Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis.

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.

Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma.

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.

[Effect of Heat-Clearing and Detoxifying Health Function of Lonicera japonica in Rats Based on Metabonomics].

Objective: To study the metabonomics for heat-clearing and detoxifying health function of Lonicera japonica in rats. Methods: Male Wistar rats were treated with decoction of Lonicera japonica through intragastric for 5 d. GC-MS was used to detect the changes in rats serum metabolites. Mass spectrometry analysis,PCA and other technologies were used to analyze the differences among their metabolites,and analyzed the endogenous product. Results: There was a decline trend in citric acid cycle intermediates of Lonicera japonica treated group. On the contrary,amino acids and fatty acid intermediate product showed significant elevation,which revealed that the pathway of tricarboxylic acid cycle has been inhibited,and consistented with heat-clearing and detoxifying effect of Lonicera japonica. Conclusion: The metabonomics method by detecting the low-molecular-weight compounds can evaluate the heat-clearing and detoxifying health function of Lonicera japonica.

[Nummular headache: 21 new cases and therapeutic results].

OBJECTIVE: To evaluate the clinical feature of nummular headache and the efficiency of treatment in China. METHOD: The data of 21 NH patients treated from February 2006 to February 2008, were analyzed. RESULTS: They were 9 men, 12 women, aged 37 +/- 12 (18 - 63) years. Headache history ranged from 7 days to 30 years. 13 patients reported head pain confined to a circular area of 0.6 to 5 centimeter, and the other 8 patients had pain in an elliptical area of 1 - 2 centimeter x 1.5 - 3 centimeter. The symptomatic area was located in the parietal (n = 7), occipital(n = 8), temporal (n = 6), or border regions between temporal and parietal (n = 1). The right side was affected in 10 patients and the left side in the 9 patients, the middle of occipital and parietal areas were affected in 1 patient, respectively. Seven patients had mild pain, 8 patients had moderate pain and 6 patients had severe pain. The characteristics of headache included stabbing pain (n = 6), sharp pain (n = 3), pulsating apin (n = 3), grinding pain (n = 1), exploding pain (n = 5), included light-dull apin (n = 3). Three patients were treated by local nerve block with lidocaine plus dexamethasone phosphate/acetate and one of them got some 30 hours of prominent pain relief, no relief was obtained for other two patients. One patient obtained pain remission by acupuncture after amitriptyline, paroxetine had been tried ineffectively. One patient, woman, 38 years old, was treated by carbamazepine (tegretol) and amitriptyline for 3 months and pain relief was obtained gradually and the head pain disappeared finally. 8 patients were treated effectively by amitriptyline combining indomethacium, ibuprofen or carbamazepine. One patient was treated effectively by nimodipine. 2 patients were treated ineffectively by amitriptyline combining indomethacium. 4 patients were not treated. 3 patients were lost to follow-up. CONCLUSION: NH is not very rare and some of NH patients may be treated effectively by acupuncture or amitriptyline combining indomethacium, ibuprofen or carbamazepine.