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1.
Cancer Gene Ther ; 29(10): 1439-1451, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35388172

RESUMEN

Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Línea Celular Tumoral , Células Endoteliales/metabolismo , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/patología , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Herpesvirus Humano 4/metabolismo , Humanos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Proteómica
2.
Mol Cancer Res ; 20(1): 161-175, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34654722

RESUMEN

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.


Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Linfangiogénesis/genética , Metástasis Linfática/fisiopatología , Carcinoma Nasofaríngeo/fisiopatología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos , Microambiente Tumoral , Regulación hacia Arriba
3.
Protein Cell ; 10(9): 668-680, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31152430

RESUMEN

Human embryonic stem cells (hESCs) depend on glycolysis for energy and substrates for biosynthesis. To understand the mechanisms governing the metabolism of hESCs, we investigated the transcriptional regulation of glucose transporter 1 (GLUT1, SLC2A1), a key glycolytic gene to maintain pluripotency. By combining the genome-wide data of binding sites of the core pluripotency factors (SOX2, OCT4, NANOG, denoted SON), chromosomal interaction and histone modification in hESCs, we identified a potential enhancer of the GLUT1 gene in hESCs, denoted GLUT1 enhancer (GE) element. GE interacts with the promoter of GLUT1, and the deletion of GE significantly reduces the expression of GLUT1, glucose uptake and glycolysis of hESCs, confirming that GE is an enhancer of GLUT1 in hESCs. In addition, the mutation of SON binding motifs within GE reduced the expression of GLUT1 as well as the interaction between GE and GLUT1 promoter, indicating that the binding of SON to GE is important for its activity. Therefore, SON promotes glucose uptake and glycolysis in hESCs by inducing GLUT1 expression through directly activating the enhancer of GLUT1.


Asunto(s)
Proteínas de Unión al ADN/fisiología , Regulación de la Expresión Génica , Transportador de Glucosa de Tipo 1/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Antígenos de Histocompatibilidad Menor/fisiología , Elementos de Facilitación Genéticos/genética , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/genética , Glucólisis , Células Madre Embrionarias Humanas/citología , Humanos , Regiones Promotoras Genéticas/genética
4.
Cancer Res ; 73(3): 1219-31, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-23269272

RESUMEN

Radiotherapy is the most successful nonsurgical treatment for nasopharyngeal carcinoma (NPC). Despite this, the prognosis remains poor. Although NPCs initially respond well to a full course of radiation, recurrence is frequent. The cancer stem cell (CSC) hypothesis provides a framework for explaining the discrepancy between the response of NPC to therapy and the poor survival rate. In this study, a stem cell-like subpopulation (PKH26+) was identified in NPC cell lines using a label-retention technique. PKH26+ cells were enriched for clonogenicity, sphere formation, side-population cells, and resistance to radiotherapy. Using genomic approaches, we show that the proto-oncogene c-MYC (MYC) regulates radiotolerance through transcriptional activation of CHK1 (CHEK1) and CHK2 (CHEK2) checkpoint kinases through direct binding to the CHK1 and CHK2 promoters. Overexpression of c-MYC in the PKH26+ subpopulation leads to increased expression of CHK1 and CHK2 and subsequent activation of the DNA-damage-checkpoint response, resulting in radioresistance. Furthermore, loss of CHK1 and CHK2 expression reverses radioresistance in PKH26+ (c-MYC high expression) cells in vitro and in vivo. This study elucidates the role of the c-MYC-CHK1/CHK2 axis in regulating DNA-damage-checkpoint responses and stem cell characteristics in the PKH26+ subpopulation. Furthermore, these data reveal a potential therapeutic application in reversal of radioresistance through inhibition of the c-MYC-CHK1/CHK2 pathway.


Asunto(s)
Neoplasias Nasofaríngeas/radioterapia , Células Madre Neoplásicas/efectos de la radiación , Proteínas Quinasas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas c-myc/fisiología , Tolerancia a Radiación , Animales , Carcinoma , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Quinasa de Punto de Control 2 , Daño del ADN , Reparación del ADN , Femenino , Humanos , Ratones , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patología , Compuestos Orgánicos/análisis , Proto-Oncogenes Mas
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