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BACKGROUND: CircRNAs are a novel class of evolutionarily conserved noncoding RNA molecules that form covalently closed continuous loop structures without 5' caps and 3' poly(A) tails. Accumulating evidence suggests that circRNAs play important regulatory roles in cancer and are promising biomarkers for cancer diagnosis and prognosis, as well as targets for cancer therapy. In this study, we identify and explore the role of a novel circRNA, circFBXO7, in ovarian cancer. METHODS: rRNA-depleted RNA-sequencing was performed to identify differentially expressed circRNAs between ovarian cancerous and normal tissues. qRT-PCR and single-molecule RNA in-situ hybridization was used to quantify circFBXO7 expression in tumor tissues. The association of circFBXO7 expression with patient prognosis was evaluated by Kaplan-Meier survival analysis. The biological function of circFBXO7 was also investigated using loss-of-function and gain-of-function assays in vivo and in vitro. Luciferase reporter and TOP/FOP-Flash reporter assays were then conducted together with RNA immunoprecipitation and western blot to assess the circFBXO7/miR-96-5p/MTSS1/Wnt/ß-catenin axis. RESULTS: circFBXO7 was downregulated in ovarian cancer which was associated with poor prognosis. Biologically, circFBXO7 overexpression significantly suppressed ovarian cancer cell proliferation, migration, and invasion in vitro, and inhibited tumor growth and metastasis in vivo, whereas its knockdown exerted an opposite role. Mechanistically, circFBXO7 functioned as a competing endogenous RNA for miR-96-5p to regulate the expression of MTSS1. Consequently, downregulation of MTSS1 led to excessive accumulation of ß-catenin and increased phosphorylation of GSK3ß, leading to the translocation of ß-catenin to the nucleus, thereby activating the Wnt/ß-catenin signaling pathway and ultimately promoting ovarian cancer progression. CONCLUSIONS: Our findings indicate that circFBXO7 acts as a bone fide tumor suppressor in ovarian cancer and that the circFBXO7/miR-96-5p/MTSS1 axis is an important regulator in the Wnt/ß-catenin signaling pathway which may provide a promising target for ovarian cancer therapy.
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MicroARNs , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas de Microfilamentos/genética , Proteínas de Neoplasias/genética , Neoplasias Ováricas/patología , ARN Circular/genética , Vía de Señalización Wnt/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Race may influence vulnerability to HPV variants in viral infection and perisistence. Integrated analysis of the virus and host transcriptomes from different populations provides an unprecedented opportunity to understand these racial disparities in the prevalence of HPV and cervical cancers. We performed RNA-Seq analysis of 90 tumors and 39 adjacent normal tissues from cervical cancer patients at Zhejiang University (ZJU) in China, and conducted a comparative analysis with RNA-Seq data of 286 cervical cancers from TCGA. We found a modestly higher rate of HPV positives and HPV integrations in TCGA than in ZJU. In addition to LINC00393 and HSPB3 as new common integration hotspots in both cohorts, we found new hotspots such as SH2D3C and CASC8 in TCGA, and SCGB1A1 and ABCA1 in ZJU. We described the first, to our knowledge, virus-transcriptome-based classification of cervical cancer associated with clinical outcome. Particularly, patients with expressed E5 performed better than those without E5 expression. However, the constituents of these virus-transcriptome-based tumor subtypes differ dramatically between the two cohorts. We further characterized the immune infiltration landscapes between different HPV statuses and revealed significantly elevated levels of regulatory T cells and M0 macrophages in HPV positive tumors, which were associated with poor prognosis. These findings increase our understanding of the racial disparities in the prevalence of HPV and its associated cervical cancers between the two cohorts, and also have important implications in the classification of tumor subtypes, prognosis, and anti-cancer immunotherapy in cervical cancer.
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Papillomaviridae , Transcriptoma , Neoplasias del Cuello Uterino , Integración Viral , China/epidemiología , Femenino , Humanos , Papillomaviridae/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/virologíaRESUMEN
According to density functional theory, monolayer (ML) MoS2 is predicted to possess electrocatalytic activity for the hydrogen evolution reaction (HER) that approaches that of platinum. However, its observed HER activity is much lower, which is widely believed to result from a large Schottky barrier between ML MoS2 and its electrical contact. In order to better understand the role of contact resistance in limiting the performance of ML MoS2 HER electrocatalysts, this study has employed well-defined test platforms that allow for the simultaneous measurement of contact resistance and electrocatalytic activity toward the HER during electrochemical testing. At open circuit potential, these measurements reveal that a 0.5 M H2SO4 electrolyte can act as a strong p-dopant that depletes free electrons in MoS2 and leads to extremely high contact resistance, even if the contact resistance of the as-made device in air is originally very low. However, under applied negative potentials this doping is mitigated by a strong electrolyte-mediated gating effect which can reduce the contact and sheet resistances of properly configured ML MoS2 electrocatalysts by more than 5 orders of magnitude. At potentials relevant to HER, the contact resistance becomes negligible and the performance of MoS2 electrodes is limited by HER kinetics. These findings have important implications for the design of low-dimensional semiconducting electrocatalysts and photocatalysts.
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INTRODUCTION: Long noncoding RNAs (lncRNAs) are emerging as key players in the development and progression of cancer. However, the biological role and clinical significance of most lncRNAs in lung carcinogenesis remain unclear. In this study, we identified and explored the role of a novel lncRNA, lung cancer associated transcript 1 (LCAT1), in lung cancer. METHODS: We predicted and validated LCAT1 from RNA-sequencing (RNA-seq) data of lung cancer tissues. The LCAT1-miR-4715-5p-RAC1 axis was assessed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Signaling pathways altered by LCAT1 knockdown were identified using RNA-seq. Furthermore, the mechanism of LCAT1 was investigated using loss-of-function and gain-of-function assays in vivo and in vitro. RESULTS: LCAT1 is an oncogene that is significantly upregulated in lung cancer tissues and associated with poor prognosis. LCAT1 knockdown caused growth arrest and cell invasion in lung cancer cells in vitro, and inhibited tumorigenesis and metastasis in the mouse xenografts. Mechanistically, LCAT1 functions as a competing endogenous RNA for miR-4715-5p, thereby leading to the upregulation of the activity of its endogenous target, Rac family small GTPase 1 (RAC1). Moreover, EHop-016, a small molecule inhibitor of RAC1, as an adjuvant could improve the Taxol monotherapy against lung cancer cells in vitro. CONCLUSIONS: LCAT1-miR-4715-5p-RAC1/PAK1 axis plays an important role in the progression of lung cancer. Our findings may provide valuable drug targets for treating lung cancer. The novel combination therapy of Taxol and EHop-016 for lung cancer warrants further investigation, especially in lung cancer patients with high LCAT1 expression.
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Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , Interferencia de ARN , ARN Largo no Codificante , Proteína de Unión al GTP rac1/genética , Animales , Apoptosis , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Femenino , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Ratones , Modelos Biológicos , Metástasis de la Neoplasia , Oncogenes , Paclitaxel/farmacología , Pronóstico , Proteína de Unión al GTP rac1/antagonistas & inhibidoresRESUMEN
BACKGROUND: Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive. METHODS: RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings. RESULTS: CircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial-mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells. CONCLUSIONS: Our findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.
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Proteína BRCA1/genética , Genes Supresores de Tumor , Proteínas del Choque Térmico HSP40/genética , Proteínas Ligadas a Lípidos/genética , MicroARNs/genética , Chaperonas Moleculares/genética , Proteínas del Tejido Nervioso/genética , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Circular/genética , Regiones no Traducidas 3' , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Factor 4 Similar a Kruppel , Ratones , Modelos Biológicos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Vía de Señalización WntRESUMEN
The experimental realization of two-dimensional (2D) gallium nitride (GaN) has enabled the exploration of 2D nitride materials beyond boron nitride. Here we demonstrate one possible pathway to realizing ultra-thin nitride layers through a two-step process involving the synthesis of naturally layered, group-III chalcogenides (GIIIC) and subsequent annealing in ammonia (ammonolysis) that leads to an atomic-exchange of the chalcogen and nitrogen species in the 2D-GIIICs. The effect of nitridation differs for gallium and indium selenide, where gallium selenide undergoes structural changes and eventual formation of ultra-thin GaN, while indium selenide layers are primarily etched rather than transformed by nitridation. Further investigation of the resulting GaN films indicates that ultra-thin GaN layers grown on silicon dioxide act as effective 'seed layers' for the growth of 3D GaN on amorphous substrates.
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Understanding the atomistic mechanisms governing the growth of two-dimensional (2D) materials is of great importance in guiding the synthesis of wafer-sized, single-crystalline, high-quality 2D crystals and heterostructures. Etching, in many cases regarded as the reverse process of material growth, has been used to study the growth kinetics of graphene. In this work, we explore a growth-etching-regrowth process of monolayer GaSe crystals, including single-crystalline triangles and irregularly shaped domains formed by merged triangles. We show that the etching begins at a slow rate, creating triangular, truncated triangular, or hexagonally shaped holes that eventually evolve to exclusively triangles that are rotated 60° with respect to the crystalline orientation of the monolayer triangular crystals. The regrowth occurs much faster than etching, reversibly filling the etched holes and then enlarging the size of the monolayer crystals. A theoretical model developed based on kinetic Wulff construction (KWC) theory and density functional theory (DFT) calculations accurately describe the observed morphology evolution of the monolayer GaSe crystals and etched holes during the growth and etching processes, showing that they are governed by the probability of atom attachment/detachment to/from different types of edges with different formation energies of nucleus/dents mediated by chemical potential difference Δµ between Ga and Se. Our growth-etching-regrowth study provides not only guidance to understand the growth mechanisms of 2D binary crystals but also a potential method for the synthesis of large, shape-controllable, high-quality single-crystalline 2D crystals and their lateral heterostructures.
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Molybdenum disulfide (MoS2) is currently under intensive study because of its exceptional optical and electrical properties in few-layer form. However, how charge transport mechanisms vary with the number of layers in MoS2 flakes remains unclear. Here, exfoliated flakes of MoS2 with various thicknesses were successfully fabricated into field-effect transistors (FETs) to measure the thickness and temperature dependences of electrical mobility. For these MoS2 FETs, measurements at both 295 K and 77 K revealed the maximum mobility for layer thicknesses between 5 layers (â¼3.6 nm) and 10 layers (â¼7 nm), with â¼70 cm(2) V(-1) s(-1) measured for 5 layer devices at 295 K. Temperature-dependent mobility measurements revealed that the mobility rises with increasing temperature to a maximum. This maximum occurs at increasing temperature with increasing layer thickness, possibly due to strong Coulomb scattering from charge impurities or weakened electron-phonon interactions for thicker devices. Temperature-dependent conductivity measurements for different gate voltages revealed a metal-to-insulator transition for devices thinner than 10 layers, which may enable new memory and switching applications. This study advances the understanding of fundamental charge transport mechanisms in few-layer MoS2, and indicates the promise of few-layer transition metal dichalcogenides as candidates for potential optoelectronic applications.
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Characterizing and controlling the interlayer orientations and stacking orders of two-dimensional (2D) bilayer crystals and van der Waals (vdW) heterostructures is crucial to optimize their electrical and optoelectronic properties. The four polymorphs of layered gallium selenide (GaSe) crystals that result from different layer stackings provide an ideal platform to study the stacking configurations in 2D bilayer crystals. Through a controllable vapor-phase deposition method, bilayer GaSe crystals were selectively grown and their two preferred 0° or 60° interlayer rotations were investigated. The commensurate stacking configurations (AA' and AB stacking) in as-grown bilayer GaSe crystals are clearly observed at the atomic scale, and the Ga-terminated edge structure was identified using scanning transmission electron microscopy. Theoretical analysis reveals that the energies of the interlayer coupling are responsible for the preferred orientations among the bilayer GaSe crystals.
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DNA methylation, an epigenetic mechanism that alters gene expression without changing DNA sequence, is essential for organism development and key biological processes like genomic imprinting and X-chromosome inactivation. Despite tremendous efforts in DNA methylation research, accurate quantification of cytosine methylation remains a challenge. Here, a single-base methylation quantification approach is introduced by weighting methylation of consecutive CpG sites (Wemics) in genomic regions. Wemics quantification of DNA methylation better predicts its regulatory impact on gene transcription and identifies differentially methylated regions (DMRs) with more biological relevance. Most Wemics-quantified DMRs in lung cancer are epigenetically conserved and recurrently occurred in other primary cancers from The Cancer Genome Atlas (TCGA), and their aberrant alterations can serve as promising pan-cancer diagnostic markers. It is further revealed that these detected DMRs are enriched in transcription factor (TF) binding motifs, and methylation of these TF binding motifs and TF expression synergistically regulate target gene expression. Using Wemics on epigenomic-transcriptomic data from the large lung cancer cohort, a dozen novel genes with oncogenic potential are discovered that are upregulated by hypomethylation but overlooked by other quantification methods. These findings increase the understanding of the epigenetic mechanism by which DNA methylation regulates gene expression.
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Metilación de ADN , Epigénesis Genética , Neoplasias Pulmonares , Metilación de ADN/genética , Epigénesis Genética/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Islas de CpG/genéticaRESUMEN
Large-area Zn2GeO4 nanorod arrays (1.5 × 5 cm) and long Zn2GeO4 nanowires (length up to 1 mm) have been controllably prepared at different areas on the substrate using a simple thermal evaporation method. The formation processes for these nanostructures were investigated carefully. The solid state reaction and vapor-solid process have been found to clearly contribute to the creation of the Zn2GeO4 nanorod arrays and long Zn2GeO4 nanowires, respectively. Photoluminescence (PL) characterization of these nanostructures showed that both the nanorod arrays and nanowires exhibited strong blue-white luminescence. Mn-doped Zn2GeO4 nanorod arrays have also been obtained by doping an appropriate amount of Mn(2+) ions in the products. Zn2GeO4 nanostructures doped with Mn(2+) exhibited bright green luminescence.
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Germanio/química , Nanotecnología , Nanotubos/química , Nanocables/química , Oxígeno/química , Zinc/química , Luminiscencia , Tamaño de la Partícula , Propiedades de Superficie , TemperaturaRESUMEN
OBJECTIVE: More than 75% of ovarian cancer patients are diagnosed at advanced stages and die of tumor cell metastasis. This study aimed to identify new epigenetic and transcriptomic alterations associated with ovarian cancer metastasis. METHODS: Two cell sublines with low- and high-metastasis potentials were derived from the ovarian cancer cell line A2780. Genome-wide DNA methylome and transcriptome profiling were carried out in these two sublines by Reduced Representation Bisulfite Sequencing and RNA-seq technologies. Cell-based assays were conducted to support the clinical findings. RESULTS: There are distinct DNA methylation and gene expression patterns between the two cell sublines with low- and high-metastasis potentials. Integrated analysis identified 33 methylation-induced genes potentially involved in ovarian cancer metastasis. The DNA methylation patterns of two of them (i.e., SFRP1 and LIPG) were further validated in human specimens, indicating that they were hypermethylated and downregulated in peritoneal metastatic ovarian carcinoma compared to primary ovarian carcinoma. Patients with lower SFRP1 and LIPG expression tend to have a worse prognosis. Functionally, knockdown of SFRP1 and LIPG promoted cell growth and migration, whereas their overexpression resulted in the opposite effects. In particular, knockdown of SFRP1 could phosphorylate GSK3ß and increase ß-catenin expression, leading to deregulated activation of the Wnt/ß-catenin signaling. CONCLUSION: Many systemic and important epigenetic and transcriptomic alterations occur in the progression of ovarian cancer. In particular, epigenetic silencing of SFRP1 and LIPG is a potential driver event in ovarian cancer metastasis. They can be used as prognostic biomarkers and therapeutic targets for ovarian cancer patients.
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Neoplasias Ováricas , beta Catenina , Humanos , Femenino , beta Catenina/genética , Transcriptoma , Neoplasias Ováricas/genética , Epigenoma , Línea Celular Tumoral , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lipasa/genética , Lipasa/metabolismoRESUMEN
BACKGROUND: Primary liver cancer has significant intratumor genetic heterogeneity (IGH), which drives cancer evolution and prevents effective cancer treatment. CRISPR/Cas9-induced mouse liver cancer models can be used to elucidate how IGH is developed. However, as CRISPR/Cas9 could induce chromothripsis and extrachromosomal DNA in cells in addition to targeted mutations, we wondered whether this effect contributes to the development of IGH in CRISPR/Cas9-induced mouse liver cancer. METHODS: CRISPR/Cas9-based targeted somatic multiplex-mutagenesis was used to target 34 tumor suppressor genes (TSGs) for induction of primary liver tumors in mice. Target site mutations in tumor cells were analyzed and compared between single-cell clones and their subclones, between different time points of cell proliferation, and between parental clones and single-cell clones derived from mouse subcutaneous allografts. Genomic instability and generation of extrachromosomal circular DNA (eccDNA) was explored as a potential mechanism underlying the oscillation of target site mutations in these liver tumor cells. RESULTS: After efficiently inducing autochthonous liver tumors in mice within 30-60 days, analyses of CRISPR/Cas9-induced tumors and single-cell clones derived from tumor nodules revealed multiplexed and heterogeneous mutations at target sites. Many target sites frequently displayed more than two types of allelic variations with varying frequencies in single-cell clones, indicating increased copy number of these target sites. The types and frequencies of targeted TSG mutations continued to change at some target sites between single-cell clones and their subclones. Even the proliferation of a subclone in cell culture and in mouse subcutaneous graft altered the types and frequencies of targeted TSG mutations in the absence of continuing CRISPR/Cas9 genome editing, indicating a new source outside primary chromosomes for the development of IGH in these liver tumors. Karyotyping of tumor cells revealed genomic instability in these cells manifested by high levels of micronuclei and chromosomal aberrations including chromosomal fragments and chromosomal breaks. Sequencing analysis further demonstrated the generation of eccDNA harboring targeted TSG mutations in these tumor cells. CONCLUSIONS: Small eccDNAs carrying TSG mutations may serve as an important source supporting intratumor heterogeneity and tumor evolution in mouse liver cancer induced by multiplexed CRISPR/Cas9.
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Sistemas CRISPR-Cas , Neoplasias Hepáticas , Ratones , Animales , Neoplasias Hepáticas/genética , Edición Génica , Mutación , Genes Supresores de Tumor , ADN , Inestabilidad Genómica , ADN CircularRESUMEN
BACKGROUND: Long non-coding RNAs (lncRNAs) are important epigenetic regulators, which play critical roles in diverse physiological and pathological processes. However, the regulatory mechanism of lncRNAs in lung carcinogenesis remains elusive. Here, we characterized a novel oncogenic lncRNA, designated as Lung Cancer Associated Transcript 3 (LCAT3). METHODS: We predicted and validated LCAT3 by analyzing RNA-sequencing (RNA-seq) data of lung cancer tissues from TCGA. Methylated RNA immunoprecipitation was performed to assess m6A modification on LCAT3. The LCAT3-FUBP1-MYC axis was assessed by dual-luciferase reporter, RNA immunoprecipitation and Chromatin immunoprecipitation assays. Signaling pathways altered by LCAT3 knockdown were identified using RNA-seq. Furthermore, the mechanism of LCAT3 was investigated using loss-of-function and gain-of-function assays in vivo and in vitro. RESULTS: LCAT3 was found to be up-regulated in lung adenocarcinomas (LUAD), and its over-expression was associated with the poor prognosis of LUAD patients. LCAT3 upregulation is attributable to N6-methyladenosine (m6A) modification mediated by methyltransferase like 3 (METTL3), leading to LCAT3 stabilization. Biologically, loss-of-function assays revealed that LCAT3 knockdown significantly suppressed lung cancer cell proliferation, migration and invasion in vitro, and inhibited tumor growth and metastasis in vivo. LCAT3 knockdown induced cell cycle arrest at the G1 phase. Mechanistically, LCAT3 recruited Far Upstream Element Binding Protein 1 (FUBP1) to the MYC far-upstream element (FUSE) sequence, thereby activating MYC transcription to promote proliferation, survival, invasion and metastasis of lung cancer cells. CONCLUSIONS: Taken together, we identified and characterized LCAT3 as a novel oncogenic lncRNA in the lung, and validated the LCAT3-FUBP1-MYC axis as a potential therapeutic target for LUAD.
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Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-myc/genética , ARN Largo no Codificante/genética , Proteínas de Unión al ARN/genética , Adenosina/análogos & derivados , Adenosina/genética , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Ratones Endogámicos BALB C , Invasividad Neoplásica/diagnóstico , Invasividad Neoplásica/genética , Pronóstico , Regulación hacia ArribaRESUMEN
DEPTOR plays vital roles in the regulation of cell proliferation and survival by directly modulating the activity of mTORC1/2. However, the physiological role of DEPTOR in lung tumorigenesis, as well as its clinical significance, remains elusive. In this study, we revealed that decreased DEPTOR expression correlated with increased tumor size, poor differentiation, and worse survival in patients with lung cancer. DEPTOR depletion promoted cell proliferation, survival, migration, and invasion in human lung cancer cells. Mechanistically, DEPTOR bound to the kinase domain of EGFR via its PDZ domain to inactivate EGFR signal. Thus, DEPTOR depletion not only directly activated mTORC1/2, but also relieved the inhibition of EGFR to subsequently activate mTOR signals, leading to the induction of cell proliferation and survival. Additionally, activated EGFR-mTOR signals upregulated the expression of ZEB1 and SLUG to induce epithelial-mesenchymal transition, resulting in enhanced migration and invasion. Importantly, Deptor deletion accelerated KrasG12D;p53fl/fl-induced lung tumorigenesis and shortened mouse life span via the activation of EGFR-mTOR signals. Collectively, our study demonstrated that DEPTOR acts as a tumor suppressor in lung tumorigenesis, and its reduction may advance the progression of human lung cancer.
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Carcinogénesis/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmón/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Células A549 , Animales , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Transición Epitelial-Mesenquimal/fisiología , Receptores ErbB/metabolismo , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Ratones , Ratones Noqueados , Regulación hacia Arriba/fisiologíaRESUMEN
Transition metal dichalcogenides exhibit a variety of electronic behaviors depending on the number of layers and width. Therefore, developing facile methods for their controllable synthesis is of central importance. We found that nickel nanoparticles promote both heterogeneous nucleation of the first layer of molybdenum disulfide and simultaneously catalyzes homoepitaxial tip growth of a second layer via a vapor-liquid-solid (VLS) mechanism, resulting in bilayer nanoribbons with width controlled by the nanoparticle diameter. Simulations further confirm the VLS growth mechanism toward nanoribbons and its orders of magnitude higher growth speed compared to the conventional noncatalytic growth of flakes. Width-dependent Coulomb blockade oscillation observed in the transfer characteristics of the nanoribbons at temperatures up to 60 K evidences the value of this proposed synthesis strategy for future nanoelectronics.
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We present a comprehensive theoretical study on thermal transport in monolayer transition metal dichalcogenides MX2 (M: Mo, W; X: S, Se) with various sample sizes. An unusually high anharmonic scattering strength is found in MoSe2 compared to the other three family members, which arises from its unique phonon band dispersion, specifically the mid-frequency phonon branches associated with the vibrations of Se atoms of MoSe2. The mid-frequency modes almost completely span the gap that exists between the high-frequency phonon branches and the acoustic ones, allowing the former to readily decay into the latter. The resultant high anharmonic scattering gives rise to a short mean free path which makes the room temperature in-plane thermal conductivity in MoSe2 even lower than WSe2 when the sample length is larger than 51.5 nm. With varying sample sizes, the ordering of thermal conductivity among the four materials changes as phonon transport transits from the ballistic to diffusive regime, driven by the competition between the phonon frequency spectrum range and the scattering strength. Our work provides a microscopic picture of phonon transport in TMDs and guidance to tailor their thermal conductivities for electronic and thermoelectric applications.
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The role of additives in facilitating the growth of conventional semiconducting thin films is well-established. Apparently, their presence is also decisive in the growth of two-dimensional transition metal dichalcogenides (TMDs), yet their role remains ambiguous. In this work, we show that the use of sodium bromide enables synthesis of TMD monolayers via a surfactant-mediated growth mechanism, without introducing liquefaction of metal oxide precursors. We discovered that sodium ions provided by sodium bromide chemically passivate edges of growing molybdenum disulfide crystals, relaxing in-plane strains to suppress 3D islanding and promote monolayer growth. To exploit this growth model, molybdenum disulfide monolayers were directly grown into desired patterns using predeposited sodium bromide as a removable template. The surfactant-mediated growth not only extends the families of metal oxide precursors but also offers a way for lithography-free patterning of TMD monolayers on various surfaces to facilitate fabrication of atomically thin electronic devices.
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Transfer RNA-derived RNA fragments (tRFs) are a class of small non-coding RNAs that are abundant in many organisms, but their role in cancer has not been fully explored. Here, we report a functional genomic landscape of tRFs in 8118 specimens across 15 cancer types from The Cancer Genome Atlas. These tRFs exhibited characteristics of widespread expression, high sequence conservation, cytoplasmic localization, specific patterns of tRNA cleavage and conserved cleavage in tissues. A cross-tumor analysis revealed significant commonality among tRF expression subtypes from distinct tissues of origins, characterized by upregulation of a group of tRFs with similar size and activation of cancer-associated signaling. One of the largest superclusters was composed of 22 nt 3'-tRFs upregulated in 13 cancer types, all of which share the activation of Ras/MAPK, RTK and TSC/mTOR signaling. tRF-based subgrouping provided clinically relevant stratifications and significantly improved outcome prediction by incorporating clinical variables. Additionally, we discovered 11 cancer driver tRFs using an effective approach for accurately exploring cross-tumor and platform trends. As a proof of concept, we performed comprehensive functional assays on a non-microRNA driver tRF, 5'-IleAAT-8-1-L20, and validated its oncogenic roles in lung cancer in vitro and in vivo. Our study also provides a valuable tRF resource for identifying diagnostic and prognostic biomarkers, developing cancer therapy and studying cancer pathogenesis.
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Herein, a general bottom-up approach is proposed for the controlled assembly of metal chalcogenide nanoparticles into biomorphic porous hollow nanostructures by a sonochemical method using bacteria as morph-biotemplates. Biomorphic PbS and ZnS hollow nanostructures have been successfully synthesized with two species of bacteria cocci and bacillus as morph-templates. The biomorphic hollow assemblies possess shape-controllable, size-tunable and shell-thickness-adjustable characteristics. Thus, the structure and morphology of the hollow assemblies may be varied in a controllable way to tailor their properties over a broad range. A preliminary study on the light-harvesting properties of PbS and ZnS hollow spheres revealed that the hollow and porous structure is clearly far more favorable for the absorption of light than solid counterparts, which accounts for both multiple scattering effects at the large voids (hollow cavities) and Rayleigh scattering by nanovoids of the exterior shells. Furthermore, photocatalytic studies of ZnS nanostructures by degradation of acid fuchsine under solar irradiation have proved that the hollow structures possess superior photocatalytic activity to the corresponding solid counterparts. This versatile approach provides an effective route for the further extensive study of the distinct properties imparted by hollow nanostructures and extends their application potentials in photocatalysis and solar energy storage/conversion.