Epstein–Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated ...nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways.
This article is part of the themed issue ‘Human oncogenic viruses’.
More than 75% of nasopharyngeal carcinoma (NPC) patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is ...essential to characterize more sensitive and specific biomarkers for screening of high risk individuals and assessment of NPC treatment effectiveness. NPC is an Epstein–Barr virus (EBV) associated tumor in which only a few viral proteins but more than 20 BamHI A rightward transcripts (BART) microRNAs are detected, at abundant levels. We hypothesized that these BART microRNAs may be novel biomarkers for NPC. Systematic analysis of EBV BART microRNA expression profiles in EBV latently infected Mutu I and Mutu III cell lines, EBV‐harboring NPC and noncancerous NP cells found that miR‐BART3, miR‐BART7 and miR‐BART13 microRNAs are highly expressed and regularly secreted into the extracellular environment of NPC cells. These BART microRNAs were evaluated for used as potential NPC biomarkers. Analysis of plasma specimens obtained from NPC patients (n = 89), and healthy (n = 28) and non‐NPC tumor patient controls (n = 18) found levels of both miR‐BART7 and miR‐BART13, but not miR‐BART3, to be distinctly presence among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. Receiver operating characteristic curve analysis combining miR‐BART7 and miR‐BART13 levels produces a 90% predictive value for the presence of NPC. Analysis of 41 NPC patients before and after radiotherapy showed that miR‐BART7 and miR‐BART13, but not miR‐BART3, were diminished after treatment. These results indicate that EBV microRNAs, miR‐BART7 and miR‐BART13, may constitute useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy.
What's new?
Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated tumor in which only a few viral proteins but more than 20 BART microRNAs are detected, at abundant levels. A systematic selection of extracellular BART microRNAs and evaluation of their usefulness as novel serological markers for NPC using clinical specimens is yet to be described. Here, the authors found that miR‐BART7 and miR‐BART13 are secreted from NPC cells into the bloodstream, with reduced plasma levels in NPC patients immediately after radiotherapy. These novel biomarkers for NPC malignancy warrant further evaluation for application in early recognition of disease onset and monitoring of treatment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and ...subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis.
We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls.
SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV.
The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens.
US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.
Exosomes, a group of secreted extracellular nanovesicles containing genetic materials and signaling molecules, play a critical role in intercellular communication. During tumorigenesis, exosomes have ...been demonstrated to promote tumor angiogenesis and metastasis while their biological functions in nasopharyngeal carcinoma (NPC) are poorly understood. In this study, we focused on the role of NPC‐derived exosomes on angiogenesis. Exosomes derived from the NPC C666‐1 cells and immortalized nasopharyngeal epithelial cells (NP69 and NP460) were isolated using ultracentrifugation. The molecular profile and biophysical characteristics of exosomes were verified by Western blotting, sucrose density gradient and electron microscopy. We showed that the C666‐1 exosomes (10 and 20 μg/ml) could significantly increase the tubulogenesis, migration and invasion of human umbilical vein endothelial cells (HUVECs) in a dose‐dependent manner. Subsequently, an iTRAQ‐based quantitative proteomics was used to identify the differentially expressed proteins in C666‐1 exosomes. Among the 640 identified proteins, 51 and 89 proteins were considered as up‐ and down‐regulated (≥ 1.5‐fold variations) in C666‐1 exosomes compared to the normal counterparts, respectively. As expected, pro‐angiogenic proteins including intercellular adhesion molecule‐1 (ICAM‐1) and CD44 variant isoform 5 (CD44v5) are among the up‐regulated proteins, whereas angio‐suppressive protein, thrombospondin‐1 (TSP‐1) was down‐regulated in C666‐1 exosomes. Further confocal microscopic study and Western blotting clearly demonstrated that the alteration of ICAM‐1 and TSP‐1 expressions in recipient HUVECs are due to internalization of exosomes. Taken together, these data strongly indicated the critical roles of identified angiogenic proteins in the involvement of exosomes‐induced angiogenesis, which could potentially be developed as therapeutic targets in future.
What's new?
Many cells secrete exosomes. These nanoscale vesicles contain signaling molecules, mRNA, and miRNA, and play a critical role in intercellular communication. In this study, the authors identified several angiogenic factors in exosomes from nasopharyngeal carcinoma (NPC) cells. Purified NPC exosomes also caused normal endothelial cells to change to an angiogenic phenotype. These findings shed new light on the mechanisms by which NPC tumors may increase their blood supply, and also suggest that these exosomes may offer a promising therapeutic target.
Chronic liver dysfunction or injury is a serious health problem worldwide. Chronic liver disease involves a wide range of liver pathologies that include fatty liver, hepatitis, fibrosis, cirrhosis, ...and hepatocellular carcinoma. The efficiency of current synthetic agents in treating chronic liver disease is not satisfactory and they have undesirable side effects. Thereby, numerous medicinal herbs and phytochemicals have been investigated as complementary and alternative treatments for chronic liver diseases. Since some herbal products have already been used for the management of liver diseases in some countries or regions, a systematic review on these herbal medicines for chronic liver disease is urgently needed. Herein, we conducted a review describing the potential role, pharmacological studies and molecular mechanisms of several commonly used medicinal herbs and phytochemicals for chronic liver diseases treatment. Their potential toxicity and side effects were also discussed. Several herbal formulae and their biological effects in chronic liver disease treatment as well as the underlying molecular mechanisms are also summarized in this paper. This review article is a comprehensive and systematic analysis of our current knowledge of the conventional medicinal herbs and phytochemicals in treating chronic liver diseases and on the potential pitfalls which need to be addressed in future study.
Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate ...pamidronate-expanded human Vγ9Vδ2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through γ/δ-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2−/−γc−/− mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded Vγ9Vδ2-T cells alone effectively prevented EBV-LPD in Rag2−/−γc−/− mice and induced EBV-LPD regression in EBV+ tumor-bearing Rag2−/−γc−/− mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of Vγ9Vδ2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through Vγ9Vδ2-T cell targeting.
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•Pamidronate-expanded Vγ9Vδ2-T cells kill EBV-LCL by engagement of Fas and TRAIL•The killing of Vγ9Vδ2-T cells requires both TCR and NKG2D receptor triggering•Adoptive transfer of Vγ9Vδ2-T cells prevents EBV-LPD and induces its regression•Pamidronate controls EBV-LPD by boosting Vγ9Vδ2-T cell immunity
Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) in immunocompromised patients is a serious condition with limited treatment options. Xiang et al. provide proof-of-principle that the aminobisphosphonate pamidronate can effectively control EBV-LPD by enhancing Vγ9Vδ2-T-cell immunity.
In recent decades Chinese medicine has been used worldwide as a complementary and alternative medicine to treat cancer. Plenty of studies have shown that microRNAs (miRNAs) play fundamental roles in ...many pathological processes, including cancer, while the anti-cancer mechanisms of Chinese medicinal herbs targeting miRNAs also have been extensively explored. Our previous studies and those of others on Chinese medicinal herbs and miRNAs in various cancer models have provided a possibility of new cancer therapies, for example, up-regulating the expression of miR-23a may activate the positive regulatory network of p53 and miR-23a involved in the mechanism underlying the anti-tumor effect of berberine in hepatocellular carcinoma (HCC). In this review, we survey the role of Chinese medicinal herbal products in regulating miRNAs in cancer and the use of mediating miRNAs for cancer treatment. In addition, the controversial roles of herb-derived exogenous miRNAs in cancer treatment are also discussed. It is expected that targeting miRNAs would provide a novel therapeutic approach in cancer therapy by improving overall response and survival outcomes in cancer treatment, especially when combined with conventional therapeutics and Chinese medicinal herbal products.
Abstract
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, ...combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing
TGFBR2
promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of
CDKN2A/CDKN2B
deletion breakpoints reveals homozygous
MTAP
deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.
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