Publications by authors named "Jian-Ning Chen"

50 Publications

-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of through Activating Multiple Cellular Protective Pathways.

Oxid Med Cell Longev 2022 31;2022:8986287. Epub 2022 Mar 31.

Key Laboratory for Aging and Regenerative Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.

The traditional Chinese medicine (commonly called "Tianma" in Chinese) has been widely used in the treatment of rheumatism, epilepsy, paralysis, headache, and dizziness. Phenolic compounds, such as gastrodin, -hydroxybenzyl alcohol (HBA), -hydroxybenzaldehyde, and vanillin are the main bioactive components isolated from . These compounds not only are structurally related but also share similar pharmacological activities, such as antioxidative and anti-inflammatory activities, and effects on the treatment of aging-related diseases. Here, we investigated the effect of -hydroxybenzyl alcohol (HBA) on neurodegenerative diseases and aging in models of (). Our results showed that HBA effectively delayed the progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease in models of . In addition, HBA could increase the average lifespan of N2 worms by more than 25% and significantly improve the age-related physiological functions of worms. Moreover, HBA improved the survival rate of worms under stresses of oxidation, heat, and pathogenic bacteria. Further mechanistic investigation revealed that HBA could activate FOXO/DAF-16 and SKN-1 to regulate antioxidative and xenobiotic metabolism pathway. HBA could also activate HSF-1 to regulate proteostasis maintenance pathway, mitochondrial unfolded stress response, endoplasmic stress response and autophagy pathways. The above results suggest that HBA activated multiple cellular protective pathways to increase stress resistance and protect against aging and aging-related diseases. Overall, our study indicates that HBA is a potential candidate for future development of antiaging pharmaceutical application.
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http://dx.doi.org/10.1155/2022/8986287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989581PMC
April 2022

EBV-Induced CXCL8 Upregulation Promotes Vasculogenic Mimicry in Gastric Carcinoma NF-κB Signaling.

Front Cell Infect Microbiol 2022 7;12:780416. Epub 2022 Mar 7.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity with a conspicuous tumor microenvironment compared with EBV-negative gastric carcinoma. However, the exact role of EBV in gastric carcinogenesis remains elusive. In the present study, we found that EBV upregulated CXCL8 expression, and CXCL8 significantly promoted vasculogenic mimicry (VM) formation of gastric carcinoma (GC) cells. In accordance with these observations, overexpression of CXCL8 increased cell proliferation and migration of AGS and BGC823 cells, while knockdown of CXCL8 with siRNA inhibited cell proliferation and migration of AGS-EBV cells. In addition, activation of NF-κB signaling was involved in VM formation induced by CXCL8, which was blocked by NF-κB inhibitors BAY 11-7082 and BMS345541. Furthermore, EBV-encoded lncRNA RPMS1 activated the NF-κB signaling cascade, which is responsible for EBV-induced VM formation. Both xenografts and clinical samples of EBVaGC exhibit VM histologically, which are correlated with CXCL8 overexpression. Finally, CXCL8 is positively correlated with overall survival in GC patients. In conclusion, EBV-upregulated CXCL8 expression promotes VM formation in GC NF-κB signaling, and CXCL8 might serve as a novel anti-tumor target for EBVaGC.
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http://dx.doi.org/10.3389/fcimb.2022.780416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936189PMC
April 2022

ebv-circRPMS1 promotes the progression of EBV-associated gastric carcinoma via Sam68-dependent activation of METTL3.

Cancer Lett 2022 06 15;535:215646. Epub 2022 Mar 15.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China. Electronic address:

Epstein-Barr virus (EBV) is a tumor virus that is associated with a variety of neoplasms, including EBV-associated gastric carcinoma (EBVaGC). Recently, EBV was reported to generate various circular RNAs (circRNAs). CircRNAs are important regulators of tumorigenesis by modulating the malignant behaviors of tumor cells. However, to date, the functions of ebv-circRNAs in EBVaGC remain poorly understood. In the present study, we observed high ebv-circRPMS1 expression in EBVaGC and showed that ebv-circRPMS1 promoted the proliferation, migration, and invasion and inhibited the apoptosis of EBVaGC cells. In addition, METTL3 was upregulated in GC cells overexpressing ebv-circRPMS1. Mechanistically, ebv-circRPMS1 bound to Sam68 to facilitate its physical interaction with the METTL3 promotor, resulting in the transactivation of METTL3 and cancer progression. In clinical EBVaGC samples, ebv-circRPMS1 was associated with distant metastasis and a poor prognosis. Based on these findings, ebv-circRPMS1 contributed to EBVaGC progression by recruiting Sam68 to the METTL3 promoter to induce METTL3 expression. ebv-circRPMS1, Sam68, and METTL3 might serve as therapeutic targets for EBVaGC.
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http://dx.doi.org/10.1016/j.canlet.2022.215646DOI Listing
June 2022

Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway.

Cancer Lett 2022 02 2;526:259-272. Epub 2021 Dec 2.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC.
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http://dx.doi.org/10.1016/j.canlet.2021.11.031DOI Listing
February 2022

Liver involvement in patients with erythropoietic protoporphyria: retrospective analysis of clinicopathological features of 5 cases.

Ann Diagn Pathol 2022 Feb 17;56:151859. Epub 2021 Nov 17.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China. Electronic address:

Erythropoietic protoporphyria (EPP) is a rare inherited disease whose morbidity is about 1:75,000 to 1:200,000. It is caused by the deficiency of porphyrin ferrochelatase (FECH). Liver involvement in EPP is even rarer. The diagnosis of EPP with liver involvement mainly relies on clinical manifestations, laboratory examinations, histopathological examinations and genetic testing, which is still a huge challenge for both clinicians and pathologists. Here, 5 cases of EPP with liver injury were collected, and the clinicopathological features of these patients were analyzed. The clinical manifestations and laboratory examinations varied from person to person, whereas the liver biopsies showed that there were dark brown deposits within the hepatocytes, Kupffer cells, bile canaliculi and the lumen of bile ducts, which was a constant finding by histopathological examination. Gene tests were conducted in two of the five cases, and the results confirmed the diagnosis. Fully understanding of the diseases can help us reduce the rate of missed diagnosis and provide proper treatment as early as possible.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151859DOI Listing
February 2022

Comparative Transcriptome Provides a Systematic Perspective on Epstein-Barr Virus-Associated Gastric Carcinoma Cell Lines.

Onco Targets Ther 2021 23;14:5169-5182. Epub 2021 Oct 23.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

Purpose: Epstein-Barr virus (EBV) is widely recognised to cause various tumours, and EBV-associated gastric carcinoma (EBVaGC) is a special type of GC. It has obviously different clinical features and pathological manifestations from EBV-negative gastric carcinoma, but its progression remains elusive. The underlying cancer progression of viral infection detected by genome-wide transcriptome analysis has been demonstrated in numerous diseases.

Methods: We performed comparative RNA sequencing to identify gene expression signatures between GC and EBVaGC cell lines. The differentially expressed (DE) genes were analysed using gene ontology and pathway enrichment.

Results: A total of 4438 DE mRNAs, 3650 DE long non-coding RNAs (lncRNAs), and 248 DE circular RNAs (circRNAs) were detected in GC cells after EBV infection, most of which were highly related to oncogenesis. Likewise, EBV-coding RNA and non-coding RNA were also well-supplemented in EBVaGC. According to bioinformatics, DE mRNAs may contribute to the completion of EBV-infected host cells and modulate mitosis. Binding to actin and participating in adherens junctions to promote contact between the virus and cells are a potential function of DE lncRNAs. The roles of DE circRNAs were enriched in DNA repair and protein modification, and a typical example of this is acting as an miRNA sponge. The establishment of a circRNA-miRNA-mRNA network helps to determine the key elements in the progression of EBVaGC.

Conclusion: This study is the first to systematically reveal the transcriptome landscape of EBVaGC, which will provide an essential resource for genomic, genetic, and molecular mechanisms in the future.
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http://dx.doi.org/10.2147/OTT.S332513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550799PMC
October 2021

Disseminated Tuberculosis Associated Hemophagocytic Lymphohistiocytosis in a Pregnant Woman With Evans syndrome: A Case Report and Literature Review.

Front Immunol 2021 10;12:676132. Epub 2021 Jun 10.

Medical Intensive Care Unit, Department of Respiratory and Critical Care Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Background: Tuberculosis (TB) is a leading cause of morbidity and mortality in underdeveloped and developing countries. Disseminated TB may induce uncommon and potentially fatal secondary hemophagocytic lymphohistiocytosis (HLH). Timely treatment with anti-tuberculosis therapy (ATT) and downmodulation of the immune response is critical. However, corticosteroid treatment for TB-associated HLH remains controversial. Herein, we report a successful case of disseminated TB-associated HLH in a pregnant woman with Evans syndrome accompanied by a literature review.

Case Presentation: A 26-year-old pregnant woman with Evans syndrome was transferred to the Third Affiliated Hospital of Sun Yat-Sen University because of severe pneumonia. She presented with cough, fever, and aggravated dyspnea. Nested polymerase chain reaction for () complex in sputum was positive. Sputum smear sample for acid-fast bacilli was also positive. Metagenome next-generation sequencing (mNGS) of the bronchoalveolar lavage fluid identified 926 DNA sequence reads and 195 RNA sequence reads corresponding to complex, respectively. mNGS of blood identified 48 DNA sequence reads corresponding to . There was no sequence read corresponding to other potential pathogens. She was initially administered standard ATT together with a low dose of methylprednisolone (40 mg/day). However, her condition deteriorated rapidly with high fever, acute respiratory distress syndrome, pancytopenia, and hyperferritinemia. Bone marrow smears showed hemophagocytosis. And caseating tuberculous granulomas were found in the placenta. A diagnosis of disseminated TB-associated HLH was made. Along with the continuation of four drug ATT regimen, therapy with a higher dose of methylprednisolone (160 mg/day) combined with immunoglobulin and plasma exchange was managed. The patient's condition improved, and she was discharged on day 19. Her condition was good at follow-up with the continuation of the ATT.

Conclusions: Clinicians encountering patients with suspected TB accompanied by unexplainable inflammation not responding to ATT should consider complications with HLH. Timely administration of ATT combined with corticosteroids may result in a favorable outcome.
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http://dx.doi.org/10.3389/fimmu.2021.676132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222916PMC
October 2021

Inositol polyphosphate multikinase IPMK-1 regulates development through IP3/calcium signaling in Caenorhabditis elegans.

Cell Calcium 2021 01 1;93:102327. Epub 2020 Dec 1.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming, Yunnan 650201, China; Graduate University of the Chinese Academy of Science, Beijing, 100049, China; Key Laboratory for Aging and Regenerative Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China. Electronic address:

Inositol polyphosphate multikinase (IPMK) is a conserved protein that initiates the production of inositol phosphate intracellular messengers and is critical for regulating a variety of cellular processes. Here, we report that the C. elegans IPMK-1, which is homologous to the mammalian inositol polyphosphate multikinase, plays a crucial role in regulating rhythmic behavior and development. The deletion mutant ipmk-1(tm2687) displays a long defecation cycle period and retarded postembryonic growth. The expression of functional ipmk-1::GFP was detected in the pharyngeal muscles, amphid sheath cells, the intestine, excretory (canal) cells, proximal gonad, and spermatheca. The expression of IPMK-1 in the intestine was sufficient for the wild-type phenotype. The IP3-kinase activity of IPMK-1 is required for defecation rhythms and postembryonic development. The defective phenotypes of ipmk-1(tm2687) could be rescued by a loss-of-function mutation in type I inositol 5-phosphatase homolog (IPP-5) and improved by a supplemental Ca in the medium. Our work demonstrates that IPMK-1 and the signaling molecule inositol triphosphate (IP3) pathway modulate rhythmic behaviors and development by dynamically regulating the concentration of intracellular Ca in C. elegans. Advances in understanding the molecular regulation of Ca homeostasis and regulation of organism development may lead to therapeutic strategies that modulate Ca signaling to enhance function and counteract disease processes. Unraveling the physiological role of IPMK and the underlying functional mechanism in C. elegans would contribute to understanding the role of IPMK in other species, especially in mammals, and benefit further research on the involvement of IPMK in disease.
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http://dx.doi.org/10.1016/j.ceca.2020.102327DOI Listing
January 2021

Preoperative identification of microvascular invasion in hepatocellular carcinoma by XGBoost and deep learning.

J Cancer Res Clin Oncol 2021 Mar 27;147(3):821-833. Epub 2020 Aug 27.

Organ Transplantation Research Center of Guangdong Province, Guangzhou, 510630, Guangdong, China.

Purpose: Microvascular invasion (MVI) is a valuable predictor of survival in hepatocellular carcinoma (HCC) patients. This study developed predictive models using eXtreme Gradient Boosting (XGBoost) and deep learning based on CT images to predict MVI preoperatively.

Methods: In total, 405 patients were included. A total of 7302 radiomic features and 17 radiological features were extracted by a radiomics feature extraction package and radiologists, respectively. We developed a XGBoost model based on radiomics features, radiological features and clinical variables and a three-dimensional convolutional neural network (3D-CNN) to predict MVI status. Next, we compared the efficacy of the two models.

Results: Of the 405 patients, 220 (54.3%) were MVI positive, and 185 (45.7%) were MVI negative. The areas under the receiver operating characteristic curves (AUROCs) of the Radiomics-Radiological-Clinical (RRC) Model and 3D-CNN Model in the training set were 0.952 (95% confidence interval (CI) 0.923-0.973) and 0.980 (95% CI 0.959-0.993), respectively (p = 0.14). The AUROCs of the RRC Model and 3D-CNN Model in the validation set were 0.887 (95% CI 0.797-0.947) and 0.906 (95% CI 0.821-0.960), respectively (p = 0.83). Based on the MVI status predicted by the RRC and 3D-CNN Models, the mean recurrence-free survival (RFS) was significantly better in the predicted MVI-negative group than that in the predicted MVI-positive group (RRC Model: 69.95 vs. 24.80 months, p < 0.001; 3D-CNN Model: 64.06 vs. 31.05 months, p = 0.027).

Conclusion: The RRC Model and 3D-CNN models showed considerable efficacy in identifying MVI preoperatively. These machine learning models may facilitate decision-making in HCC treatment but requires further validation.
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http://dx.doi.org/10.1007/s00432-020-03366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873117PMC
March 2021

A Dihydroflavonoid Naringin Extends the Lifespan of . and Delays the Progression of Aging-Related Diseases in PD/AD Models via DAF-16.

Oxid Med Cell Longev 2020 31;2020:6069354. Epub 2020 Jul 31.

Key Laboratory for Aging and Regenerative Medicine, Department of Pharmacology School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.

Naringin is a dihydroflavonoid, which is rich in several plant species used for herbal medicine. It has a wide range of biological activities, including antineoplastic, anti-inflammatory, antiphotoaging, and antioxidative activities. So it would be interesting to know if naringin has an effect on aging and aging-related diseases. We examined the effect of naringin on the aging of (. ). Our results showed that naringin could extend the lifespan of . . Moreover, naringin could also increase the thermal and oxidative stress tolerance, reduce the accumulation of lipofuscin, and delay the progress of aging-related diseases in . models of AD and PD. Naringin could not significantly extend the lifespan of long-lived mutants from genes in insulin/IGF-1 signaling (IIS) and nutrient-sensing pathways, such as -, -, -, -, -., and -. Naringin treatment prolonged the lifespan of long-lived - mutants, which have decreased reproductive stem cells. Naringin could not extend the lifespan of a null mutant of the fox-head transcription factor DAF-16. Moreover, naringin could increase the mRNA expression of genes regulated by - and itself. In conclusion, we show that a natural product naringin could extend the lifespan of . and delay the progression of aging-related diseases in . models via DAF-16.
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http://dx.doi.org/10.1155/2020/6069354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422489PMC
June 2021

Epstein-Barr virus-derived circular RNA LMP2A induces stemness in EBV-associated gastric cancer.

EMBO Rep 2020 10 12;21(10):e49689. Epub 2020 Aug 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Cancer stem cells (CSCs) are cancer-initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5-fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU-4th, which displays properties of CSCs and mainly consists of CD44 CD24 cells. In SNU-4th cells, an EBV-encoded circRNA, ebv-circLMP2A, expression increased and plays crucial roles in inducing and maintaining stemness phenotypes through targeting miR-3908/TRIM59/p53 axis. Additionally, high expression of ebv-circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv-circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.
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http://dx.doi.org/10.15252/embr.201949689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534631PMC
October 2020

Secoisolariciresinol Diglucoside Delays the Progression of Aging-Related Diseases and Extends the Lifespan of via DAF-16 and HSF-1.

Oxid Med Cell Longev 2020 14;2020:1293935. Epub 2020 Jul 14.

Key Laboratory for Aging and Regenerative Medicine, Department of Pharmacology School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.

Secoisolariciresinol diglucoside (SDG) is a phytoestrogen and rich in food flaxseed, sunflower seeds, and sesame seeds. Among the beneficial pharmacological activities of SDG on health, many are age related, such as anticancer, antidiabetes, antioxidant, and neuroprotective effects. Thus, we investigated if SDG had an effect on antiaging in (). Our results showed that SDG could extend the lifespan of by up to 22.0%, delay age-related decline of body movement, reduce the lethality of heat and oxidative stress, alleviate dopamine neurodegeneration induced by 6-hydroxydopamine (6-OHDA), and decrease the toxicity of A protein in . SDG could increase the expression of the downstream genes of DAF-16, DAF-12, NHR-80, and HSF-1 at mRNA level. SDG could not extend the lifespan of mutants from genes , , , , , , and . The above results suggested that SDG might enhance the stress resistance, delay the progression of aging-related diseases, and extend the lifespan of via DAF-16 and HSF-1.
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http://dx.doi.org/10.1155/2020/1293935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378611PMC
May 2021

EBV-miR-BART10-3p and EBV-miR-BART22 promote metastasis of EBV-associated gastric carcinoma by activating the canonical Wnt signaling pathway.

Cell Oncol (Dordr) 2020 Oct 12;43(5):901-913. Epub 2020 Jun 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Rd, Guangzhou, 510630, China.

Purpose: Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) constitutes the largest subpopulation in EBV-associated tumors worldwide. To date, 44 mature EBV-encoded microRNAs (EBV miRNAs) have been identified, but their roles in EBVaGC development are still poorly understood. In this study, we aimed to investigate the roles and targets of ebv-miR-BART10-3p (BART10-3p) and ebv-miR-BART22 (BART22) in EBVaGC.

Methods: EBV miRNA expression in EBVaGCs was evaluated by deep sequencing and qRT-PCR, and relationships between BART10-3p or BART22 expression and clinicolpathological characteristics and survival rates of patients with EBVaGC were analyzed. The roles of BART10-3p and BART22 and their underlying mechanisms were further investigated through exogenous overexpression or silencing in EBVaGC cells, and validated in clinical EBVaGC tissue samples.

Results: BART10-3p and BART22 were found to be highly expressed in the EBVaGC cell lines SNU719 and YCCEL1. Higher expression of BART10-3p or BART22 in primary EBVaGC samples was significantly associated with lymph node metastasis and a worse 5-year overall survival. BART10-3p and BART22 promoted cell migration and invasion by targeting adenomatous polyposis coli (APC) and Dickkopf 1 (DKK1), thereby activating the Wnt signaling pathway and, consequently, upregulating downstream Twist and downregulating downstream E-cadherin. In 874 primary gastric carcinoma samples, APC and DKK1 were found to be lower expressed in EBVaGC than in EBV-negative samples, and their expression levels were inversely correlated with those of BART10-3p and BART22 in 71 EBVaGC samples.

Conclusions: From our data we conclude that BART10-3p and BART22 play vital roles in promoting EBVaGC metastasis by targeting APC and DKK1 and, subsequently, activating the Wnt signaling pathway, thereby providing novel prognostic biomarkers and potential therapeutic targets for EBVaGC.
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http://dx.doi.org/10.1007/s13402-020-00538-0DOI Listing
October 2020

Tectochrysin increases stress resistance and extends the lifespan of Caenorhabditis elegans via FOXO/DAF-16.

Biogerontology 2020 10 6;21(5):669-682. Epub 2020 Jun 6.

Key Laboratory for Aging and Regenerative Medicine, Department of Pharmacology School of Pharmacy, Southwest Medical University, 319 Zhongshan Road, Luzhou, 646000, Sichuan, China.

Aging is related to the lowered overall functioning and increased risk for various age-related diseases in humans. Tectochrysin is a flavonoid compound and rich in a traditional Chinese Medicine Alpinia oxyphylla Miq., which has antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, anti-diarrhea, hepatoprotective, and neuro-protective effects. Therefore, we tested if tectochrysin had an effect on aging in Caenorhabditis elegans (C. elegans). Our results showed that tectochrysin could extend the lifespan of C. elegans by up to 21.0%, delay the age-related decline of body movement, improve high temperature-stress resistance and anti-infection capacity, and protected worms against Aβ1-42-induced toxicity. Tectochrysin could not extend the lifespan of the mutants from genes daf-2, daf-16, eat-2, aak-2, skn-1, and hsf-1. Tectochrysin could increase the expression of DAF-16 regulated genes. The extension of lifespan by tectochrysin requires FOXO/DAF-16 and HSF-1. Overall, our findings suggest that tectochrysin may have a potential effect on extending lifespan and age-related diseases.
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http://dx.doi.org/10.1007/s10522-020-09884-wDOI Listing
October 2020

Improving pathological early diagnosis and differential biomarker value for hepatocellular carcinoma via RNAscope technology.

Hepatol Int 2020 Jan 12;14(1):96-104. Epub 2019 Dec 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, People's Republic of China.

Background: The diagnostic and prognostic values of glypican3 (GPC3) and glutamine synthetase (GS) proteins in hepatocellular carcinoma (HCC) have been reported, but their specificity and sensitivity remain low. Here, we applied RNAscope to improve HCC early pathological and differential diagnosis by estimating GPC3 and GS mRNAs.

Methods: We performed RNAscope and immunohistochemistry (IHC) to detect GPC3 and GS biomarkers on the tissue sections of 194 cases, including high- and low-grade liver dysplastic nodules; highly, moderately, and poorly differentiated HCCs; intrahepatic cholangiocarcinomas (ICCs); metastatic HCC; and carcinomas from other organs.

Results: The results showed that all the cases that were negative for GPC3 by RNAscope were also negative for this protein by IHC. The use of RNAscope assay improved the GPC3 and GS specificity and sensitivity by 20-30%. Hence, HCC shows early recognition and upgrades the metastatic HCC differentiation by 23% compared with IHC (p = 0.0001, 0.0064). Meanwhile, all liver cirrhosis, cholangiocytes and non-HCC samples were negative for GPC3 and GS except lymphocytes in lymphomas, and 2 (8.3%) out of the 24 ICC samples but not in the cancer cells.

Conclusion: RNAscope for GPC3 and GS panel was highly specific and sensitive for the pathological identification of dysplastic nodules, early stages of HCCs, and would differentiate them from HCCs and metastatic tumors compared with IHC.
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http://dx.doi.org/10.1007/s12072-019-10006-zDOI Listing
January 2020

Cytomegalovirus infection in a T-cell lymphoma patient presenting with multiple gastrointestinal ulcers: a case report.

Endosc Int Open 2019 Apr 12;7(4):E615-E620. Epub 2019 Apr 12.

Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Gastrointestinal ulcers are responsible for a wide spectrum of diseases. Infection, drug-induced enteritis, malignancy, vasculitis and Inflammatory bowel disease are the most common causes; their clinical expression often varies according to the site and severity of intestinal involvement. We report on a 68-year-old male presenting with dyspepsia and melena and multiple gastrointestinal ulcers on endoscopy. We could not establish diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) despite multiple biopsies taken on several endoscopic sessions, and cytomegalovirus (CMV) infection was documented by presence of inclusion bodies on pathology. The immunohistochemical study showed a mixture of B lymphocytes and predominantly T lymphocytes, negative for cluster of differentiation (CD)7. Southern blot gene rearrangement was positive for T-cell receptor beta. Our patient eventually expired from a massive gastrointestinal hemorrhage following four cycles of chemotherapy. We wish to emphasize that a CMV infection, as a comorbidity, can potentially mask and delay diagnosis of PTCL-NOS, especially in cases with aberrant immunophenotype presentation.
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http://dx.doi.org/10.1055/a-0869-7828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461553PMC
April 2019

The roles of EBV-encoded microRNAs in EBV-associated tumors.

Crit Rev Oncol Hematol 2019 Mar 25;135:30-38. Epub 2019 Jan 25.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China. Electronic address:

Epstein-Barr virus (EBV) is believed to be a pathogen causing a number of human cancers, but the pathogenic mechanisms remain unclear. An increasing number of studies have indicated that EBV-encoded microRNAs (EBV miRNAs) are expressed in a latency type- and tumor type-dependent manner, playing important roles in the development and progression of EBV-associated tumors. By targeting one or more genes of the virus and the host, EBV miRNAs are responsible for the deregulation of a variety of viral and host cell biological processes, including viral replication, latency maintenance, immune evasion, cell apoptosis and metabolism, and tumor proliferation and metastasis. In addition, some EBV miRNAs can be used as excellent diagnostic, prognostic and treatment efficacy predictive biomarkers for EBV-associated tumors. More importantly, EBV miRNA-targeting therapeutics have emerged and have been developing rapidly, which may open a new era in the treatment of EBV-associated tumors in the near future.
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http://dx.doi.org/10.1016/j.critrevonc.2019.01.014DOI Listing
March 2019

Identification of virus-encoded circular RNA.

Virology 2019 03 16;529:144-151. Epub 2019 Jan 16.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

Circular RNAs (circRNAs) are a novel class of non-coding RNA molecules in eukaryotic organisms that have potentially important roles in gene regulation. Nevertheless, whether viruses can encode circRNA is still uncertain. To examine whether large genome DNA viruses can generate circRNA during the infection of human cells, we performed RNA sequencing of ribosomal RNA-depleted total RNA from Epstein-Barr virus (EBV)-infected cell lines, including SNU-719, AGS-EBV, C666-1 and Akata. We identified an EBV-encoded circRNA, ebv_circ_RPMS1, that consists of the head-to-tail splicing of exons 2-4 from the RPMS1 gene. Furthermore, we demonstrated that ebv_circ_RPMS1 was localized in both cytoplasm and nuclei. Given that circRNAs shape gene expression by titrating microRNAs, regulating transcription and/or interfering with splicing, we identified a novel viral regulator of host and/or viral gene expression.
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http://dx.doi.org/10.1016/j.virol.2019.01.014DOI Listing
March 2019

The implication of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric carcinoma.

Hum Pathol 2019 03 15;85:82-91. Epub 2018 Nov 15.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct entity that has conspicuously inflammatory infiltration compared with EBV-negative gastric carcinoma. To date, the local immune status in EBVaGC and its relationship with patient prognosis and apoptosis of tumor cells are largely unknown. In this study, we evaluated the density of different types of tumor-infiltrating lymphocytes (TILs) in 53 EBVaGCs and 67 EBV-negative gastric carcinomas and analyzed its relationship with patient outcomes and apoptosis of tumor cells in EBVaGC. The average number of CD3+ total T cells, CD8+ T cells, CD79α+ B cells, CD56+ natural killer cells, Fascin+ dendritic cells (DCs), and FoxP3+ Tregs and the average proportions of Ki-67, interleukin 1β, granzyme B, interferon γ, and interleukin 10 in TILs were higher in EBVaGC, and CD8+ T cells were the predominant constituent cells of TILs in EBVaGC. Patients with higher numbers of CD3+ total T cells, CD8+ T cells, CD79α+ B cells, and Fascin+ DCs survived longer in EBVaGC, and CD8+ T cells and Fascin+ DCs were independent prognostic factors for patient survival. Besides, CD8+ T cells were positively correlated with apoptotic index of tumor cells. However, the apoptosis of tumor cells was lower, and the expression of survivin and NF-κBp65 in tumor cells was up-regulated in EBVaGC. These findings suggested that CD3+ total T cells, CD8+ T cells, CD79α+ B cells, and Fascin+ DCs predict a better prognosis in EBVaGC; CD8+ T cells might through a nonapoptotic pathway eliminate tumor cells, thereby improving the patient prognosis.
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http://dx.doi.org/10.1016/j.humpath.2018.11.002DOI Listing
March 2019

Determination and genome-wide analysis of Epstein-Barr virus (EBV) sequences in EBV-associated gastric carcinoma from Guangdong, an endemic area of nasopharyngeal carcinoma.

J Med Microbiol 2018 Nov 21;67(11):1614-1627. Epub 2018 Sep 21.

1​Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No.600 Tianhe Road, Guangzhou 510630, PR China.

About 10 % of gastric carcinoma worldwide is associated with EBV, which is defined as EBV-associated gastric carcinoma (EBVaGC). To date, EBV sequence data from EBVaGC in Guangdong, China, an endemic area of nasopharyngeal carcinoma (NPC), are not available. In the present study, two EBV genomes from EBVaGC specimens from Guangdong (designated as GDGC1 and GDGC2) were determined by next-generation sequencing, de novo assembly and joining of contigs by Sanger sequencing. In addition, we sequenced EBV from two Korean EBVaGC cell lines, YCCEL1 and SNU-719. Genomic diversity, including single nucleotide polymorphisms (SNPs) and insertions and deletions (indels), phylogenetic analysis and rates of protein evolution, was performed using bioinformatics software. The four gastric carcinoma-derived EBV (GC-EBV) were all type I. Compared with the reference EBV genome, a total of 1815 SNPs (146 indels), 1519 SNPs (106 indels), 1812 SNPs (126 indels) and 1484 SNPs (106 indels) were found in GDGC1, GDGC2, YCCEL1 and SNU-719, respectively. These variations were distributed across the entire genome, especially in latent genes. In contrast, the sequences of promoters and non-coding RNAs were strictly conserved. Phylogenetic analyses suggested the presence of at least two parental lineages of EBV among the GC-EBV genomes. Rates of protein evolution analyses showed that lytic genes were under purifying selection; in contrast, latency genes were under positive selection. In conclusion, this study determined the EBV genomes in EBVaGC from Guangdong and performed a detailed genome-wide analysis of GC-EBV, which would be helpful for further understanding of the relationship between EBV genomic variation and EBVaGC carcinogenesis.
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http://dx.doi.org/10.1099/jmm.0.000839DOI Listing
November 2018

Expression of CCL21 by EBV-associated gastric carcinoma cells protects CD8CCR7 T lymphocytes from apoptosis via the mitochondria-mediated pathway.

Pathology 2018 Oct 24;50(6):613-621. Epub 2018 Aug 24.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address:

About 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV), which are defined as EBV-associated gastric carcinomas (EBVaGCs). EBVaGCs are usually accompanied by massive lymphocytes infiltration, among which CD8 T cells are predominant. To date, the apoptosis of the infiltrating CD8 T cells in EBVaGC has not been investigated. In the present study, we assessed the immunophenotype and apoptosis of tumour infiltrating lymphocytes (TILs) in both EBVaGC and EBV-negative gastric carcinoma (EBVnGC). We found that CD8CCR7 T lymphocytes were increased in EBVaGC compared to EBVnGC [60.53 ± 28.41/high power fields (HPF) vs 19.63 ± 15.97/HPF; p < 0.001]. Moreover, the apoptosis index of TILs was lower in EBVaGC than that in EBVnGC (1.34 ± 0.90 vs 5.94 ± 3.77; p < 0.001). Given that the CCL21-CCR7 axis is reported to be potentially involved in apoptosis, we examined the expression of CCL21 in both EBVaGC and EBVnGC. We found that CCL21 expression was higher in EBVaGC than in EBVnGC (p < 0.001). We also showed that the expression of CCL21 by EBVaGC cells protected CD8CCR7 T lymphocytes from apoptosis. Furthermore, the up-regulation of Bcl-2 contributed to the inhibition of apoptosis in CD8CCR7 T cells. Collectively, these findings suggest that expression of CCL21 by EBVaGC cells protects CD8CCR7 T lymphocytes from apoptosis via the mitochondria-mediated pathway. To our best knowledge, this is the first study to investigate the apoptosis of CD8 T cells in EBVaGC.
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http://dx.doi.org/10.1016/j.pathol.2018.05.004DOI Listing
October 2018

Collapsin response mediator protein 4 promotor methylation level as a potential predictor for diagnosing primary malignant lymphoma of the prostate.

Cancer Cell Int 2018 4;18. Epub 2018 Jan 4.

Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630 China.

Background: Primary malignant lymphoma of the prostate (PMLP) is prone to occur in the elderly, and it has no significant correlation with lactate dehydrogenase (LDH) and prostate specific antigen (PSA). Clinical symptoms and imaging data of PMLP remain unspecific, and its prognosis is poor. A previous result showed that collapsin response mediator protein 4 (CRMP4) promotor methylation can be used as a predictor for lymph node metastases in prostate biopsies. However, the relationship between CRMP4 promotor methylation and PMLP has not been studied.

Methods: We investigated the clinicopathological features of PMLP and the significance of CRMP4 methylation in PMLP. The clinical data and diagnosis information of 10 patients with PMLP were retrospectively analyzed. The CRMP4 promotor methylation level in paraffin-embedded tissues of the 10 patients with PMLP were determined and then compared to limited prostate cancer (LPCa) and its negative lymph node tissue [LPCa-LN (-) (10 cases)] and also to metastatic prostate adenocarcinoma (mPCa) and its positive lymph node tissue [mPCa-LN (+) (10 cases)]. Methylation of the CRMP4 promotor in each group was analyzed statistically. A receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of CRMP4 methylation in PMLP.

Results: The average methylation value of CRMP4 in 10 PMLP patients, 20 cases of prostate adenocarcinoma tissue, 10 cases LPCa-LN (-) and 10 cases mPCa-LN (+) were 42.3, 30.6, 6.7 and 20.3%, respectively. A Kruskal-Wallis test showed that the difference of CRMP4 methylation was significant (X = 38.0, P < 0.001). An ROC curve analysis found that CRMP4 methylation > 40.9% could diagnose PMLP. This method had 90% sensitivity and 95% specificity under conditions of CRMP4 methylation > 40.9%. The area under the curve (AUC) was 0.957.

Conclusions: Methylation of the CRMP4 gene was significantly increased in PMLP, and it is expected to become a new predictor for PMLP.
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http://dx.doi.org/10.1186/s12935-017-0484-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753574PMC
January 2018

Expression pattern of cancer-associated fibroblast and its clinical relevance in intrahepatic cholangiocarcinoma.

Hum Pathol 2017 07 27;65:92-100. Epub 2017 Apr 27.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China. Electronic address:

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and lack of effective treatment, characterized by dense desmoplastic stroma rich in cancer-associated fibroblasts (CAFs), which have been indicated to facilitate tumor progression in several types of human cancer. However, the clinical relevance of CAFs in ICC has not been fully characterized. Here, we evaluated the histological phenotype of CAFs and immunohistochemical expressions of α-SMA, FSP-1, and PDGFRβ in 71 ICC cases, and found that immature CAF phenotype was significantly associated with lymph node metastasis (P=.045), advanced TNM stage (P=.025) and poor 5-year overall survival (OS) (38.5% versus 78.6%, P=.015). In addition, α-SMA, FSP-1, and PDGFRβ were positively expressed in stromal fibroblasts in 63.4% (45/71), 84.5% (60/71), and 78.9% (56/71) of patients, respectively. Positive expression of α-SMA was correlated with poor differentiation (P=.032); FSP-1 expression in stromal fibroblasts was linked with lymph node metastasis (P=.022) and immature phenotype (P=.048). What's more, positive expression of FSP-1 in cancer cells was observed in 22.5% (16/71) of cases and was correlated with worse 5-year OS (36.4% versus 76.7%, P=.014). Importantly, in multivariate analysis, histological CAF phenotype was an independent prognostic factor for OS in ICC. Our findings demonstrated histological categorization of CAFs was a useful predictor for prognosis, providing new evidence that CAFs play a crucial role in tumor progression and can serve as potential therapeutic targets in ICC.
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http://dx.doi.org/10.1016/j.humpath.2017.04.014DOI Listing
July 2017

Clinical significance of spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia in Epstein-Barr virus-associated and Epstein-Barr virus-negative gastric cancer.

Hum Pathol 2017 05 12;63:128-138. Epub 2017 Mar 12.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:

Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) have been recognized as neoplastic precursors in gastric carcinogenesis. We explored the relationship between SPEM and IM in Epstein-Barr virus-associated (EBVaGC) and Epstein-Barr virus-negative (EBVnGC) gastric cancer. Sixty-four EBVaGC and one hundred and fifty-four EBVnGC patients were included. EBV positivity was identified using Epstein-Barr virus-encoded RNA-1 in situ hybridization. SPEM was subclassified into absent, early, and advanced SPEM. Acute and chronic inflammation was graded as absent, mild, moderate, and marked. Univariate and multivariate logistic regression analyses were conducted to analyze the correlation between SPEM, IM, and inflammation. Our study revealed that SPEM was detected in 87.5% EBVaGC and 85.1% EBVnGC patients. Distribution of patients according to the SPEM classification was significantly different between EBVaGC and EBVnGC groups (P=.038). IM was observed less frequently in EBVaGC when compared with EBVnGC patients (P<.001). No difference was observed between EBVaGC and EBVnGC in the levels of acute and chronic inflammation. A positive correlation between IM and SPEM status was observed in both EBVaGC and EBVnGC patients. Furthermore, advanced SPEM was an independent influential factor to IM in EBVnGC (P=.013). In conclusion, SPEM was associated with both EBVaGC and EBVnGC more frequently than IM. Moreover, advanced SPEM had a stronger association with IM than early SPEM in EBVnGC. These results suggest that identification of SPEM should be used as a high-risk indicator for detecting early gastric carcinoma, and should be brought to the attention of pathologists and clinicians.
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http://dx.doi.org/10.1016/j.humpath.2017.02.016DOI Listing
May 2017

Comparative analysis of 22 Epstein-Barr virus genomes from diseased and healthy individuals.

J Gen Virol 2017 Jan 22;98(1):96-107. Epub 2017 Feb 22.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, PR China.

Epstein-Barr virus (EBV) infects most of the world's population and is causally associated with several human cancers, but little is known about how EBV genetic variations might influence EBV-associated diseases and their geographical patterns. In the present study, 22 EBV whole-genome sequences from diseased and healthy individuals were analysed to explore EBV sequence variations at the whole-genome level. We found that the 22 EBV genomes were generally highly similar to each other at the genome level. However, varying degrees of genetic diversity were detected across the entire genome, especially in the latent genes. In contrast, the sequences of promoters and non-coding RNAs were strictly conserved. These findings suggested that both latent genes and non-coding RNAs play important roles in the EBV life cycle. When we investigated changes in known T-cell epitopes in some latent and lytic proteins, we observed that some T-cell epitopes were changed, while others were conserved. These findings indicate that the effect of EBV variations in protein sequences that seem to have been selected by the host immune system should be considered when conducting EBV-targeted immunotherapy. Taken together, our results provide a global view of EBV genome sequence variation, which not only is important for designing vaccines and immunotherapy for EBV but also adds to the understanding of EBV biology and the relationships between viral sequence variation and EBV-associated diseases.
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http://dx.doi.org/10.1099/jgv.0.000699DOI Listing
January 2017

The Role of Annexin A4 in Triple-Negative Breast Cancer Progression and Its Clinical Application.

Ann Clin Lab Sci 2016 Sep;46(5):515-21

Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

Background: The expression of annexin A4 in triple-negative breast cancer (TNBC) remains unclear. In the present study, we investigated the expression of annexin A4 in TNBC tissues, as well as its relationship with clinicopathological and prognostic indicators, with an aim to assess its application value.

Methods: We adopted immunohistochemical and western blot to detect annexin A4 expression in TNBC and para-carcinoma tissues, and to explore the relationship between abnormal expression of annexin A4 and clinicopathological features of TNBC patients.

Results: The annexin A4 expression was significantly higher in TNBC tissues than in adjacent tissues. We analyzed the relationship between annexin A4 expression level and clinicopathological characteristics of TNBC patients. The results suggested that annexin A4 expression level was closely related to TNM stage, vascular involvement, lymphovascular invasion, and lymph node status of TNBC patients. The results survival analysis suggested upregulated expression of annexin A4 in TNBC patients with a shorter survival time. The results of a multifactor analysis showed that high annexin A4 expression rate was an independent predictive factor of the prognosis of the TNBC patients.

Conclusions: The high annexin A4 expression indicates the poor prognosis of TNBC patients; thus, annexin A4 can be regarded as an important molecular marker in TNBC prognosis.
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September 2016

Expression and prognostic roles of PIK3CA, JAK2, PD-L1, and PD-L2 in Epstein-Barr virus-associated gastric carcinoma.

Hum Pathol 2016 07 4;53:25-34. Epub 2016 Mar 4.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:

As a special subtype of gastric carcinoma, Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. The Cancer Genome Atlas Research Network revealed that EBVaGC also has distinct molecular features: PIK3CA mutations, DNA hypermethylation, and JAK2, PD-L1, and PD-L2 amplification. Here, we evaluated PIK3CA, JAK2, PD-L1, and PD-L2 expression in 59 EBVaGC and 796 EBV-negative gastric carcinoma (EBVnGC) cases using immunohistochemistry and found that PIK3CA, JAK2, PD-L1, and PD-L2 were highly expressed in 75.9% and 48.8% (P<.001), 81.8% and 71.1% (P=.091), 92.5% and 84.8% (P=.132), and 98.1% and 89.7% (P=.049) of the EBVaGC and EBVnGC cases, respectively. However, the expression of PIK3CA, JAK2, PD-L1, or PD-L2 was not significantly associated with clinicopathological features or patient outcomes in EBVaGC. In contrast, in EBVnGC, high PIK3CA expression was significantly associated with indolent clinicopathological features and independently predicted better 5-year overall survival (57.8% versus 33.4%, P<.001). Our study indicated that the protein expression of the 4 characteristic molecules of EBVaGC was basically consistent with their genetic alterations, making them potential characteristic protein biomarkers and therapeutic targets of EBVaGC. The favorable impact of PIK3CA overexpression on survival found in this study gives us new insight into the clinical significance of PIK3CA in EBVnGC.
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http://dx.doi.org/10.1016/j.humpath.2016.02.007DOI Listing
July 2016

Accumulation Mechanisms of CD4(+)CD25(+)FOXP3(+) Regulatory T Cells in EBV-associated Gastric Carcinoma.

Sci Rep 2015 Dec 17;5:18057. Epub 2015 Dec 17.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, China.

Approximately 10% of gastric carcinomas are associated with Epstein-Barr virus (EBV) and are defined as EBV-associated gastric carcinomas (EBVaGCs). EBVaGCs are known to be accompanied by massive CD8(+) cytotoxic T cell (CTL) infiltration; however, adoptive cellular immunotherapy based on EBV-specific CD8(+) CTLs has been explored with limited success. Because regulatory T cells (Tregs) are regarded as a critical hurdle in anti-tumour immunity, we assessed the distribution of Tregs in 45 cases of EBVaGC and 45 cases of EBV-negative gastric carcinoma (EBVnGC) with matched clinicopathological parameters by immunohistochemistry. We showed that Tregs were significantly increased in EBVaGC compared to EBVnGC (15.92 ± 11.45/HPF vs. 8.45 ± 6.16/HPF, p = 0.001). In addition, we explored the accumulation mechanisms of Tregs in EBVaGC by using EBV (+) gastric carcinoma cell lines SNU719 and GT39 as ex vivo models. When peripheral blood mononuclear cells (PBMCs) were co-cultured with EBV (+) gastric carcinoma cell lines, the Treg frequency increased, and they underwent phenotypic and functional changes. The enhanced recruitment by CCL22 produced by EBVaGC cells, the decreased emigration due to CCR7 downregulation on the Treg surface, the higher proliferation rate, and the lower apoptosis rate of Tregs at tumour sites may promote the accumulation of Tregs in EBVaGC.
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http://dx.doi.org/10.1038/srep18057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682180PMC
December 2015

High prevalence of the EBER variant EB-8m in endemic nasopharyngeal carcinomas.

PLoS One 2015 25;10(3):e0121420. Epub 2015 Mar 25.

Department of Medical Microbiology, Qingdao University Medical College, Qingdao, People's Republic of China.

Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are the most highly expressed transcripts in all EBV-associated tumors and are involved in both lymphoid and epithelioid carcinogenesis. Our previous study on Chinese isolates from non-endemic area of nasopharyngeal carcinoma (NPC) identified new EBER variants (EB-8m and EB-10m) which were less common but relatively more frequent in NPC cases than healthy donors. In the present study, we determined the EBER variants in NPC cases and healthy donors from endemic and non-endemic areas of NPC within China and compared the EBER variants, in relation to the genotypes at BamHI F region (prototype F and f variant), between population groups and between two areas. According to the phylogenetic tree, four EBER variants (EB-6m, EB-8m, EB-10m and B95-8) were identified. EB-6m was dominant in all population groups except for endemic NPC group, in which EB-8m was dominant. EB-8m was more common in endemic NPC cases (82.0%, 41/50) than non-endemic NPC cases (33.7%, 32/95) (p<0.0001), and it was also more frequent in healthy donors from endemic area (32.4%, 24/74) than healthy donors from non-endemic area (1.1%, 1/92) (p<0.0001). More importantly, the EB-8m was more prevalent in NPC cases than healthy donors in both areas (p<0.0001). The f variant, which has been suggested to associate with endemic NPC, demonstrated preferential linkage with EB-8m in endemic isolates, however, the EB-8m variant seemed to be more specific to NPC isolates than f variant. These results reveal high prevalence of EBER EB-8m variant in endemic NPC cases, suggesting an association between NPC development and EBV isolates carrying EB-8m variant. Our finding identified a small healthy population group that shares the same viral strain which predominates in NPC cases. It could be interesting to carry extensive cohort studies following these individuals to evaluate the risk to develop NPC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373760PMC
February 2016

Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas.

Med Oncol 2015 Apr 27;32(4):92. Epub 2015 Feb 27.

Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China.

Alterations in global DNA methylation and specific regulatory gene methylation are frequently found in cancer, but the significance of these epigenetic changes in EBV-associated gastric carcinoma (EBVaGC) remains unclear. We evaluated global DNA methylation status in 49 EBVaGC and 45 EBV-negative gastric carcinoma (EBVnGC) tissue samples and cell lines by 5-methylcytosine immunohistochemical staining and methylation quantification. We determined promoter methylation status and protein expression for the p16, FHIT, CRBP1, WWOX, and DLC-1 genes in tissues and studied the correlation between CpG island methylator phenotype (CIMP) class and clinicopathological characteristics. Changes in gene methylation and mRNA expression in EBVaGC cell line SNU-719 and in EBVnGC cell lines SGC-7901, BGC-823, and AGS were assessed after treatment with 5-aza-2'-deoxycytidine (5-aza-dC), trichostatin A (TSA), or a combination of both, by methylation-specific PCR and quantitative real-time RT-PCR. Global genomic DNA hypomethylation was more pronounced in EBVnGC than in EBVaGC. Promoter methylation of all five genes was more frequent in EBVaGC than in EBVnGC (p < 0.05). p16 and FHIT methylation was reversely correlated with protein expression in EBVaGC. Most (41/49) EBVaGC exhibited CIMP-high (CIMP-H), and the prognosis of CIMP-H patients was significantly worse than that of CIMP-low (p = 0.027) and CIMP-none (p = 0.003) patients. Treatment with 5-aza-dC and/or TSA induced upregulation of RNA expression of all five genes in SNU-719; meanwhile, individual gene expression increased in EBVnGC cell lines. In summary, EBV-induced hypermethylation of p16, FHIT, CRBP1, WWOX, and DLC-1 may contribute to EBVaGC development. Demethylation therapy may represent a novel therapeutic strategy for EBVaGC.
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http://dx.doi.org/10.1007/s12032-015-0525-yDOI Listing
April 2015
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