RESUMEN

Hypopharyngeal carcinoma is one of the malignant tumors of the head and neck with a particularly poor prognosis. Recurrence and metastasis are important reasons for poor prognosis of hypopharyngeal cancer patients, and malignant proliferation, migration, and invasion of tumor cells are important factors for recurrence and metastasis of hypopharyngeal cancer. Therefore, elucidating hypopharyngeal cancer cells' proliferation, migration, and invasion mechanism is essential for improving diagnosis, treatment, and prognosis. Plasmacytoma Variant Translocation 1 (PVT1) is considered a potential diagnostic marker and therapeutic target for tumors. However, it remains unclear whether PVT1 is related to the occurrence and development of hypopharyngeal cancer and its specific mechanism. In this study, the promoting effect of PVT1 on the proliferation, migration, and invasion of hypopharyngeal carcinoma FaDu cells was verified by cell biology experiments and animal studies, and it was found that PVT1 inhibited the expression of TGF-ß, suggesting that PVT1 may regulate the occurrence and development of hypopharyngeal carcinoma FaDu cells through TGF-ß.

Asunto(s)

Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hipofaríngeas , Invasividad Neoplásica , ARN Largo no Codificante , Neoplasias Hipofaríngeas/patología , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/metabolismo , Humanos , ARN Largo no Codificante/genética , Animales , Ratones , Pronóstico , Factor de Crecimiento Transformador beta/metabolismo , Células Tumorales Cultivadas , Apoptosis , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Línea Celular Tumoral , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/genética , Ratones Endogámicos BALB C , Masculino , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética

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Introduction: Pulmonary fibrosis (PF) and tissue remodeling can greatly impair pulmonary function and often lead to fatal outcomes. Methodology: In the present study, we explored a novel molecular interplay of long noncoding (Lnc) RNA CBR3-AS1/ miRNA-29/ FIZZ1 axis in moderating the inflammatory processes, immunological responses, and oxidative stress pathways in bleomycin (BLM)-induced lung fibrosis. Furthermore, we investigated the pharmacological potential of Trimetazidine (TMZ) in ameliorating lung fibrosis. Results: Our results revealed that the BLM-treated group exhibited a significant upregulation in the expression of epigenetic regulators, lncRNA CBR3-AS1 and FIZZ1, compared to the control group (P<0.0001), along with the downregulation of miRNA-29 expression. Furthermore, Correlation analysis showed a significant positive association between lnc CBR3-AS1 and FIZZ1 (R=0.7723, p<0.05) and a significant negative association between miRNA-29 and FIZZ1 (R=-0.7535, p<0.05), suggesting lnc CBR3-AS1 as an epigenetic regulator of FIZZ1 in lung fibrosis. BLM treatment significantly increased the expression of Notch, Jagged1, Smad3, TGFB1, and hydroxyproline. Interestingly, the administration of TMZ demonstrated the ability to attenuate the deterioration effects caused by BLM treatment, as indicated by biochemical and histological analyses. Our investigations revealed that the therapeutic potential of TMZ as an antifibrotic drug could be ascribed to its ability to directly target the epigenetic regulators lncRNA CBR3-AS1/ miRNA-29/ FIZZ1, which in turn resulted in the mitigation of lung fibrosis. Histological and immunohistochemical analyses further validated the potential antifibrotic effects of TMZ by mitigating the structural damage associated with fibrosis. Discussion: Taken together, our study showed for the first time the interplay between epigenetic lncRNAs CBR3-AS1 and miRNA-29 in lung fibrosis and demonstrated that FIZZ1 could be a downregulatory gene for lncRNA CBR3-AS1 and miRNA-29. Our key findings demonstrate that TMZ significantly reduces the expression of fibrotic, oxidative stress, immunomodulatory, and inflammatory markers, along with epigenetic regulators associated with lung fibrosis. This validates its potential as an effective antifibrotic agent by targeting the CBR3-AS1/miRNA-29/FIZZ1 axis.

Asunto(s)

Bleomicina , MicroARNs , Fibrosis Pulmonar , ARN Largo no Codificante , Trimetazidina , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Animales , Ratones , Trimetazidina/farmacología , Masculino , Ratones Endogámicos C57BL

RESUMEN

Aim: This study investigated the role of lncRNA LINC01232 in ferroptosis of colorectal cancer (CRC).Materials & methods: Real time quantitative polymerase chain reaction or western blot experiments were performed to examine relevant mRNAs and proteins expression. The kit assays evaluated malondialdehyde, iron, Fe2+ and glutathione levels. ROS levels were verified by flow cytometry. Chromatin immunoprecipitation and RNA immunoprecipitation analysis monitored the correlation among LINC01232, H3K27ac, p300 and ARNTL2.Results: LINC01232 or ARNTL2 knockdown facilitated erastin-induced ferroptosis. The interaction between LINC01232 and p300 resulted in the enhancement of H3K27ac levels at ARNTL2 promoter to promote ARNTL2 transcriptional activity. ARNTL2 overexpression reversed the promoting effect of LINC01232 knockdown on ferroptosis.Conclusion: LINC01232 inhibited the ferroptosis in CRC by epigenetically upregulating the transcriptional activity of ARNTL2.

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Colorectal cancer (CRC) is a malignant disease of the digestive tract that occurs worldwide, which has high morbidity and mortality but has not effective targeted therapy. Ferroptosis has emerged as a new target for treating CRC since its proposed in 2012. Long noncoding RNAs are noncoding RNAs with a length greater than 200 nucleotides and their role in ferroptosis of cancer cells has attracted more and more attention in recent years. Herein, our study explored the effect of long noncoding RNA LINC01232 on CRC progression. This research exhibited the relationship between LINC01232 and the ferroptosis at the occurrence and development of CRC, which is expected to provide a potential therapeutic target for the treatment of CRC.

Asunto(s)

Factores de Transcripción ARNTL , Neoplasias Colorrectales , Ferroptosis , ARN Largo no Codificante , Activación Transcripcional , Humanos , Ferroptosis/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , ARN Largo no Codificante/genética , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Histonas/metabolismo , Proteína p300 Asociada a E1A/metabolismo , Proteína p300 Asociada a E1A/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral

RESUMEN

Altered metabolism is a hallmark of cancer, and reprogramming of energy metabolism, known as the "Warburg effect", has long been associated with cancer. Cancer cells use the process of glycolysis to quickly manufacture energy from glucose, pyruvic acid, and lactate, which in turn accelerates the growth of cancer and glycolysis becomes a key target for anti-cancer therapies. Recent groundbreaking discoveries regarding long noncoding RNAs (lncRNAs) have opened a new chapter in the mechanism of cancer occurrence. It is widely recognized that lncRNAs regulate energy metabolism through glycolysis in cancer cells. LncRNAs have been demonstrated to engage in several cancer processes such as proliferation, apoptosis, migration, invasion, and chemoresistance, whereas glycolysis is enhanced or inhibited by the dysregulation of lncRNAs. As a result, cancer survival and development are influenced by different signaling pathways. In this review, we summarize the roles of lncRNAs in a variety of cancers and describe the mechanisms underlying their role in glycolysis. Additionally, the predictive potential of glycolysis and lncRNAs in cancer therapy is discussed.

RESUMEN

BACKGROUND: Circulating tumor markers with satisfactory sensitivity and specificity play crucial roles in cancer diagnosis and therapy. This prospective study aimed to evaluate the potential of circulating lncRNAs as biomarkers for hepatocellular carcinoma (HCC). METHODS: A total of 74 patients with HCC and 94 healthy controls were enrolled. The expression levels of candidate genes in serum were detected by qRT-PCR. Receiver operating characteristic (ROC) curve analysis and logistic regression were employed to investigate the diagnostic capacity of lncRNAs. The analysis of 3-year overall survival (OS) was conducted using the Kaplan-Meier method and log-rank test. RESULTS: Of the 9 candidate genes, 6 lncRNAs could be stably detected in serum. The expression levels of circulating MALAT1 and HOTTIP in HCC patients were significantly higher than those in controls (P < 0.001). ROC analysis showed that MALAT1 and HOTTIP were more effective than alpha-fetoprotein (AFP) (P < 0.010) in the diagnosis of HCC, with AUCs of 0.896 and 0.899, respectively. Additionally, a panel consisting of MALAT1, HOTTIP, and AFP was constructed to obtain an AUC of 0.968 with a sensitivity of 87.8% and specificity of 94.7% in HCC diagnosis. Moreover, the upregulation of MALAT1 was not only related to multiple tumor lesions, HCV infection, AST level, and AFP level, but also suggested shorter OS. A high expression level of HOTTIP was associated with metastasis. CONCLUSION: Serum MALAT1 and HOTTIP play indicative roles as non-invasive biomarkers for HCC.

Asunto(s)

Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/diagnóstico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Estudios de Casos y Controles , Pronóstico , alfa-Fetoproteínas/análisis , alfa-Fetoproteínas/metabolismo , Adulto , Regulación Neoplásica de la Expresión Génica

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MicroRNA827 (miR827) is functionally conserved among different plant species and displays species-specific characteristics, but the mechanisms by which miR827 regulates phosphate (Pi) starvation tolerance and maize development remain elusive. We found that miR827 selectively targets the Pi transporter genes SPX-MFS1 and SPX-MFS5. miR827 overexpression improved the Pi starvation tolerance, plant architecture and grain yield and quality, whereas miR827 suppression yielded a contrasting phenotype. In addition, we identified a specific long noncoding RNA (lncRNA767) that serves as a direct target and a facilitator of miR827 and can stabilize the SPX-MFS1 and SPX-MFS5 transcripts, leading to their translation inhibition. The orchestrated regulation of SPX-MFS1 and SPX-MFS5 modulates PHR1; 1 and PHR1; 2, which are critical transcription factors in Pi signalling, and thereby affects the expression of downstream Pi starvation-induced genes. Together, these findings demonstrate that miR827, assisted by lncRNA767, enhances SPX-MFS1 and SPX-MFS5 suppression and thus exerts a significant impact on Pi homeostasis and several essential agronomic traits of maize.

RESUMEN

Lipid disorders increase the risk for the development of cardiometabolic disorders, including type 2 diabetes, atherosclerosis, and cardiovascular disease. Lipids levels, apart from diet, smoking, obesity, alcohol consumption, and lack of exercise, are also influenced by genetic factors. Recent studies suggested the role of long noncoding RNAs (lncRNAs) in the regulation of lipid formation and metabolism. Despite their lack of protein-coding capacity, lncRNAs are crucial regulators of various physiological and pathological processes since they affect the transcription and epigenetic chromatin remodelling. LncRNAs act as molecular signal, scaffold, decoy, enhancer, and guide molecules. This review summarises available data concerning the impact of lncRNAs on lipid levels and metabolism, as well as impact on cardiovascular disease risk. This relationship is significant because altered lipid metabolism is a well-known risk factor for cardiovascular diseases, and lncRNAs may play a crucial regulatory role. Understanding these mechanisms could pave the way for new therapeutic strategies to mitigate cardiovascular disease risk through targeted modulation of lncRNAs. The identification of dysregulated lncRNAs may pose promising candidates for therapeutic interventions, since strategies enabling the restoration of their levels could offer an effective means to impede disease progression without disrupting normal biological functions. LncRNAs may also serve as valuable biomarker candidates for various pathological states, including cardiovascular disease. However, still much remains unknown about the functions of most lncRNAs, thus extensive studies are necessary elucidate their roles in physiology, development, and disease.

Asunto(s)

Enfermedades Cardiovasculares , Metabolismo de los Lípidos , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Humanos , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Metabolismo de los Lípidos/genética , Animales , Regulación de la Expresión Génica , Factores de Riesgo

RESUMEN

Metastasis continues to negatively impact individuals diagnosed with colorectal cancer (CRC). Research has revealed the important role of long noncoding RNAs (lncRNAs) in CRC metastasis, but the underlying mechanisms remain unclear. Here, we revealed that the lncRNA small nucleolar RNA host gene 1 (SNHG1) is expressed at higher levels in metastatic CRC tissues than in primary CRC tissues, and that high lncRNA SNHG1 expression indicates poor patient outcomes. We found that lncRNA SNHG1 promotes the migration and invasion of tumor cells both in vivo and in vitro. Moreover, lncRNA SNHG1 increases serpin family A member 3 (SERPINA3) mRNA stability by interacting with the heterogeneous nuclear ribonucleoprotein D (HNRNPD) protein, and subsequently upregulates SERPINA3 expression. Moreover, HNRNPD and SERPINA3 reversed the effects of lncRNA SNHG1 knockdown on CRC cell metastasis. In conclusion, we report that the lncRNA SNHG1 recruits HNRNPD, in turn upregulating SERPINA3 expression and ultimately facilitating CRC cell migration and invasion. Targeting the lncRNA SNHG1/HNRNPD/SERPINA3 signaling pathway might be a therapeutic option for preventing CRC metastasis.

RESUMEN

Oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs) is considered to result in two populations: premyelinating and myelinating OLs. Recent single-cell RNA sequence data subdivided these populations into newly formed (NFOLs), myelin-forming (MFOLs), and mature (MOLs) oligodendrocytes. However, which newly proposed population corresponds to premyelinating or myelinating OLs is unknown. We focused on the NFOL-specific long non-coding oligodendrocyte 1 gene (LncOL1) and sought to label NFOLs under the control of the LncOL1 promoter using a tetracycline-controllable gene induction system. We demonstrated that LncOL1 was expressed by premyelinating OLs and that the MFOL-specific gene, Ctps, was not, indicating that NFOLs correspond to premyelinating OLs and that MFOLs and MOLs correspond to myelinating OLs. We then generated a LncOL1-tTA mouse in which a tetracycline transactivator (tTA) cassette was inserted downstream from the LncOL1 transcription initiation site. By crossing the LncOL1-tTA mice with tetO reporter mice, we generated LncOL1-tTA::tetO-yellow fluorescent protein (YFP) double-transgenic (LncOL1-YFP) mice. Although LncOL1 is non-coding, YFP was detected in LncOL1-YFP mice, indicating successful tTA translation. Unexpectedly, we found that the morphology of LncOL1-tTA-driven YFP+ cells was distinct from that of LncOL1+ premyelinating OLs and that the labeled cells instead appeared as myelinating OLs. We demonstrated from their RNA expression that YFP-labeled OLs were MFOLs, but not MOLs. Using the unique property of delayed YFP induction, we sought to determine whether MFOLs are constantly supplied from OPCs and differentiate into MOLs, or whether MFOLs pause their differentiation and sustain this stage in the adult brain. To achieve this objective, we irradiated adult LncOL1-YFP brains with X-rays to deplete dividing OPCs and their progeny. The irradiation extinguished YFP-labeled OLs, indicating that adult OPCs differentiated into MOLs during a single period. We established a new transgenic mouse line that genetically labels MFOLs, providing a reliable tool for investigating the dynamics of adult oligodendrogenesis.

RESUMEN

The long noncoding RNAs (lncRNA) are primarily associated with several essential gene regulations but are also connected to cancer metabolism and progression. HOTAIR and MALAT1 are two such lncRNAs that are detected in malignancies of various origins and are responsible for the poor prognosis of cancer patients. Due to these factors, the lncRNAs have emerged as prime targets for the development of anticancer therapeutics. However, nonviral delivery of lncRNA-targeted antisense oligonucleotides (ASOs) still remains a critical challenge while maintaining their structural and functional integrity. Herein, we have designed and synthesized a new series of ionizable lipids with variations in their head groups to prepare lipid nanoparticle (LNP) formulation along with cholesterol-based twin cationic lipid and amphiphilic zwitterionic lipid. The context responsiveness of these formulations in delivering the ASOs has been thoroughly investigated by various bioanalytical techniques, and an optimum formulation has been identified. The LNPs are utilized to deliver the ASOs targeting HOTAIR lncRNA in human cancer cell lines and MALAT1 lncRNA in mouse models. This study thus standardizes an advanced nanomaterial system for nonviral gene delivery that has been validated by a considerable reduction in the target lncRNA level under in vitro and a significant reduction in tumor volume under in vivo settings.

Asunto(s)

Neoplasias de la Mama , Lípidos , Nanopartículas , Oligonucleótidos Antisentido , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Humanos , Nanopartículas/química , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/farmacología , Animales , Ratones , Femenino , Lípidos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Ratones Desnudos

RESUMEN

Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

Asunto(s)

Adenosina , Neoplasias Cerebelosas , Meduloblastoma , ARN Largo no Codificante , Transcriptoma , Humanos , Meduloblastoma/genética , Meduloblastoma/patología , Meduloblastoma/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Pronóstico , Niño , Perfilación de la Expresión Génica/métodos , Masculino , Femenino , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Metiltransferasas

RESUMEN

Nasopharyngeal carcinoma (NPC) is closely related to Epstein-Barr virus (EBV) infection. Long noncoding RNAs (lncRNAs) play important roles in cancers. However, the molecular mechanism underlying the roles of lncRNAs in EBV-associated NPC remains largely unclear. In this study, we confirmed that the expression of the lncRNA brain cytoplasmic 200 (BC200) was significantly increased in EBV-infected NPC cells and tissues. BC200 facilitated the growth and migration of NPC cells, suggesting that it participated in NPC progression by functioning as an oncogene. Mechanistically, BC200 was found to act as a ceRNA by sponging and inhibiting miR-6834-5p. Thymidylate synthetase (TYMS), whose high expression was reported to be an independent indicator of poor prognosis in NPC via an unknown mechanism, was identified as a target gene of miR-6834-5p in the present study. BC200 upregulated TYMS expression in a manner that depends on miR-6834-5p. TYMS was abnormally upregulated in EBV-positive NPC cells and tissues, and its ectopic expression contributed to the proliferation and migration of NPC cells. This study highlights the role of lncRNA BC200, which is upregulated by EBV, in promoting the development of NPC, suggesting that BC200-mediated ceRNA network may be valuable biomarkers for the diagnosis and treatment of EBV-associated NPC.

Asunto(s)

Movimiento Celular , Proliferación Celular , Infecciones por Virus de Epstein-Barr , Regulación Neoplásica de la Expresión Génica , Herpesvirus Humano 4 , MicroARNs , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , ARN Largo no Codificante , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/virología , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , MicroARNs/genética , MicroARNs/metabolismo , Herpesvirus Humano 4/genética , Línea Celular Tumoral , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Proliferación Celular/genética , Movimiento Celular/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virología , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Timidilato Sintasa/genética , Timidilato Sintasa/metabolismo , Regulación hacia Arriba/genética

RESUMEN

OBJECTIVE: Emerging evidence highlights the pivotal roles of long non-coding RNAs (lncRNAs) in lipid metabolism. Apoprotein C3 (ApoC3) is a well-established therapeutic target for hypertriglyceridemia and exhibits a strong association with cardiovascular disease. However, the exact mechanisms via which the lncRNAs control ApoC3 expression remain unclear. METHODS: We identified a novel long noncoding RNA (lncRNA), GM47544, within the ApoA1/C3/A4/A5 gene cluster. Subsequently, the effect of GM47544 on intracellular triglyceride metabolism was analyzed. The diet-induced mouse models of hyperlipidemia and atherosclerosis were established to explore the effect of GM47544 on dyslipidemia and plaque formation in vivo. The molecular mechanism was explored through RNA sequencing, immunoprecipitation, RNA pull-down assay, and RNA immunoprecipitation. RESULTS: GM47544 was overexpressed under high-fat stimulation. GM47544 effectively improved hepatic steatosis, reduced blood lipid levels, and alleviated atherosclerosis in vitro and in vivo. Mechanistically, GM47544 directly bound to ApoC3 and facilitated the ubiquitination at lysine 79 in ApoC3, thereby facilitating ApoC3 degradation via the ubiquitin-proteasome pathway. Moreover, we identified AP006216.5 as the human GM47544 transcript, which fulfills a comparable function in human hepatocytes. CONCLUSIONS: The identification of GM47544 as a lncRNA modulator of ApoC3 reveals a novel mechanism of post-translational modification, with significant clinical implications for the treatment of hypertriglyceridemia and atherosclerosis.

Asunto(s)

Apolipoproteína C-III , Ratones Endogámicos C57BL , ARN Largo no Codificante , Triglicéridos , Ubiquitinación , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/genética , Apolipoproteína C-III/metabolismo , Apolipoproteína C-III/genética , Animales , Ratones , Humanos , Triglicéridos/metabolismo , Masculino , Metabolismo de los Lípidos , Proteolisis , Aterosclerosis/metabolismo , Aterosclerosis/genética

RESUMEN

Airway remodeling is a key characteristic of allergic asthma. Epithelial-mesenchymal transition (EMT) induced by various factors, particularly transforming growth factor (TGF)-ß1, orchestrates airway remodeling. Protein phosphatase 2A (PP2A), an important serine-threonine phosphatase, is involved in TGF-ß1 production and EMT. Long noncoding RNAs (lncRNAs) have emerged as novel players in regulating EMT. Here, we aimed to explore the effects and mechanisms of action of lincR-PPP2R5C, a lncRNA that affects PP2A activity, on airway remodeling in a mouse model of chronic allergic asthma. LincR-PPP2R5C knockout (KO) alleviated inflammatory responses in house dust mite (HDM)-induced chronic allergic asthma. Moreover, airway remodeling and EMT were reduced in lung tissues of lincR-PPP2R5C KO mice. HDM extract induced EMT in airway epithelial cells, which was decreased following lincR-PPP2R5C KO. Mechanistically, lincR-PPP2R5C deficiency enhanced PP2A activity, which inhibited TGF-ß1 production in epithelial cells. In conclusion, lincR-PPP2R5C deficiency prevented HDM-induced airway remodeling in mice by reversing EMT, which was mediated by the PP2A/TGF-ß1 signaling pathway. Thus, lncRNAs, i.e., lincR-PPP2R5C, may be potential targets to prevent airway remodeling in allergic asthma.

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Potential exposure to cobalt nanoparticles (CoNPs) occurs in various fields, including hard alloy industrial production, the increasing use of new energy lithium-ion batteries, and millions of patients with metal-on-metal joint prostheses. Evidence from human, animal, and in vitro experiments suggests a close relationship between CoNPs and neurotoxicity. However, a systematic assessment of central nervous system (CNS) impairment due to CoNPs exposure and the underlying molecular mechanisms is lacking. In this study, we found that CoNPs induced neurodegenerative damage both in vivo and in vitro, including cognitive impairment, ß-amyloid deposition and Tau hyperphosphorylation. CoNPs promoted the formation of autophagosomes and impeding autophagosomal-lysosomal fusion in vivo and in vitro, leading to toxic protein accumulation. Moreover, CoNPs exposure reduced the level of transcription factor EB (TFEB) and the abundance of lysosome, causing a blockage in autophagosomal-lysosomal fusion. Interestingly, overexpression of long noncoding RNA NR_030777 mitigated CoNPs-induced neurodegenerative damage in both in vivo and in vitro models. Fluorescence in situ hybridization assay revealed that NR_030777 directly binds and stabilizes TFEB mRNA, alleviating the blockage of autophagosomal-lysosomal fusion and ultimately restoring neurodegeneration induced by CoNPs in vivo and in vitro. In summary, our study demonstrates that autophagic dysfunction is the main toxic mechanism of neurodegeneration upon CoNPs exposure and NR_030777 plays a crucial role in CoNPs-induced autophagic dysfunction. Additionally, the proposed adverse outcome pathway contributes to a better understanding of CNS toxicity assessment of CoNPs.

Asunto(s)

Autofagosomas , Cobalto , Lisosomas , Nanopartículas del Metal , ARN Largo no Codificante , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Autofagosomas/metabolismo , Autofagosomas/efectos de los fármacos , Cobalto/química , Cobalto/farmacología , Animales , Nanopartículas del Metal/química , Humanos , Ratones , Masculino , Autofagia/efectos de los fármacos , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/inducido químicamente

RESUMEN

Background: Pancreatic cancer (PC) is an exceedingly malignant ailment that is not only characterized by its insidious onset and rapid progression but also by its poor therapeutic effects. Recently, emerging evidence has shed light on the significant role that non-coding RNAs (ncRNAs), particularly long ncRNAs (lncRNAs) and microRNAs (miRNAs), play in the pathogenesis of PC. This investigation aimed to construct a network of interactions between miRNAs, lncRNAs, and mRNAs, as well as to perform correlation analyses in the context of PC. Methods: This study carried out in Kerman City, southeastern Iran in 2023. We utilized the GSE119794 dataset from the Gene Expression Omnibus (GEO) to analyze differentially expressed lncRNAs (DE-lncRNAs), miRNAs (DE-miRNAs), and mRNAs (DE-mRNAs). Following the identification of the DE-lncRNAs, DE-mRNAs, and DE-miRNAs, we proceeded to examine differentially expressed epithelialmesenchymal transition (EMT) genes. Subsequently, we utilized the RNAInter database to predict interactions among lncRNAs, miRNAs, and mRNAs. Finally, we employed Cytoscape to visualize and analyze the constructed network. Results: 14 DE-lncRNAs, 14 DE-miRNAs, 545 DE-mRNAs, and 65 DE-EMT from pancreatic cancer and its adjacent tissue RNA-Seq data were identified. 1184 EMT genes from dbEMT were obtained, among which 65 DE-EMT were assigned as EMT genes and correlated with tumor progression. One functional lncRNA (UCA1) was identified as a key functional lncRNA. The area under the ROC curve (AUC) of UCA1 and miR-708-5p were 0.79 and 0.86, respectively. Thus, it is reasonable to believe that this prognostic risk model helps predict PC metastasis. Conclusion: UCA1 is a new lncRNA linked with EMT in PC and contributes to a better knowledge of the regulatory mechanisms related to lncRNAs in PC.

RESUMEN

BACKGROUND: Nuclear-enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), has been implicated in the colorectal cancer (CRC) progression. However, its upstream mechanism has not been well studied. In the present study, the functions and mechanisms of NEAT1 in CRC were investigated. METHODS: The NEAT1 expression in CRC tissues and CRC cells was analyzed by RT-qPCR. The genes co-expressed with NEAT1 in CRC were obtained from UALCAN, which were intersected with the transcription factors targeting NEAT1 from hTFtarget. Dual-luciferase assay, RT-qPCR, and ChIP were conducted to analyze the transcriptional regulatory relationship between BHLHE40 and NEAT1. LoVo and HCT-15 cells knocking down BHLHE40 and overexpressing NEAT1 were subjected to MTT, Transwell, Western blot, and flow cytometry to examine the malignant aggressiveness of CRC cells. The effects of knocking down BHLHE40 and overexpressing NEAT1 on tumor and lung metastasis were investigated in mice using HE and immunohistochemical analyses. RESULTS: NEAT1 and BHLHE40 were significantly overexpressed in CRC tissues and cells. BHLHE40 has a binding relationship with the NEAT1 promoter. Knockdown of BHLHE40 resulted in a reverted malignant phenotype in vitro and slowed tumor growth and metastasis dissemination in vivo, which were reversed by NEAT1 overexpression. Overexpression of BHLHE40 increased Wnt/ß-catenin pathway activity, but knockdown of NEAT1 decreased Wnt/ß-catenin pathway activity. CONCLUSIONS: BHLHE40 mediates the transcriptional activation of NEAT1, which activates the Wnt/ß-catenin pathway and promotes the CRC progression.

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OBJECTIVE: Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are widely expressed in the brain and are associated with the development of neurological and neurodegenerative diseases. However, their roles and molecular mechanisms in major depressive disorder (MDD) remain largely unknown. This study aimed to identify lncRNAs and miRNAs involved in the development of MDD and elucidate their molecular mechanisms. METHODS: Transcriptome and bioinformatic analyses were performed to identify miRNAs and lncRNAs related to MDD. C57 mice were subjected to chronic unpredictable mild stress (CUMS) to establish a depression model. Lentiviruses containing either lncRNA NPTN-IT1-201 or miR-142-5p were microinjected into the hippocampal region of these mice. Behavioral tests including the sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST) were conducted to evaluate depressive-like behaviors. RESULTS: The results revealed that overexpression of lncRNA NPTN-IT1-201 or inhibition of miR-142-5p significantly ameliorated depressive-like behaviors in CUMS-treated mice. Dual-luciferase reporter assays confirmed interactions between miR-142-5p with both brain-derived neurotrophic factor (BDNF) and NPTN-IT1-201. ELISA analysis revealed significant alterations in relevant biomarkers in the blood samples of MDD patients compared to healthy controls. Histological analyses, including HE and Nissl staining, showed marked structural changes in brain tissues following CUMS treatment, which were partially reversed by lncRNA NPTN-IT1-201 overexpression or miR-142-5p inhibition. Immunofluorescence imaging demonstrated significant differences in the levels of BAX, Bcl2, p65, Iba1 among different treatment groups. TUNEL assays confirmed reduced apoptosis in brain tissues following these interventions. Western blotting showed the significant differences in BDNF, BAX, and Bcl2 protein levels among different treatment groups. CONCLUSION: NPTN-IT1-201 regulates inflammation and apoptosis in MDD by targeting BDNF via miR-142-5p, making it a potential therapeutic target for MDD.

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The ATR-Chk1 pathway is essential in cellular responses to DNA damage and replication stress, whereas the role of long noncoding RNAs (lncRNAs) in regulating this pathway remains largely unknown. In this study, we identify an ATR and Chk1 interacting lncRNA (ACIL, also known as LRRC75A-AS1 or SNHG29), which promotes the phosphorylation of Chk1 by ATR upon DNA damages. High ACIL levels are associated with chemoresistance to DNA damaging agents and poor outcome of breast cancer patients. ACIL knockdown sensitizes breast cancer cells to DNA damaging drugs in vitro and in vivo. ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.