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Liquid fluidity is a most key prerequisite for a broad range of technologies, from energy, fluid machineries, microfluidic devices, water, and oil transportation to bio-deliveries. While from thermodynamics, the liquid fluidity gradually diminishes as temperature decreases until completely solidified below icing points. Here, self-driven droplet motions are discovered and demonstrated occurring in icing environments and accelerating with both moving distances and droplet volumes. The self-driven motions, including self-depinning and continuous wriggling, require no surface pre-preparation or energy input but are triggered by the overpressure spontaneously established during icing and then continuously accelerated by capillary pulling of frosts. Such self-driven motions are generic to a broad class of liquid types, volumes, and numbers on various micro-nanostructured surfaces and can be facilely manipulated by introducing pressure gradients spontaneously or externally. The discovery and control of self-driven motions below icing points can greatly broaden liquid-related applications in icing environments.
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The wicking phenomenon, including wicking and hemiwicking, has attracted increasing attention for its critical importance to a wide range of engineering applications, such as thermal management, water harvesting, fuel cells, microfluidics, and biosciences. There exists a more urgent demand for anisotropic wicking behaviors since an increasing number of advanced applications are significantly complex. For example, special-shaped vapor chambers and heating atomizers in some electronic cigarettes need liquid replenishing with various velocities in different directions. Here, we report two-dimensional anisotropic hemiwicking behaviors with elliptical shapes on laser structured prismatic microgrooves. The prismatic microgrooves were fabricated via one-step femtosecond laser direct writing, and the anisotropic hemiwicking behaviors were observed when utilizing glycerol, glycol, and water as the test liquid. Specifically, the ratios of horizontal wicking distance in directions along short and long axes were tan 0°, tan 15°, tan 30°, and tan 45° for samples with cross-angles of 0°, 30°, 60°, and 90°, respectively. The vertical water wicking front displayed corresponding angles under the guidance of laser structured prismatic microgrooves. Theoretical analysis shows that the wicking distance is mainly dependent on the cross-angle θ and surface roughness, in which the wicking distance is proportional to cos(θ/2). Driven by the capillary pressure forming in the narrow microgrooves, the liquid initially filled the valleys of microgrooves and then surrounded and covered the prismatic ridges with laser-induced nanoparticles. The abundant nanoparticles increased the surface roughness, leading to the enhancement of wicking performance, which was further evidenced by the larger wicking speed of the sample with more nanoparticles. The mechanism of anisotropic hemiwicking behaviors revealed in this work paves the way for wicking control, and the proposed prismatic microgrooved surfaces with two-dimensional anisotropic hemiwicking performance and superhydrophilicity could serve in a broad range of applications, especially for the advanced thermal management with specific heat load configurations.
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Lymphatic metastasis constitutes a leading cause of recurrence and mortality in bladder cancer. Accumulating evidence indicates that lymphangiogenesis is indispensable to trigger lymphatic metastasis. However, the specific mechanism is poorly understood. In the present study, we revealed a pathway involved in lymphatic metastasis of bladder cancer, in which a circular RNA (circRNA) facilitated lymphangiogenesis in a vascular endothelial growth factor C (VEGF-C)-independent manner. Novel circRNA circEHBP1 was markedly upregulated in bladder cancer and correlated positively with lymphatic metastasis and poor prognosis of patients with bladder cancer. circEHBP1 upregulated transforming growth factor beta receptor 1 (TGFBR1) expression through physically binding to miR-130a-3p and antagonizing the suppression effect of miR-130a-3p on the 3' UTR region of TGFBR1. Subsequently, circEHBP1-mediated TGFßR1 overexpression activated the TGF-ß/SMAD3 signaling pathway, thereby promoting the secretion of VEGF-D and driving lymphangiogenesis and lymphatic metastasis in bladder cancer. Importantly, administration of VEGF-D neutralizing antibodies remarkably blocked circEHBP1-induced lymphangiogenesis and lymphatic metastasis in vivo. Our findings highlighted that the circEHBP1/miR-130a-3p/TGFßR1/VEGF-D axis contributes to lymphangiogenesis and lymphatic metastasis of bladder cancer independent of VEGF-C, which might lead to the development of circEHBP1 as a potential biomarker and promising therapeutic target for lymphatic metastasis in bladder cancer.
Assuntos
Metástase Linfática/patologia , MicroRNAs/genética , RNA Circular/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Neoplasias da Bexiga Urinária/patologia , Fator D de Crescimento do Endotélio Vascular/metabolismo , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfangiogênese , Metástase Linfática/genética , Masculino , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Regulação para Cima , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismoRESUMO
BACKGROUND: The purpose of this study was to explore the impact of extreme precipitation on the risk of outpatient visits for depression and to further explore its associated disease burden and vulnerable population. METHODS: A quasi-Poisson generalized linear regression model combined with distributed lag non-linear model (DLNM) was used to investigate the exposure-lag-response relationship between extreme precipitation (≥95th percentile) and depression outpatient visits from 2017 to 2019 in Suzhou city, Anhui Province, China. RESULTS: Extreme precipitation was positively associated with the outpatient visits for depression. The effects of extreme precipitation on depression firstly appeared at lag4 [relative risk (RR): 1.047, 95% confidence interval (CI): 1.005-1.091] and lasted until lag7 (RR = 1.047, 95% CI: 1.009-1.087). Females, patients aged ≥65 years and patients with multiple outpatient visits appeared to be more sensitive to extreme precipitation. The attributable fraction (AF) and numbers (AN) of extreme precipitation on outpatient visits for depression were 5.00% (95% CI: 1.02-8.82%) and 1318.25, respectively. CONCLUSIONS: Our findings suggested that extreme precipitation may increase the risk of outpatient visits for depression. Further studies on the burden of depression found that females, aged ≥65 years, and patients with multiple visits were priority targets for future warnings. Active intervention measures against extreme precipitation events should be taken to reduce the risk of depression outpatient visits.
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Efeitos Psicossociais da Doença , Depressão , China/epidemiologia , Cidades , Depressão/epidemiologia , Feminino , Hospitais , HumanosRESUMO
BACKGROUND: The activation of NF-κB signaling pathway is regarded as the dominant process that correlates with tumorigenesis. Recently, increasing evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-κB signaling pathway. However, the underlying mechanisms have not yet been elucidated. METHODS: The expression and clinical features of PLACT1 were analyzed in a 166-case cohort of PDAC by qRT-PCR and in situ hybridization. The functional role of PLACT1 was evaluated by both in vitro and in vivo experiments. Chromatin isolation by RNA purification assays were utilized to examine the interaction of PLACT1 with IκBα promoter. RESULTS: We identified a novel lncRNA-PLACT1, which was significantly upregulated in tumor tissues and correlated with progression and poor survival in PDAC patients. Moreover, PLACT1 promoted the proliferation and invasion of PDAC cells in vitro. Consistently, PLACT1 overexpression fostered the progression of PDAC both in orthotopic and lung metastasis mice models. Mechanistically, PLACT1 suppressed IκBα expression by recruiting hnRNPA1 to IκBα promoter, which led to increased H3K27me3 that decreased the transcriptional level of IκBα. Furthermore, E2F1-mediated overexpression of PLACT1 modulated the progression of PDAC by sustained activation of NF-κB signaling pathway through forming a positive feedback loop with IκBα. Importantly, administration of the NF-κB signaling pathway inhibitor significantly suppressed PLACT1-induced sustained activation of NF-κB signaling pathway, leading to reduced tumorigenesis in vivo. CONCLUSIONS: Our findings suggest that PLACT1 provides a novel epigenetic mechanism involved in constitutive activation of NF-κB signaling pathway and may represent a new therapeutic target of PDAC.
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Fator de Transcrição E2F1/metabolismo , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Fator de Transcrição E2F1/genética , Feminino , Humanos , Camundongos , Inibidor de NF-kappaB alfa/genética , NF-kappa B/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Patients with lymph node (LN)-positive pancreatic ductal adenocarcinoma (PDAC) have extremely poor survival rates. Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNAs, have been proposed to mediate the progression of diverse types of tumors. However, the role and underlying regulatory mechanisms of circRNAs in the LN metastasis of PDAC remain unknown. METHODS: Next-generation sequencing was used to identify differentially expressed circRNAs between PDAC and normal adjacent tissues. In vitro and in vivo experiments were conducted to evaluate the functional role of circNFIB1. RNA pulldown and luciferase assays were performed to examine the binding of circNFIB1 and miR-486-5p. RESULTS: In the present study, we identified that a novel circRNA (circNFIB1, hsa_circ_0086375) was downregulated in PDAC and negatively associated with LN metastasis in PDAC patients. Functionally, circNFIB1 knockdown promoted lymphangiogenesis and LN metastasis of PDAC both in vitro and in vivo. Mechanistically, circNFIB1 functioned as a sponge of miR-486-5p, and partially reversed the effect of miR-486-5p. Moreover, circNFIB1 attenuated the oncogenic effect of miR-486-5p and consequently upregulated PIK3R1 expression, which further downregulated VEGF-C expression through inhibition of the PI3K/Akt pathway, and ultimately suppressed lymphangiogenesis and LN metastasis in PDAC. CONCLUSIONS: Our findings provide novel insight into the underlying mechanism of circRNA-mediated LN metastasis of PDAC and suggest that circNFIB1 may serve as a potential therapeutic target for LN metastasis in PDAC.
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Carcinoma Ductal Pancreático/patologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , MicroRNAs/genética , Fatores de Transcrição NFI/genética , Neoplasias Pancreáticas/patologia , RNA Circular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfangiogênese , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , Células Tumorais Cultivadas , Fator C de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Accumulating evidence suggests that circular RNAs (circRNAs) are important participants in cancer progression. However, the biological processes and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) are unclear. METHOD: CircRNAs were verified by Sanger sequencing. Colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), and Transwell assays were performed to investigate the effect of circBFAR on the proliferation, invasion, and migration of PDAC cells in vitro. RNA pull-down assays were conducted to verify the binding of circBFAR with microRNA miR-34b-5p. RESULTS: In the present study, we identified a novel circRNA (termed as circBFAR, hsa_circ_0009065) that was upregulated in a 208-case cohort of patients with PDAC. The ectopic expression of circBFAR correlated positively with the tumor-node-metastasis (TNM) stage and was related to poorer prognosis of patients with PDAC. Moreover, circBFAR knockdown dramatically inhibited the proliferation and motility of PDAC cells in vitro and their tumor-promoting and metastasis properties in in vivo models. Mechanistically, circBFAR upregulated mesenchymal-epithelial transition factor (MET) expression via sponging miR-34b-5p. Additionally, circBFAR overexpression increased the expression of MET and activated downstream phosphorylation of Akt (Ser 473) and further activated the MET/PI3K/Akt signaling pathway, which ultimately promoted the progression of PDAC cells. Importantly, application of MET inhibitors could significantly attenuate circBFAR-mediated tumorigenesis in vivo. CONCLUSIONS: Our findings showed that circBFAR plays an important role in the proliferation and metastasis of PDAC, which might be explored as a potential prognostic marker and therapeutic target for PDAC.
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Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , MicroRNAs/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Circular/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Process monitoring of woven fabric thermoplastic composite is crucial to enhance the quality of composite products. In this work, a new fiber Bragg grating based technique was proposed to achieve hybrid temperature and stress monitoring according to the changes of wavelength and reflectivity, respectively. The sensor head consisting of a pre-annealed fiber Bragg grating and a steel capillary was properly designed to overcome the challenge of high forming temperatures up to 332 °C, complex woven structure, and high forming pressure of 2 MPa, which hinder the use of the conventional fiber Bragg grating sensor during the forming process. The forming temperature changes of thermoplastic composite in the heating, dwelling, and cooling phases can be precisely measured by the proposed sensor head after using a curve-reconstruction algorithm based on cubic polynomial fitting. The measured difference from the reference thermocouple is 2.92 °C, averaged from three sets of repeated experiments. Meanwhile, the change of the residual stresses of the composite can be illustrated by using the micro-bending-caused optical power loss of the fiber pigtail commencing at the glass-transition temperature in the cooling phase. The decrease of grating reflectivity that was equivalent to the optical loss was discussed by comparing to strain change detected by strain gauges and a calculated theoretical curve. These results are beneficial for developing an advanced in situ monitoring technique and understanding the forming process of the woven fabric thermoplastic composite.
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Transient electronics is an emerging technology that enables unique functional transformation or the physical disappearance of electronic devices, and is attracting increasing attention for potential applications in data secured hardware as an ultimate solution against data breaches. Developing smart triggered degradation modalities of silicon (Si) remain the key challenge to achieve advanced non-recoverable on-demand transient electronics. Here, we present a novel electrochemically triggered transience mechanism of Si by lithiation, allowing complete and controllable destruction of Si devices. The depth and microstructure of the lithiation-affected zone over time is investigated in detail and the results suggest a few hours of lithiation is sufficient to create microcracks and significantly promote lithium penetration. Finite element models are proposed to confirm the mechanism. Electrochemically triggered degradation of thin film Si ribbons and Si integrated circuit chips with metal-oxide-semiconductor field-effect transistors from a commercial 0.35 micrometer complementary metal-oxide-semiconductor technology node is performed to demonstrate the potential applications for commercial electronics. This work opens new opportunities for versatile triggered transience of Si-based devices for critical secured information systems and green consumer electronics.
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BACKGROUND: Transurethral resection of the prostate (TURP) is a well-established surgical method for treatment of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO). This has traditionally been provided as monopolar TURP (MTURP), but morbidity associated with MTURP has led to the introduction of other surgical techniques. In bipolar TURP (BTURP), energy is confined between electrodes at the site of the resectoscope, allowing the use of physiological irrigation medium. There remains uncertainty regarding differences between these surgical methods in terms of patient outcomes. OBJECTIVES: To compare the effects of bipolar and monopolar TURP. SEARCH METHODS: A comprehensive systematic electronic literature search was carried out up to 19 March 2019 via CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, PubMed, and WHO ICTRP. Handsearching of abstract proceedings of major urological conferences and of reference lists of included trials, systematic reviews, and health technology assessment reports was undertaken to identify other potentially eligible studies. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared monopolar and bipolar TURP in men (> 18 years) for management of LUTS secondary to BPO. DATA COLLECTION AND ANALYSIS: Two independent review authors screened the literature, extracted data, and assessed eligible RCTs for risk of bias. Statistical analyses were undertaken according to the statistical guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions. The quality of evidence (QoE) was rated according to the GRADE approach. MAIN RESULTS: A total of 59 RCTs with 8924 participants were included. The mean age of included participants ranged from 59.0 to 74.1 years. Mean prostate volume ranged from 39 mL to 82.6 mL. Primary outcomes BTURP probably results in little to no difference in urological symptoms, as measured by the International Prostate Symptom Score (IPSS) at 12 months on a scale of 0 to 35, with higher scores reflecting worse symptoms (mean difference (MD) -0.24, 95% confidence interval (CI) -0.39 to -0.09; participants = 2531; RCTs = 16; I² = 0%; moderate certainty of evidence (CoE), downgraded for study limitations), compared to MTURP. BTURP probably results in little to no difference in bother, as measured by health-related quality of life (HRQoL) score at 12 months on a scale of 0 to 6, with higher scores reflecting greater bother (MD -0.12, 95% CI -0.25 to 0.02; participants = 2004; RCTs = 11; I² = 53%; moderate CoE, downgraded for study limitations), compared to MTURP. BTURP probably reduces transurethral resection (TUR) syndrome events slightly (risk ratio (RR) 0.17, 95% CI 0.09 to 0.30; participants = 6745; RCTs = 44; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 20 fewer TUR syndrome events per 1000 participants (95% CI 22 fewer to 17 fewer). Secondary outcomes BTURP may carry a similar risk of urinary incontinence at 12 months (RR 0.20, 95% CI 0.01 to 4.06; participants = 751; RCTs = 4; I² = 0%; low CoE, downgraded for study limitations and imprecision), compared to MTURP. This corresponds to four fewer events of urinary incontinence per 1000 participants (95% CI five fewer to 16 more). BTURP probably slightly reduces blood transfusions (RR 0.42, 95% CI 0.30 to 0.59; participants = 5727; RCTs = 38; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 28 fewer events of blood transfusion per 1000 participants (95% CI 34 fewer to 20 fewer). BTURP may result in similar rates of re-TURP (RR 1.02, 95% CI 0.44 to 2.40; participants = 652; RCTs = 6; I² = 0%; low CoE, downgraded for study limitations and imprecision). This corresponds to one more re-TURP per 1000 participants (95% CI 19 fewer to 48 more). Erectile function as measured by the International Index of Erectile Function score (IIEF-5) at 12 months on a scale from 5 to 25, with higher scores reflecting better erectile function, appears to be similar (MD 0.88, 95% CI -0.56 to 2.32; RCTs = 3; I² = 68%; moderate CoE, downgraded for study limitations) for the two approaches. AUTHORS' CONCLUSIONS: BTURP and MTURP probably improve urological symptoms, both to a similar degree. BTURP probably reduces both TUR syndrome and postoperative blood transfusion slightly compared to MTURP. The impact of both procedures on erectile function is probably similar. The moderate certainty of evidence available for the primary outcomes of this review suggests that there is no need for further RCTs comparing BTURP and MTURP.
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Sintomas do Trato Urinário Inferior/cirurgia , Hiperplasia Prostática/complicações , Ressecção Transuretral da Próstata/métodos , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Procedimentos Cirúrgicos UrológicosRESUMO
Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival. Knockdown of HOXD-AS1 inhibited the proliferation and chemo-resistance of CRPC cells in vitro and in vivo. Furthermore, we identified several cell cycle, chemo-resistance, and castration-resistance-related genes, including PLK1, AURKA, CDC25C, FOXM1, and UBE2C, that were activated transcriptionally by HOXD-AS1. Further investigation revealed that HOXD-AS1 recruited WDR5 to directly regulate the expression of target genes by mediating histone H3 lysine 4 tri-methylation (H3K4me3). In conclusion, our findings indicate that HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance in prostate cancer by recruiting WDR5. This sheds a new insight into the regulation of CRPC by lncRNA and provides a potential approach for the treatment of CRPC.
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Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Neoplasias de Próstata Resistentes à Castração/genética , Interferência de RNA , RNA Longo não Codificante/genética , Adulto , Idoso , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Metilação de DNA , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapiaRESUMO
Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an essential RNA- and DNA-binding protein that regulates diverse biological events, especially DNA transcription. hnRNPK overexpression is related to tumorigenesis in several cancers. However, both the expression patterns and biological mechanisms of hnRNPK in bladder cancer are unclear. We investigated hnRNPK expression by immunohistochemistry in 188 patients with bladder cancer, and found that hnRNPK expression levels were significantly increased in bladder cancer tissues and that high-hnRNPK expression was closely correlated with poor prognosis. Loss- and gain-of-function assays demonstrated that hnRNPK promoted proliferation, anti-apoptosis, and chemoresistance in bladder cancer cells in vitro, and hnRNPK knockdown suppressed tumorigenicity in vivo. Mechanistically, hnRNPK regulated various functions in bladder cancer by directly mediating cyclin D1, G0/G1 switch 2 (G0S2), XIAP-associated factor 1, and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) transcription. In conclusion, we discovered that hnRNPK plays an important role in bladder cancer, suggesting that it is a potential prognostic marker and a promising target for treating bladder cancer.
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Carcinogênese/genética , Proliferação de Células/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Neoplasias da Bexiga Urinária/genética , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fosforilação , Prognóstico , Neoplasias da Bexiga Urinária/patologiaRESUMO
Hypoxia-inducible factor-2α (HIF-2α) plays an important role in increasing cancer progression and distant metastasis in a variety of tumour types. We aimed to investigate its biological function and clinical significance in human pancreatic ductal adenocarcinoma (PDAC). A total of 283 paired PDAC tissues and adjacent normal tissues were collected from patients who underwent surgery or biopsy at Sun Yat-sen Memorial Hospital between February 2004 and October 2016. In this study, we noted that HIF-2α expression was significantly up-regulated in PDAC, positively associated with disease stage, lymph-node metastasis and patient survival, and identified as an independent prognostic factor of PDAC patients. We demonstrated that HIF-2α silencing could reduce proliferation, migration and invasion of PDAC cells in vitro. The similar effect on growth was demonstrated in vivo. Furthermore, we noted that knock-down of HIF-2α significantly decreased the expression of glutamate oxaloacetate transaminase 1 (GOT1). Importantly, we confirmed that the PI3K/mTORC2 pathway promoted GOT1 expression by targeting HIF-2α. Our study validated HIF-2α was an important factor in PDAC progression and poor prognosis and may promote non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway. Targeting HIF-2α represents a novel prognostic biomarker and therapeutic target for patients with PDAC.
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Aspartato Aminotransferase Citoplasmática/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Idoso , Animais , Aspartato Aminotransferase Citoplasmática/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Glutamina/metabolismo , Humanos , Metástase Linfática , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Transplante de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de SobrevidaRESUMO
The L-plastin gene is involved in the invasion and metastasis of prostate cancer. However, the molecular mechanisms underlying L-plastin transcription are unclear. We hypothesize that the occurrence of polymorphic genetic variations in the L-plastin promoter might affect an individual's susceptibility to prostate cancer. In this study, we identified a single nucleotide polymorphism (SNP) at position -1,687 in the L-plastin promoter by genotype sequencing. The SNP -1,687 showed different transcriptional activity in the luciferase assay in vitro. The TRANSFAC software was applied to predict the multiple cis-elements, and luciferase assay was used to further identify the L-plastin regulatory region. We performed EMSAs, supershift assays and ChIP-qPCR demonstrated that the transcriptional suppressor NKX3.1 binds to the SNP site of the L-plastin promoter. SNP -1,687 (T/T) led to an increase in the affinity of NKX3.1 for L-plastin promoter, resulted in lower levels of L-plastin RNA and protein expression. Furthermore, we collected and sequenced samples from 640 individuals (372 prostate cancer patients and 268 healthy controls) from 2000 to 2013. The results showed that SNP -1,687 (T/T) occurred more frequently in the healthy individuals than that in the prostate cancer patients compared to SNP -1,687 (C/C). Similarly, SNP -1,687 (T/T) genotype occurred more frequently compared to SNP -1,687 (C/C) genotype in the patients with low and moderately differentiated tumors. In conclusion, SNP -1,687, located in the NKX3.1 binding site within the L-plastin promoter, might reduce the expression of L-plastin and potentially decrease the tumorigenesis and progression of prostate cancer. This SNP could be a potential prognostic factor for prostate cancer.
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Sítios de Ligação , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Glicoproteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Fatores de Transcrição/metabolismo , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Frequência do Gene , Técnicas de Silenciamento de Genes , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Masculino , Razão de Chances , Neoplasias da Próstata/patologia , Ligação Proteica , Análise de Sequência de DNA , Fatores de Transcrição/genética , Ativação TranscricionalRESUMO
PbSn solders are used in semiconductor devices for aerospace or military purposes with high levels of reliability requirements. Microalloying has been widely adopted to improve the reliability for Pb-free solders, but its application in PbSn solders is scarce. In this article, the optimization of PbSn solder reliability with Ge microalloying was investigated using both experimental and calculation methods. Intermetallic compounds (IMC) growth and morphologies evolution during reliability tests were considered to be the main factors of device failure. Through first-principle calculation, the growth mechanism of interfacial Ni3Sn4 was discussed, including the formation of vacancies, the Ni-vacancies exchange diffusion and the dominant Ni diffusion along the [1 0 0] direction. The doping of Ge in the cell increased the exchange energy barrier and thus inhibited the IMC development and coarsening trend. In three reliability tests, only 0.013 wt% Ge microalloying in Pb60Sn40 was able to reduce IMC thickness by an increment of 22.6~38.7%. The proposed Ge microalloying method in traditional PbSn solder could yield a prospective candidate for highly reliable applications.
RESUMO
Aberrant gene expression is a prominent feature of metastatic cancer. Translational initiation is a vital step in fine-tuning gene expression. Thus, exploring translation initiation regulators may identify therapeutic targets for preventing and treating metastasis. Herein, we identified that DHCR24 was overexpressed in lymph node (LN) metastatic bladder cancer and correlated with poor prognosis of patients. DHCR24 promoted lymphangiogenesis and LN metastasis of bladder cancer in vitro and in vivo. Mechanistically, DHCR24 mediated and recognized the SUMO2 modification at lysine 108 of hnRNPA2B1 to foster TBK1 mRNA circularization and eIF4F initiation complex assembly by enhancing hnRNPA2B1-eIF4G1 interaction. Moreover, DHCR24 directly anchored to TBK1 mRNA 3'-untranslated region to increase its stability, thus forming a feed forward loop to elevate TBK1 expression. TBK1 activated PI3K/Akt signaling to promote VEGFC secretion, resulting in lymphangiogenesis and LN metastasis. DHCR24 silencing significantly impeded bladder cancer lymphangiogenesis and lymphatic metastasis in a patient-derived xenograft model. Collectively, these findings elucidate DHCR24-mediated translation machinery that promotes lymphatic metastasis of bladder cancer and supports the potential application of DHCR24-targeted therapy for LN-metastatic bladder cancer. SIGNIFICANCE: DHCR24 is a SUMOylation regulator that controls translation initiation complex assembly and orchestrates TBK1 mRNA circularization to activate Akt/VEGFC signaling, which stimulates lymphangiogenesis and promotes lymph node metastasis in bladder cancer.
Assuntos
Fosfatidilinositol 3-Quinases , Neoplasias da Bexiga Urinária , Humanos , Metástase Linfática , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sumoilação , Linhagem Celular Tumoral , Neoplasias da Bexiga Urinária/patologia , Linfangiogênese/genéticaRESUMO
Ubiquitination plays an essential role in protein stability, subcellular localization, and interactions. Crosstalk between different types of ubiquitination results in distinct biological outcomes for proteins. However, the role of ubiquitination-related crosstalk in lymph node (LN) metastasis and the key regulatory factors controlling this process have not been determined. Using high-throughput sequencing, we found that ubiquitin-conjugating enzyme E2 C (UBE2C) was overexpressed in bladder cancer (BCa) and was strongly associated with an unfavorable prognosis. Overexpression of UBE2C increased BCa lymphangiogenesis and promoted LN metastasis both in vitro and in vivo. Mechanistically, UBE2C mediated sodium-coupled neutral amino acid transporter 2 (SNAT2) monoubiquitination at lysine 59 to inhibit K63-linked polyubiquitination at lysine 33 of SNAT2. Crosstalk between monoubiquitination and K63-linked polyubiquitination increased SNAT2 membrane protein levels by suppressing epsin 1-mediated (EPN1-mediated) endocytosis. SNAT2 facilitated glutamine uptake and metabolism to promote VEGFC secretion, ultimately leading to lymphangiogenesis and LN metastasis in patients with BCa. Importantly, inhibition of UBE2C significantly attenuated BCa lymphangiogenesis in a patient-derived xenograft model. Our results reveal the mechanism by which UBE2C mediates crosstalk between the monoubiquitination and K63-linked polyubiquitination of SNAT2 to promote BCa metastasis and identify UBE2C as a promising target for treating LN-metastatic BCa.
Assuntos
Metástase Linfática , Enzimas de Conjugação de Ubiquitina , Ubiquitinação , Neoplasias da Bexiga Urinária , Animais , Feminino , Humanos , Masculino , Camundongos , Sistema ASC de Transporte de Aminoácidos , Linhagem Celular Tumoral , Linfangiogênese/genética , Antígenos de Histocompatibilidade Menor , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/genéticaRESUMO
Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)-dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer.
Assuntos
Fibroblastos Associados a Câncer , Modelos Animais de Doenças , Vesículas Extracelulares , Neoplasias Pancreáticas , Animais , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Camundongos , Masculino , Linhagem Celular Tumoral , Invasividade Neoplásica , Feminino , Proteína 1 de Ligação a Y-BoxRESUMO
Cancer-associated fibroblasts (CAFs) exhibit considerable heterogeneity in advanced cancers; however, the functional annotation and mechanism of CAFs in early-stage cancers remain elusive. Utilizing single-cell RNA sequencing and spatial transcriptomic, we identify a previously unknown PDGFRα+ITGA11+ CAF subset in early-stage bladder cancer (BCa). Multicenter clinical analysis of a 910-case cohort confirms that PDGFRα+ITGA11+ CAFs are associated with lymphovascular invasion (LVI) and poor prognosis in early-stage BCa. These CAFs facilitate LVI and lymph node (LN) metastasis in early-stage BCa, as evidenced in a PDGFRα+ITGA11+ CAFs-specific deficient mouse model. Mechanistically, PDGFRα+ITGA11+ CAFs promote lymphangiogenesis via recognizing ITGA11 surface receptor SELE on lymphatic endothelial cells to activate SRC-p-VEGFR3-MAPK pathway. Further, CHI3L1 from PDGFRα+ITGA11+ CAFs aligns the surrounding matrix to assist cancer cell intravasation, fostering early-stage BCa LVI and LN metastasis. Collectively, our study reveals the crucial role of PDGFRα+ITGA11+ CAFs in shaping metastatic landscape, informing the treatment of early-stage BCa LVI.