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J Virol ; 94(3)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31723026


Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an AIDS-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency virus (HIV)-infected AIDS patients has been ascribed to an interaction between HIV type 1 (HIV-1) and KSHV, focusing on secretory proteins. The HIV-1 secreted protein HIV Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long noncoding RNA (lncRNA) that interacts with HIV Tat. We found that LINC00313 overexpression inhibits cell migration, invasion, and tube formation, and this suppressive effect was relieved by HIV Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components, and this interaction was disrupted by HIV Tat, suggesting that LINC00313 may mediate transcription repression through recruitment of PRC2 and that HIV Tat alleviates repression through disruption of this association. This notion was further supported by bioinformatics analysis of transcriptome profiles in LINC00313 overexpression combined with HIV Tat treatment. Ingenuity Pathway Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell movement and migration pathways, and enrichment of these pathways was absent in the presence of HIV Tat. Collectively, our results illustrate that an angiogenic repressive lncRNA, LINC00313, which is upregulated during KSHV reactivation, interacts with HIV Tat to promote endothelial cell motility. These results demonstrate that an lncRNA serves as a novel connector in HIV-KSHV interactions.IMPORTANCE KS is a prevalent tumor associated with infections with two distinct viruses, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the virus-virus interaction associated with KS formation has focused on secretory factors. HIV Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA upregulated during KSHV lytic reactivation, as a novel HIV Tat-interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially by interacting with chromatin remodeling complex PRC2 and downregulation of cell migration-regulating genes. An interaction between HIV Tat and LINC00313 contributed to the dissociation of PRC2 from LINC00313 and the disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV coinfection.

Int J Cancer ; 145(8): 2209-2224, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30980673


The dynamic cell-cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are extracellular vesicles that actively participate in cell-cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the ß-catenin/Tcf-4-activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA-146a-5p (miR-146a) is the major miRNA in CRCSC exosomes and exosomal miR-146a promotes stem-like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR-146a expression in serum exhibits higher miR-146aHigh /NumbLow CRCSC traits, an increased number of tumor-filtrating CD66(+) neutrophils and a decreased number of tumor-infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome-mediated stemness expansion.

Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Exossomos/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Proteínas rab de Ligação ao GTP/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HT29 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Interferência de RNA , Microambiente Tumoral/genética , Proteínas rab de Ligação ao GTP/metabolismo
J Hematol Oncol ; 12(1): 10, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683126


BACKGROUND: Cell-cell interactions maintain tissue homeostasis and contribute to dynamic alteration of the tumor microenvironment (TME). Communication between cancer and host cells not only promotes advanced disease aggression but also determines therapeutic response in cancer patients. Despite accumulating evidence supporting the role of tumor-infiltrating immunocytes in modulating tumor immunity, the interplay between heterogeneous tumor subpopulations and immunocytes is elusive. METHODS: We expanded colorectal cancer stem cells (CRCSCs) as cancer spheroids from the murine colorectal cancer (CRC) cell line CT26 to interrogate tumor-host interactions using a syngeneic tumor model. RNA-sequencing analysis of host cells and tumor exosomes was performed to identify molecular determinants that mediate the crosstalk between CRCSCs and immunocytes. The Cancer Genome Atlas (TCGA) database was used to validate the clinical significance in CRC patients. RESULTS: The expanded CT26 cancer spheroids showed increased stemness gene expression, enhanced spheroid and clonogenicity potential, and an elevated tumor-initiating ability, characteristic of CRCSCs. By examining immune cell composition in syngeneic tumor-bearing mice, a systemic increase in CD11b+/Ly6GHigh/Ly6CLow neutrophils was observed in mice bearing CRCSC-derived tumors. An increased secretion of CRCSC exosomes was observed in vitro, and through in vivo tracking, CRCSC exosomes were found to be transported to the bone marrow. Moreover, CRCSC exosomes prolonged the survival of bone marrow-derived neutrophils and engendered a protumoral phenotype in neutrophils. Mechanistically, tumor exosomal tri-phosphate RNAs induced the expression of interleukin-1ß (IL-1ß) through a pattern recognition-NF-κB signaling axis to sustain neutrophil survival. CRCSC-secreted CXCL1 and CXCL2 then attracted CRCSC-primed neutrophils to promote tumorigenesis of CRC cells via IL-1ß. Moreover, neutrophil depletion using a Ly6G-specific antibody (clone 1A8) attenuated the tumorigenicity of CRCSCs. In human specimens, CRC patients exhibiting an active CRCSC signal (Snail+IL8+) showed elevated tumor infiltration of MPO+ neutrophils, and high (in the top 10%) MPO expression predicted poor survival of CRC patients. CONCLUSIONS: This study elucidates a multistep CRCSC-neutrophil interaction during advanced cancer progression. Strategies targeting aberrant neutrophil activation may be developed for combating CSC-related malignancy.

Carcinogênese/metabolismo , Comunicação Celular , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Exossomos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neutrófilos/metabolismo , RNA/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular , Células HEK293 , Humanos , Interleucina-1beta/metabolismo , Isoenxertos , Camundongos , Camundongos Endogâmicos BALB C , Subunidade p50 de NF-kappa B/metabolismo , Peroxidase/metabolismo , Esferoides Celulares/metabolismo , Microambiente Tumoral
Chemosphere ; 146: 113-20, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26714293


In this study, a multiwalled carbon nanotubes-chitosan (CNTs-CS) composite electrode was fabricated to enable water purification by electrosorption. The CNTs-CS composite electrode was shown to possess excellent capacitive behaviors and good pore accessibility by electrochemical impedance spectroscopy, galvanostatic charge-discharge, and cyclic voltammetry measurements in 1 M H2SO4 electrolyte. Moreover, the CNTs-CS composite electrode showed promising performance for capacitive water desalination. At an electric potential of 1.2 V, the electrosorption capacity and electrosorption rate of NaCl ions on the CNTs-CS composite electrode were determined to be 10.7 mg g(-1) and 0.051 min(-1), respectively, which were considerably higher than those of conventional activated electrodes. The improved electrosorption performance could be ascribed to the existence of mesopores. Additionally, the feasibility of electrosorptive removal of aniline from an aqueous solution has been demonstrated. Upon polarization at 0.6 V, the CNTs-CS composite electrode had a larger electrosorption capacity of 26.4 mg g(-1) and a higher electrosorption rate of 0.006 min(-1) for aniline compared with the open circuit condition. The enhanced adsorption resulted from the improved affinity between aniline and the electrode under electrochemical assistance involving a nonfaradic process. Consequently, the CNT-CS composite electrode, exhibiting typical double-layer capacitor behavior and a sufficient potential range, can be a potential electrode material for application in the electrosorption process.

Quitosana/química , Nanotubos de Carbono/química , Cloreto de Sódio/química , Purificação da Água/métodos , Adsorção , Técnicas Eletroquímicas , Eletrodos
Sensors (Basel) ; 12(12): 17372-89, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23443403


The integration of the Inertial Navigation System (INS) and the Global Positioning System (GPS) is widely applied to seamlessly determine the time-variable position and orientation parameters of a system for navigation and mobile mapping applications. For optimal data fusion, the Kalman filter (KF) is often used for real-time applications. Backward smoothing is considered an optimal post-processing procedure. However, in current INS/GPS integration schemes, the KF and smoothing techniques still have some limitations. This article reviews the principles and analyzes the limitations of these estimators. In addition, an on-line smoothing method that overcomes the limitations of previous algorithms is proposed. For verification, an INS/GPS integrated architecture is implemented using a low-cost micro-electro-mechanical systems inertial measurement unit and a single-frequency GPS receiver. GPS signal outages are included in the testing trajectories to evaluate the effectiveness of the proposed method in comparison to conventional schemes.

Algoritmos , Sistemas de Informação Geográfica , Sistemas Microeletromecânicos , Humanos , Integração de Sistemas
Biomed Mater Eng ; 17(1): 53-68, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17264387


The biological properties of commercial pure titanium (cp-Ti) dental implants can be improved by surface treatment. In this study, the cp-Ti surfaces were prepared to enable machined surfaces (TM) to be compared to the machined, sandblasted, laser irradiated and dual-acid etched surfaces (TA). The surface elements and roughness were characterized. The biocompatibility was evaluated by cell and organ culture in vitro. The removal torque was measured in rabbit implantation. Surface characterization revealed that TA surface was more oxidized than TM surface. The TA surface had micrometric, beehive-like coarse concaves. The average roughness (2.28 mum) was larger than that typical of acid-etched surfaces. Extracts of both materials were not cytotoxic to bone cells. The morphology of cells attached on the TA surface was superior to that on the TM surface. TA promoted cell migration and repaired damaged bones more effectively in organ culture. The formation of bone-like nodules on TA disk exceeded that on TM disk. Rabbit tibia implantation also proved that TA implant had greater removal torque value. These results suggested that TA had good osteoconductivity and was a potential material for dental implantation.

Ácidos/farmacologia , Implantes Dentários , Lasers , Teste de Materiais , Titânio , Animais , Animais Recém-Nascidos , Adesão Celular , Proliferação de Células , Células Cultivadas , Implantes Dentários/efeitos adversos , Masculino , Camundongos , Coelhos , Ratos , Ratos Sprague-Dawley , Crânio/citologia , Propriedades de Superfície/efeitos dos fármacos , Propriedades de Superfície/efeitos da radiação , Titânio/efeitos adversos , Titânio/química , Titânio/efeitos da radiação