RESUMO

OBJECTIVES: This study was directed towards exploring the impacts of lncRNA HOXA11-AS-mediated microRNA (miR)-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis (OA). METHODS: The articular cartilages were provided by OA patients who received total knee arthroplasty, and Human Chondrocyte (HC)-OA (HCOA) was also attained. The miR-506-3p and HOXA11-AS expressions in articular cartilages from OA patients and HCOA cells were analyzed via qPCR. After gain- and loss-of-function assays in HCOA cells, MTT assay and flow cytometry (FC) were used for assessing cell viability and apoptosis, accordingly. The levels of PIK3CA, AKT, and mTOR as well as AKT and mTOR phosphorylation levels assessed using western blotting (WB). The targeting correlation of HOXA11-AS and miR-506-3p as well as miR-506-3p and PIK3CA was assessed through Dual-Luciferase Reporter gene Assay (DLRA). RESULT: The articular cartilages from OA patients and Human Chondrocyte (HC)-OA (HCOA) cells showed increased HOXA11-AS and decreased miR-506-3p. Mechanistically, HOXA11-AS was capable of binding to miR-506-3p to increase PIK3CA, the target gene of miR-506-3p. miR-506-3p suppression facilitated HCOA cell proliferation and reduced their apoptosis, which was nullified by further silencing HOXA11-AS or silencing PIK3CA. The down-regulation of HOXA11-AS disrupted the PI3K/AKT/mTOR pathway, which was counteracted by further miR-506-3p inhibition. CONCLUSION: The silencing of HOXA11-AS might block the PI3K/AKT/mTOR pathway through miR-506-3p up-regulation, thereby restricting HCOA cell proliferation and provoking apoptosis.

Assuntos

Apoptose , Proliferação de Células , Condrócitos , Regulação para Baixo , MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Condrócitos/metabolismo , Apoptose/genética , Proliferação de Células/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cartilagem Articular/metabolismo , Pessoa de Meia-Idade , Masculino , Feminino , Células Cultivadas

RESUMO

Hepatoblastoma stands as the most prevalent liver cancer in the pediatric population. Characterized by a low mutational burden, chromosomal and epigenetic alterations are key drivers of its tumorigenesis. Transcriptome analysis is a powerful tool for unraveling the molecular intricacies of hepatoblastoma, shedding light on the effects of genetic and epigenetic changes on gene expression. In this study conducted in Brazilian patients, an in-depth whole transcriptome analysis was performed on 14 primary hepatoblastomas, compared to control liver tissues. The analysis unveiled 1,492 differentially expressed genes (1,031 upregulated and 461 downregulated), including 920 protein-coding genes (62%). Upregulated biological processes were linked to cell differentiation, signaling, morphogenesis, and development, involving known hepatoblastoma-associated genes (DLK1, MEG3, HDAC2, TET1, HMGA2, DKK1, DKK4), alongside with novel findings (GYNG4, CDH3, and TNFRSF19). Downregulated processes predominantly centered around oxidation and metabolism, affecting amines, nicotinamides, and lipids, featuring novel discoveries like the repression of SYT7, TTC36, THRSP, CCND1, GCK and CAMK2B. Two genes, which displayed a concordant pattern of DNA methylation alteration in their promoter regions and dysregulation in the transcriptome, were further validated by RT-qPCR: the upregulated TNFRSF19, a key gene in the embryonic development, and the repressed THRSP, connected to lipid metabolism. Furthermore, based on protein-protein interaction analysis, we identified genes holding central positions in the network, such as HDAC2, CCND1, GCK, and CAMK2B, among others, that emerged as prime candidates warranting functional validation in future studies. Notably, a significant dysregulation of non-coding RNAs (ncRNAs), predominantly upregulated transcripts, was observed, with 42% of the top 50 highly expressed genes being ncRNAs. An integrative miRNA-mRNA analysis revealed crucial biological processes associated with metabolism, oxidation reactions of lipids and carbohydrates, and methylation-dependent chromatin silencing. In particular, four upregulated miRNAs (miR-186, miR-214, miR-377, and miR-494) played a pivotal role in the network, potentially targeting multiple protein-coding transcripts, including CCND1 and CAMK2B. In summary, our transcriptome analysis highlighted disrupted embryonic development as well as metabolic pathways, particularly those involving lipids, emphasizing the emerging role of ncRNAs as epigenetic regulators in hepatoblastomas. These findings provide insights into the complexity of the hepatoblastoma transcriptome and identify potential targets for future therapeutic interventions.

RESUMO

Gastric cancer is the fifth most common malignancy worldwide having the fourth highest mortality rate. Energy metabolism is key and closely linked to tumour development. Most important in the reprogramming of cancer metabolism is the Warburg effect, which suggests that tumour cells will utilise glycolysis even with normal oxygen levels. Various molecules exert their effects by acting on enzymes in the glycolytic pathway, integral to glycolysis. Second, mitochondrial abnormalities in the reprogramming of energy metabolism, with consequences for glutamine metabolism, the tricarboxylic acid cycle and oxidative phosphorylation, abnormal fatty acid oxidation and plasma lipoprotein metabolism are important components of tumour metabolism. Third, inflammation-induced oxidative stress is a danger signal for cancer. Fourth, patterns of signalling pathways involve all aspects of metabolic transduction, and many clinical drugs exert their anticancer effects through energy metabolic signalling. This review summarises research on energy metabolism genes, enzymes and proteins and transduction pathways associated with gastric cancer, and discusses the mechanisms affecting their effects on postoperative treatment resistance and prognoses of gastric cancer. We believe that an in-depth understanding of energy metabolism reprogramming will aid the diagnosis and subsequent treatment of gastric cancer.

Assuntos

Neoplasias , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Metabolismo Energético/fisiologia , Neoplasias/patologia , Glicólise/genética , Ciclo do Ácido Cítrico , Fosforilação Oxidativa

RESUMO

Abstract Objectives This study was directed towards exploring the impacts of lncRNA HOXA11-AS-mediated microRNA (miR)-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis (OA). Methods The articular cartilages were provided by OA patients who received total knee arthroplasty, and Human Chondrocyte (HC)-OA (HC-OA) was also attained. The miR-506-3p and HOXA11-AS expressions in articular cartilages from OA patients and HC-OA cells were analyzed via qPCR. After gain- and loss-of-function assays in HC-OA cells, MTT assay and flow cytometry (FC) were used for assessing cell viability and apoptosis, accordingly. The levels of PIK3CA, AKT, and mTOR as well as AKT and mTOR phosphorylation levels assessed using western blotting (WB). The targeting correlation of HOXA11-AS and miR-506-3p as well as miR-506-3p and PIK3CA was assessed through Dual-Luciferase Reporter gene Assay (DLRA). Result The articular cartilages from OA patients and Human Chondrocyte (HC)-OA (HC-OA) cells showed increased HOXA11-AS and decreased miR-506-3p. Mechanistically, HOXA11-AS was capable of binding to miR-506-3p to increase PIK3CA, the target gene of miR-506-3p. miR-506-3p suppression facilitated HC-OA cell proliferation and reduced their apoptosis, which was nullified by further silencing HOXA11-AS or silencing PIK3CA. The down-regulation of HOXA11-AS disrupted the PI3K/AKT/mTOR pathway, which was counteracted by further miR-506-3p inhibition. Conclusion The silencing of HOXA11-AS might block the PI3K/AKT/mTOR pathway through miR-506-3p up-regulation, thereby restricting HC-OA cell proliferation and provoking apoptosis.

RESUMO

The long noncoding RNA (lncRNA) AUXIN-REGULATED PROMOTER LOOP (APOLO) recognizes a subset of target loci across the Arabidopsis thaliana genome by forming RNA-DNA hybrids (R-loops) and modulating local three-dimensional chromatin conformation. Here, we show that APOLO regulates shade avoidance syndrome by dynamically modulating expression of key factors. In response to far-red (FR) light, expression of APOLO anti-correlates with that of its target BRANCHED1 (BRC1), a master regulator of shoot branching in Arabidopsis thaliana. APOLO deregulation results in BRC1 transcriptional repression and an increase in the number of branches. Accumulation of APOLO transcription fine-tunes the formation of a repressive chromatin loop encompassing the BRC1 promoter, which normally occurs only in leaves and in a late response to far-red light treatment in axillary buds. In addition, our data reveal that APOLO participates in leaf hyponasty, in agreement with its previously reported role in the control of auxin homeostasis through direct modulation of auxin synthesis gene YUCCA2, and auxin efflux genes PID and WAG2. We show that direct application of APOLO RNA to leaves results in a rapid increase in auxin signaling that is associated with changes in the plant response to far-red light. Collectively, our data support the view that lncRNAs coordinate shade avoidance syndrome in A. thaliana, and reveal their potential as exogenous bioactive molecules. Deploying exogenous RNAs that modulate plant-environment interactions may therefore become a new tool for sustainable agriculture.

Assuntos

Proteínas de Arabidopsis , Arabidopsis , RNA Longo não Codificante , Arabidopsis/genética , Arabidopsis/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Arabidopsis/metabolismo , Ácidos Indolacéticos/metabolismo , Epigênese Genética , Cromatina/metabolismo , Regulação da Expressão Gênica de Plantas , Luz , Fatores de Transcrição/metabolismo

RESUMO

Tapping panel dryness (TPD) results in a severe reduction in latex yield in Hevea brasiliensis. However, the molecular regulatory mechanisms of TPD occurrence are still largely unclear. In this study, whole-transcriptome sequencing was carried out on latex from TPD and healthy trees. In total, 7078 long noncoding RNAs (lncRNAs), 3077 circular RNAs (circRNAs), 4956 miRNAs, and 25041 mRNAs were identified in latex, among which 435 lncRNAs, 68 circRNAs, 320 miRNAs, and 1574 mRNAs were differentially expressed in the latex of TPD trees. GO and KEGG analyses indicated that plant hormone signal transduction, MAPK signaling pathway, and ubiquitin-mediated proteolysis were the key pathways associated with TPD onset. Phytohormone profiling revealed significant changes in the contents of 28 hormonal compounds, among which ACC, ABA, IAA, GA, and JA contents were increased, while SA content was reduced in TPD latex, suggesting that hormone homeostasis is disrupted in TPD trees. Furthermore, we constructed a TPD-related competitive endogenous RNA (ceRNA) regulatory network of lncRNA/circRNA-miRNA-mRNA with 561 edges and 434 nodes (188 lncRNAs, 5 circRNAs, 191 miRNAs, and 50 mRNAs) and identified two hub lncRNAs (MSTRG.11908.1 and MSTRG.8791.1) and four hub miRNAs (hbr-miR156, miR156-x, miRf10477-y, and novel-m0452-3p). Notably, the lncRNA-miR156/157-SPL module containing three hubs probably plays a crucial role in TPD onset. The expression of network hubs and the lncRNA-miR156/157-SPL module were further validated by qRT-PCR. Our results reveal the TPD-associated ceRNA regulatory network of lncRNA/circRNA-miRNA-mRNA in latex and lay a foundation for further investigation of molecular regulatory mechanisms for TPD onset in H. brasiliensis.

Assuntos

Hevea , MicroRNAs , RNA Longo não Codificante , Látex , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Hevea/genética , Hevea/metabolismo , RNA Longo não Codificante/genética , Reguladores de Crescimento de Plantas/metabolismo , Redes Reguladoras de Genes

RESUMO

Background: Diabetes mellitus is characterized by chronic hyperglycemia with loss of ß-cell function and mass. An attractive therapeutic approach to treat patients with diabetes in a non-invasive way is to harness the innate regenerative potential of the pancreas. The Islet Neogenesis-Associated Protein pentadecapeptide (INGAP-PP) has been shown to induce ß-cell regeneration and improve their function in rodents. To investigate its possible mechanism of action, we report here the global transcriptional effects induced by the short-term INGAP-PP in vitro treatment of adult rat pancreatic islets. Methods and findings: Rat pancreatic islets were cultured in vitro in the presence of INGAP-PP for 4 days, and RNA-seq was generated from triplicate treated and control islet samples. We performed a de novo rat gene annotation based on the alignment of RNA-seq reads. The list of INGAP-PP-regulated genes was integrated with epigenomic data. Using the new gene annotation generated in this work, we quantified RNA-seq data profiled in INS-1 cells treated with IL1ß, IL1ß+Calcipotriol (a vitamin D agonist) or vehicle, and single-cell RNA-seq data profiled in rat pancreatic islets. We found 1,669 differentially expressed genes by INGAP-PP treatment, including dozens of previously unannotated rat transcripts. Genes differentially expressed by the INGAP-PP treatment included a subset of upregulated transcripts that are associated with vitamin D receptor activation. Supported by epigenomic and single-cell RNA-seq data, we identified 9 previously unannotated long noncoding RNAs (lncRNAs) upregulated by INGAP-PP, some of which are also differentially regulated by IL1ß and vitamin D in ß-cells. These include Ri-lnc1, which is enriched in mature ß-cells. Conclusions: Our results reveal the transcriptional program that could explain the enhancement of INGAP-PP-mediated physiological effects on ß-cell mass and function. We identified novel lncRNAs that are induced by INGAP-PP in rat islets, some of which are selectively expressed in pancreatic ß-cells and downregulated by IL1ß treatment of INS-1 cells. Our results suggest a relevant function for Ri-lnc1 in ß-cells. These findings are expected to provide the basis for a deeper understanding of islet translational results from rodents to humans, with the ultimate goal of designing new therapies for people with diabetes.

Assuntos

Diabetes Mellitus , Ilhotas Pancreáticas , RNA Longo não Codificante , Ratos , Humanos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Associadas a Pancreatite/genética , Proteínas Associadas a Pancreatite/metabolismo , Proteínas Associadas a Pancreatite/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Peptídeos/metabolismo , Diabetes Mellitus/metabolismo , Vitamina D/metabolismo

RESUMO

Gastric cancer (GC) remains among the most common cancers worldwide with a high mortality-to-incidence ratio. Accumulated evidence suggests that long noncoding RNAs (lncRNAs) are involved in gastric carcinogenesis. These transcripts are longer than 200 nucleotides and modulate gene expression at multiple molecular levels, inducing or inhibiting biological processes and diseases. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the best-studied lncRNAs with comprehensive actions contributing to cancer progression. This lncRNA regulates gene expression at the transcriptional and posttranscriptional levels through interactions with microRNAs and proteins. In the present review, we discussed the molecular mechanism of MALAT1 and summarized the current knowledge of its expression in GC. Moreover, we highlighted the potential use of MALAT1 as a biomarker, including liquid biopsy.

RESUMO

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive form of cancer unresponsive to androgen deprivation therapy (ADT) that spreads quickly to other organs. Despite reduced androgen levels after ADT, mCRPC development and lethality continues to be conducted by the androgen receptor (AR) axis. The maintenance of AR signaling in mCRPC is a result of AR alterations, androgen intratumoral production, and the action of regulatory elements, such as noncoding RNAs (ncRNAs). ncRNAs are key elements in cancer signaling, acting in tumor growth, metabolic reprogramming, and tumor progression. In prostate cancer (PCa), the ncRNAs have been reported to be associated with AR expression, PCa proliferation, and castration resistance. In this study, we aimed to reconstruct the lncRNA-centered regulatory network of mCRPC and identify the lncRNAs which act as master regulators (MRs). METHODS: We used publicly available RNA-sequencing to infer the regulatory network of lncRNAs in mCRPC. Five gene signatures were employed to conduct the master regulator analysis. Inferred MRs were then subjected to functional enrichment and symbolic regression modeling. The latter approach was applied to identify the lncRNAs with greater predictive capacity and potential as a biomarker in mCRPC. RESULTS: We identified 31 lncRNAs involved in cellular proliferation, tumor metabolism, and invasion-metastasis cascade. SNHG18 and HELLPAR were the highlights of our results. SNHG18 was downregulated in mCRPC and enriched to metastasis signatures. It accurately distinguished both mCRPC and primary CRPC from normal tissue and was associated with epithelial-mesenchymal transition (EMT) and cell-matrix adhesion pathways. HELLPAR consistently distinguished mCRPC from primary CRPC and normal tissue using only its expression. CONCLUSION: Our results contribute to understanding the regulatory behavior of lncRNAs in mCRPC and indicate SNHG18 and HELLPAR as master regulators and potential new diagnostic targets in this tumor.

Assuntos

Neoplasias de Próstata Resistentes à Castração , RNA Longo não Codificante , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Longo não Codificante/genética , Androgênios , Antagonistas de Androgênios , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Regulação Neoplásica da Expressão Gênica

RESUMO

Increasingly advanced biology technique has revealed that long non-coding RNAs (lncRNA) as critical factors that exert significant regulatory effects on biological functions by modulating gene transcription, epigenetic modifications and protein translation. A newly emerging lncRNA, ladybird homeobox 2 (LBX2)-antisense RNA 1 (LBX2-AS1), was found to be highly expressed in various tumors. Moreover, it is functionally linked to the regulation of essential tumor-related biological processes, such as cell proliferation and apoptosis, through interactions with multiple signaling molecules/pathways. The important roles played by LBX2-AS1 in cancer initiation and progression suggest that this lncRNA has enormous clinical potential for use as a novel biomarker or therapeutic target. In this article, we retrospectively review the latest advances in research exploring the roles of the lncRNA LBX2-AS1 in oncology field, highlighting its involvement in a comprehensive network of molecular mechanisms underlying diverse cancers and examining its potential applications in clinical practice.

Assuntos

Neoplasias , RNA Longo não Codificante , Humanos , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Estudos Retrospectivos , RNA Longo não Codificante/genética , Transdução de Sinais

RESUMO

Ancistrus presents a wide karyotypic diversity, resulting from numeric and structural chromosomal rearrangements. It has been proposed that some genome-specific regions containing repetitive units could organize prone-to-break DNA sites in Loricariidae, triggering chromosomal rearrangements such as Robertsonian fusions (Rb fusions), centric fissions, translocations, and inversions. The tandemly repeats of the small nuclear RNAs (snRNAs) gene families are considered good cytogenetic markers for understanding chromosomal remodeling events among closely related species, but these snRNAs have been scarcely analyzed in Ancistrus. This study presented the nucleotide sequencing and comparative in situ location of U snRNA sequences from Ancistrus aguaboensis, Ancistrus cf. multispinis, and Ancistrus sp. (2n = 50, 52, and 50, respectively), aiming to provide information about snRNA clusters in the genome and chromosome evolution in Ancistrus. U snRNA nucleotide sequences of Ancistrus presented identity to orthologous copies and folded their secondary structures correctly. In situ localization and karyotyping of the three Ancistrus species revealed clustered copies of U2 and U5 snRNA gene families to a single chromosome site, one chromosome pair bearing U1 snRNA sequence, and one main locus of U4 snRNA sequence, besides scattered signals along the chromosomes. Previous studies related the participation of the rRNA gene families in centric fusion events, contributing to chromosome rearrangements and karyotype plasticity present in Loricariidae. In this study, homeologies in U snRNA loci chromosomal locations were detected, indicating the occurrence of conserved sites of these gene families in these three Ancistrus species with 2n = 50 or 52 chromosomes.

Assuntos

Peixes-Gato , Animais , Peixes-Gato/genética , Peixe-Zebra/genética , Cariótipo , Cariotipagem , RNA Nuclear Pequeno/genética , Análise de Sequência , Nucleotídeos

RESUMO

BACKGROUND: RNA-DNA hybrid (R-loop)-associated long noncoding RNAs (lncRNAs), including the Arabidopsis lncRNA AUXIN-REGULATED PROMOTER LOOP (APOLO), are emerging as important regulators of three-dimensional chromatin conformation and gene transcriptional activity. RESULTS: Here, we show that in addition to the PRC1-component LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), APOLO interacts with the methylcytosine-binding protein VARIANT IN METHYLATION 1 (VIM1), a conserved homolog of the mammalian DNA methylation regulator UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1). The APOLO-VIM1-LHP1 complex directly regulates the transcription of the auxin biosynthesis gene YUCCA2 by dynamically determining DNA methylation and H3K27me3 deposition over its promoter during the plant thermomorphogenic response. Strikingly, we demonstrate that the lncRNA UHRF1 Protein Associated Transcript (UPAT), a direct interactor of UHRF1 in humans, can be recognized by VIM1 and LHP1 in plant cells, despite the lack of sequence homology between UPAT and APOLO. In addition, we show that increased levels of APOLO or UPAT hamper VIM1 and LHP1 binding to YUCCA2 promoter and globally alter the Arabidopsis transcriptome in a similar manner. CONCLUSIONS: Collectively, our results uncover a new mechanism in which a plant lncRNA coordinates Polycomb action and DNA methylation through the interaction with VIM1, and indicates that evolutionary unrelated lncRNAs with potentially conserved structures may exert similar functions by interacting with homolog partners.

Assuntos

Proteínas de Arabidopsis , Arabidopsis , RNA Longo não Codificante , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , DNA/metabolismo , Metilação de DNA , Histonas/metabolismo , Humanos , Ácidos Indolacéticos/metabolismo , Plantas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo

RESUMO

Thousands of long noncoding RNAs (lncRNAs) are actively transcribed in mammalian genomes. This class of RNAs has important regulatory functions in a broad range of cellular processes and diseases. Numerous lncRNAs have been demonstrated to mediate gene regulation through RNA-based mechanisms. Simultaneously, non-functional lncRNA transcripts derived from the activity of lncRNA loci have been identified, which underpin the notion that a considerable fraction of lncRNA loci exert regulatory functions through mechanisms associated with the production or the activity of lncRNA loci beyond the synthesized transcripts. We particularly distinguish two main RNA-independent components associated with regulatory effects; the act of transcription and the activity of DNA regulatory elements. We describe the experimental approaches to distinguish and understand the functional mechanisms derived from lncRNA loci. These scenarios reveal emerging mechanisms important to understanding the lncRNA implications in genome biology.

Assuntos

RNA Longo não Codificante , Animais , Regulação da Expressão Gênica , Genoma , Mamíferos/genética , RNA Longo não Codificante/genética , Sequências Reguladoras de Ácido Nucleico

RESUMO

PURPOSE: Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored. METHODS: We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways. RESULTS: We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation. CONCLUSIONS: Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development.

Assuntos

Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , RNA Longo não Codificante , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno , Neoplasias Pancreáticas

RESUMO

Visceral leishmaniasis (VL) is a vector-borne infectious disease that can be potentially fatal if left untreated. In Brazil, it is caused by Leishmania infantum parasites. Blood transcriptomics allows us to assess the molecular mechanisms involved in the immunopathological processes of several clinical conditions, namely, parasitic diseases. Here, we performed mRNA sequencing of peripheral blood from patients with visceral leishmaniasis during the active phase of the disease and six months after successful treatment, when the patients were considered clinically cured. To strengthen the study, the RNA-seq data analysis included two other non-diseased groups composed of healthy uninfected volunteers and asymptomatic individuals. We identified thousands of differentially expressed genes between VL patients and non-diseased groups. Overall, pathway analysis corroborated the importance of signaling involving interferons, chemokines, Toll-like receptors and the neutrophil response. Cellular deconvolution of gene expression profiles was able to discriminate cellular subtypes, highlighting the contribution of plasma cells and NK cells in the course of the disease. Beyond the biological processes involved in the immunopathology of VL revealed by the expression of protein coding genes (PCGs), we observed a significant participation of long noncoding RNAs (lncRNAs) in our blood transcriptome dataset. Genome-wide analysis of lncRNAs expression in VL has never been performed. lncRNAs have been considered key regulators of disease progression, mainly in cancers; however, their pattern regulation may also help to understand the complexity and heterogeneity of host immune responses elicited by L. infantum infections in humans. Among our findings, we identified lncRNAs such as IL21-AS1, MIR4435-2HG and LINC01501 and coexpressed lncRNA/mRNA pairs such as CA3-AS1/CA1, GASAL1/IFNG and LINC01127/IL1R1-IL1R2. Thus, for the first time, we present an integrated analysis of PCGs and lncRNAs by exploring the lncRNA-mRNA coexpression profile of VL to provide insights into the regulatory gene network involved in the development of this inflammatory and infectious disease.

Assuntos

Leishmania infantum , Leishmaniose Visceral , Leishmaniose , RNA Longo não Codificante , Humanos , Leishmania infantum/genética , Leishmaniose Visceral/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Transcriptoma

RESUMO

SUMMARY OBJECTIVE: A growing volume of literature has suggested long noncoding RNAs (lncRNAs) as important players in tumor progression. In this study, we aimed to investigate the expression and prognostic value of lncRNA LINC00173 (LINC00173) in melanoma. METHODS: LINC00173 expression was measured in 163 paired cancerous and noncancerous specimen samples by real-time polymerase chain reaction. The correlations between LINC00173 expression with clinicopathological characteristics and prognosis were analyzed by chi-square test, log-rank test, and multivariate survival analysis. Receiver-operating characteristic curves were used for the assessment of the diagnostic value of LINC00173 for melanoma patients. RESULTS: The expression level of LINC00173 in melanoma specimens was distinctly higher than that in adjacent non-neoplasm specimens (p<0.01). Besides, LINC00173 was expressed more frequently in patients with advanced melanoma than in patients with early melanoma. Multivariate assays confirmed that LINC00173 expression level was an independent prognostic predictor of melanoma patients (p<0.05). CONCLUSION: Our data indicated that LINC00173 expression could serve as an unfavorable prognostic biomarker for melanoma patients.

Assuntos

Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Melanoma/diagnóstico , Melanoma/genética , Prognóstico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Estimativa de Kaplan-Meier

RESUMO

Introduction: Fatty liver disease, defined by the presence of liver fat infiltration, is part of a cluster of disorders that occur in the context of metabolic syndrome. Epigenetic factors - defined as stable and heritable changes in gene expression without changes in the DNA sequence - may not only play an important role in the disease development in adulthood, but they may start exerting their influence in the prenatal stage.Areas covered: By using systems biology approaches, we review the main epigenetic modifications and highlight their likely roles in the pathogenesis of nonalcoholic fatty liver disease.Expert opinion: Knowledge of the mechanisms by which epigenetic modifications participate in complex disorders would not only help scientists find novel therapeutic strategies but could also aid in implementing preventive care measures at gestation.

Assuntos

Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Adulto , Epigênese Genética , Epigenômica , Humanos , Fígado/patologia , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo

Assuntos

Histonas , Esfingolipídeos , Acetilação , Metilação de DNA , Epigênese Genética , Expressão Gênica , Histonas/metabolismo , Humanos

RESUMO

MicroRNAs (miRNAs) are small noncoding RNAs that are recognized as posttranscriptional regulators of gene expression. These molecules have been shown to play important roles in several cellular processes. MiRNAs act on their target by guiding the RISC complex and binding to the mRNA molecule. Thus, it is recognized that the function of a miRNA is determined by the function of its target (s). By using high-throughput methodologies, novel miRNAs are being identified, but their functions remain uncharted. Target validation is crucial to properly understand the specific role of a miRNA in a cellular pathway. However, molecular techniques for experimental validation of miRNA-target interaction are expensive, time-consuming, laborious, and can be not accurate in inferring true interactions. Thus, accurate miRNA target predictions are helpful to understand the functions of miRNAs. There are several algorithms proposed for target prediction and databases containing miRNA-target information. However, these available computational tools for prediction still generate a large number of false positives and fail to detect a considerable number of true targets, which indicates the necessity of highly confident approaches to identify bona fide miRNA-target interactions. This chapter focuses on tools and strategies used for miRNA target prediction, by providing practical insights and outlooks.

Assuntos

Biologia Computacional , Algoritmos , MicroRNAs/genética , RNA Mensageiro/genética , Pequeno RNA não Traduzido