformatics analysis.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , ARN Largo no Codificante/genética , ARN Mensajero/genética , Transcriptoma , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Glioblastoma/genética , Glioblastoma/mortalidad , Humanos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Tasa de Supervivencia
11.
Wiad Lek ; 73(1): 12-16, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32124799

RESUMEN

OBJECTIVE: The aim: to study the association between rs1899663-polymorphic variant of HOTAIR gene and clear cell renal cell carcinoma (CCRCC) development in Ukrainian population. PATIENTS AND METHODS: Materials and methods: whole venous blood from 101 Ukrainians with CCRCC (42 females and 59 males) and 100 control subjects (34 females and 66 males) were enrolled in the study. DNA extraction was performed using GeneJET Whole Blood Genomic DNA Purification Mini Kit (Thermo Fisher Scientific, USA). Polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) was used for HOTAIR rs1899663 genotyping. The Statistical Package for Social Science software (SPSS, version 17.0, Chicago, IL, USA) was used for all calculations. RESULTS: Results: It was found the lack of association between HOTAIR rs1899663 single nucleotide polymorphism and CCRCC emergence as well as tumor metastasis property in dominant, recessive, over-dominant and additive crude models of inheritance, as well after the adjustment for age, sex, smoking and excessive alcohol consumption (P > 0.05). CONCLUSION: Conclusions: No association was found between HOTAIR rs1899663-polymorphic variant and CCRCC development in Ukrainian population. Further studies with extended samples are required to validate these results.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino
12.
Adv Clin Chem ; 95: 105-147, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32122521

RESUMEN

Long noncoding RNAs (lncRNAs) have recently gained considerable attention as key players in biological regulation; however, the mechanisms by which lncRNAs govern various disease processes remain mysterious and are just beginning to be understood. The ease of next-generation sequencing technologies has led to an explosion of genomic information, especially for the lncRNA class of noncoding RNAs. LncRNAs exhibit the characteristics of mRNAs, such as polyadenylation, 5' methyl capping, RNA polymerase II-dependent transcription, and splicing. These transcripts comprise more than 200 nucleotides (nt) and are not translated into proteins. Directed interrogation of annotated lncRNAs from RNA-Seq datasets has revealed dramatic differences in their expression, largely driven by alterations in transcription, the cell cycle, and RNA metabolism. The fact that lncRNAs are expressed cell- and tissue-specifically makes them excellent biomarkers for ongoing biological events. Notably, lncRNAs are differentially expressed in several cancers and show a distinct association with clinical outcomes. Novel methods and strategies are being developed to study lncRNA function and will provide researchers with the tools and opportunities to develop lncRNA-based therapeutics for cancer.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , ARN Largo no Codificante/antagonistas & inhibidores , Animales , Humanos , Neoplasias/genética , Neoplasias/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo
14.
Gene ; 743: 144606, 2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32199948

RESUMEN

DNA demethylation and suppression of de novo DNA methylation are activities that maintain an unmethylated state. However, the strength of these two activities at the same locus has not been estimated separately. Furthermore, the association between these two activities and the unmethylated state remains unclear. Octamer-binding transcription factor-binding sequences (OBSs) and CCCTC-binding factor-binding sequences (CBSs) within the mouse H19-imprinted control region (ICR) are involved in the induction of DNA demethylation and maintenance of the unmethylated state in mouse undifferentiated embryonic cell lines. To reveal the association between the two cis-elements and the two unmethylated state maintenance activities in maintaining the unmethylated state of the ICR, we evaluated the altered DNA methylation levels at sites that were initially methylated or unmethylated using a stable transfection-based assay, and estimated the strength of the two unmethylated state maintenance activities separately via a Poisson process model that described the DNA methylation state regulatory process. Although DNA demethylation depending on OBSs affected almost the entire ICR, DNA demethylation depending on CBSs occurred near CBSs, resulting in redundant demethylation of CBS regions. Detailed analysis of the CBS4 region suggested that OBSs were required to induce unmethylated state maintenance activities, and that CBSs-dependent activities contributed, but diminished, during incubation when protection of the CBS4 region by OBSs-dependent activities was absent. Analysis via the Poisson process model indicated that the unmethylated state at the CBS4 region was maintained by OBSs-dependent suppression of de novo DNA methylation rather than DNA demethylation. We propose that the hierarchical regulation of redundant protection of the CBS region via cooperation between the two unmethylated state maintenance activities is a potential function of the ICR that effectively maintains allele-specific methylation status in the same DNA sequence.


Asunto(s)
Desmetilación del ADN , Metilación de ADN/genética , Impresión Genómica , Región de Control de Posición/genética , Animales , Factor de Unión a CCCTC/metabolismo , Línea Celular Tumoral , Ratones , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , ARN Largo no Codificante/genética
15.
Gene ; 739: 144518, 2020 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-32119915

RESUMEN

Glioblastomas (GBMs) are primary brain tumors with extremely bad prognosis and therefore; discovery of novel regulators of their pathology is of immense importance. LncRNAs (long noncoding RNAs) regulate nuclear structure, embryonic pluripotency, cell differentiation, development and carcinogenesis. Many lncRNAs have weak evolutionary conservation; however, a nuclear lncRNA, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), is exceptionally conserved and is among the most abundant lncRNAs in benign tissues. The majority of cell culture studies and clinico-epidemiological studies demonstrated that MALAT1 acts a tumor promoter in GBMs and inhibition of MALAT1 suppressed tumor growth in various preclinical models of GBM. MALAT1 involves in stemness of GBM cells by regulating SOX2, nestin and members of WNT pathway. MALAT1 induces protective autophagy and suppresses apoptosis in GBM cells via sponging miRNA-101 and increases temozolomide chemoresistance via enhancing epithelial-mesenchymal transition, suppressing miR-203 and promoting thymidilate synthase. Moreover, knockdown of MALAT1 expression enhances blood-brain tumor barrier permeability via miR-140, which may provide a double benefit of MALAT1 suppression by increasing the delivery of chemotherapy agents into the GBM tissues. On the other hand, there also exist some cell culture and animal studies showing that MALAT1 acts as a tumor suppressor in GBMs by suppression of ERK/MAPK and MMP2 signaling and by repression of miR-155 with subsequent increase of FBXW7. Whether protective or detrimental, MALAT1 seems to be an important component of GBM pathogenesis and hence; novels studies are needed in versatile models, including many different primary GBM cultures, orthotopic and xenogreft in vivo models and transgenic mice.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Glioblastoma/diagnóstico , Glioblastoma/terapia , Humanos , MicroARNs/metabolismo , Nestina/genética , Nestina/metabolismo , Pronóstico , ARN Largo no Codificante/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Vía de Señalización Wnt/genética
16.
Medicine (Baltimore) ; 99(13): e19606, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32221083

RESUMEN

Intrahepatic cholangiocarcinoma (ICC) is an aggressive biliary epithelial tumor with poor prognosis. There are increasing evidences that long non-coding RNAs (lncRNAs) are dysregulated in multifarious tumors, revealing potential significant role of lncRNAs in tumorigenesis.We used the ICC dataset retrieved from The Cancer Genome Atlas and the Gene Expression Omnibus database to obtain the lncRNAs expression profiles and identify potential prognostic lncRNAs for predicting the prognosis in ICC. Univariate and multivariate Cox regression analyses were performed to construct a prognostic index (PI). Furthermore, coexpression analysis and functional assessment were performed to initially investigate the function of these prognostic lncRNAs.A total of 255 differentially expressed lncRNAs (DElncRNAs) were identified among two RNA sequencing dataset of a total 63 ICC patients with 98 samples using R platform. Thirteen of 255 DElncRNAs were identified as prognostic lncRNAs and used for a PI. Patients with high PI were associated with poor prognostic (P = .0064), and the Cox regression showed consistent result (P = .042). The time-dependent receiver operating characteristic analysis showed the PI performed well in ICC survival prediction with an area under curve of 0.921, 0.801, and 0.717 for 1-, 3-, and 5-year survival, respectively.In conclusion, we included 13 identified prognostic DElncRNAs and constructed a prognostic signature/PI. ICC patient with higher PI was associated with poorer prognosis. However, the clinical role as well as biological functions of constructed PI and these prognostic DElncRNAs need to be verified in future study.


Asunto(s)
Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genética , Anciano , Biomarcadores de Tumor , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC
17.
Nat Struct Mol Biol ; 27(3): 297-304, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32157249

RESUMEN

Understanding the targeting and spreading patterns of long non-coding RNAs (lncRNAs) on chromatin requires a technique that can detect both high-intensity binding sites and reveal genome-wide changes in spreading patterns with high precision and confidence. Here we determine lncRNA localization using biotinylated locked nucleic acid (LNA)-containing oligonucleotides with toehold architecture capable of hybridizing to target RNA through strand-exchange reaction. During hybridization, a protecting strand competitively displaces contaminating species, leading to highly specific RNA capture of individual RNAs. Analysis of Drosophila roX2 lncRNA using this approach revealed that heat shock, unlike the unfolded protein response, leads to reduced spreading of roX2 on the X chromosome, but surprisingly also to relocalization to sites on autosomes. Our results demonstrate that this improved hybridization capture approach can reveal previously uncharacterized changes in the targeting and spreading of lncRNAs on chromatin.


Asunto(s)
Cromatina/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Oligonucleótidos/química , ARN Largo no Codificante/química , Proteínas de Unión al ARN/genética , Cromosoma X/química , Animales , Emparejamiento Base , Sitios de Unión , Biotinilación , Cromatina/metabolismo , Mapeo Cromosómico , Cromosomas de Insectos/química , Cromosomas de Insectos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Respuesta al Choque Térmico , Nanotecnología/métodos , Hibridación de Ácido Nucleico , Oligonucleótidos/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismo , Cromosoma X/metabolismo
18.
DNA Cell Biol ; 39(4): 724-732, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32213078

RESUMEN

Long noncoding RNA growth-arrest-specific transcript 5 (GAS5) has been proved to play a crucial role in cancer chemoresistance. However, the function of GAS5 and its underlying molecular mechanism in hepatocellular carcinoma (HCC) chemoresistance remain unknown. In this study, we aimed to investigate its function and underlying molecular mechanism in HCC cisplatin (CDDP) resistance. The results demonstrated that GAS5 was significantly downregulated in HCC tissues and cells, especially in CDDP-resistant HCC tissues and cells. Low GAS5 expression was tightly correlated with shorter survival in patients with HCC. Functionally, GAS5 overexpression sensitized CDDP-resistant HepG2/CDDP and Huh7/CDDP cells to CDDP. Mechanically, GAS5 improved the sensitivity of HCC cells to CDDP through sponging miR-222. Taken together, these observations suggested that overexpression of GAS5 overcame CDDP resistance of HCC cells by regulating miR-222, providing a potential therapeutic target for overcoming the chemoresistance of HCC cells.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/genética , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico
19.
Mol Genet Genomics ; 295(3): 741-749, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32125527

RESUMEN

Psoriasis is a common chronic autoimmune inflammatory skin disease that involves genetic and environmental factors. To date, psoriasis is still incurable. Thus, detection of its underlying molecular mechanisms is urgent. Weighted gene co-expression network analysis (WGCNA) was performed on the basis of the RNA-Seq data of psoriatic and normal (NN) skin tissues to detect the key mRNAs and long non-coding RNAs (LncRNAs) implicated in psoriasis and to identify psoriasis-related gene modules. Subsequently, 23 independent modules were obtained, and the pink module that contained differentially expressed 212 mRNAs and 100 LncRNAs was the most remarkable. Differentially expressed genes (DEGs) between psoriasis and healthy control in other RNA-Seq and microarray datasets were integrated to identify convinced psoriasis-associated genes. A total of 312 genes in the pink module and 613 DEGs were scanned. Eleven overlapped key mRNAs were identified, including two known genes (e.g., KRT15 and CCL27) and nine novel ones (e.g., ARSF, CLDN1, DACH1, LONRF1, PAMR1, RORC, SLC26A2, STS, UNC93A). A total of 11 key mRNAs were selected to construct a co-expression network to investigate potential candidate LncRNAs. Seventy-six pairs of LncRNA-mRNA co-expression relationships were found. To validate the findings, CCL27 and LncRNA-AL162231.4 expressions were detected in psoriatic and NN skin tissues. Result of RT-qPCR showed that CCL27 and LncRNA-AL162231.4 decreased in psoriatic lesions with statistical significance (P ≤ 0.05). Our study provides a new direction for elucidating the pathogenesis of psoriasis, but further experiments are still required.


Asunto(s)
Biomarcadores/análisis , Biología Computacional/métodos , Redes Reguladoras de Genes , Psoriasis/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Humanos
20.
J Cancer Res Clin Oncol ; 146(4): 883-896, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32124023

RESUMEN

PURPOSE: The role of non-coding RNA, once thought to be dark matter, is increasingly prominent in cancer. Our article explores the effect of non-coding RNA in lung adenocarcinoma and lung squamous cell carcinoma by mining TCGA public database. METHODS: Download the data by applying the official TCGA software. The data were analyzed by R data analysis packages, 'edgeR', 'gplots' and 'survival'. We better illustrate the potential networks of lung cancer genes by constructing ceRNAs, using Cytoscape software. RESULTS: We obtained genes which were differentially expressed in lung adenocarcinoma and lung squamous cell carcinoma analysis. Within these differentially expressed genes, we also conducted a survival analysis to find differentially expressed genes associated with prognosis in both lung adenocarcinoma and lung squamous cell carcinoma. Based on genes differentially expressed of both lung adenocarcinoma and lung squamous cell carcinoma, we constructed a ceRNA network to illustrate the mechanism of lung adenocarcinoma and lung squamous cell carcinoma. Our study analyzed genes which were differentially expressed in lung adenocarcinoma and lung squamous cell carcinoma using the TCGA database. CONCLUSION: Based on this, the prognosis in both lung squamous cell carcinoma and lung adenocarcinoma was analyzed. We have also constructed a ceRNA network to provide a basis for the study of ceRNA in lung adenocarcinoma and lung squamous cell carcinoma.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Adenocarcinoma del Pulmón/genética , Carcinoma de Células Escamosas/genética , Minería de Datos , Bases de Datos Genéticas , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Transcriptoma
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